Skip to main content

Advertisement

SpringerLink
Log in

Uncovering Cell Cycle Dysregulations and Associated Mechanisms in Cancer and Neurodegenerative Disorders: A Glimpse of Hope for Repurposed Drugs

  • Review
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The cell cycle is the sequence of events orchestrated by a complex network of cell cycle proteins. Unlike normal cells, mature neurons subsist in a quiescent state of the cell cycle, and aberrant cell cycle activation triggers neuronal death accompanied by neurodegeneration. The periodicity of cell cycle events is choreographed by various mechanisms, including DNA damage repair, oxidative stress, neurotrophin activity, and ubiquitin-mediated degradation. Given the relevance of cell cycle processes in cancer and neurodegeneration, this review delineates the overlapping cell cycle events, signaling pathways, and mechanisms associated with cell cycle aberrations in cancer and the major neurodegenerative disorders. We suggest that dysregulation of some common fundamental signaling processes triggers anomalous cell cycle activation in cancer cells and neurons. We discussed the possible use of cell cycle inhibitors for neurodegenerative disorders and described the associated challenges. We propose that a greater understanding of the common mechanisms driving cell cycle aberrations in cancer and neurodegenerative disorders will open a new avenue for the development of repurposed drugs.

Graphical Abstract

Cell cycle activation and cell cycle re-entry are the two critical cellular phenomena associated with cancer and neurodegeneration, respectively. Various regulatory proteins, such as cyclin-dependent kinases (CDKs), cyclins, and checkpoint kinases, control the cell cycle dynamics at different phases. Further, the integrity of cell cycle is controlled by different mechanisms like DNA damage response, oxidative stress, neurotrophin activity, and the ubiquitin–proteasome system (UPS), the alterations which play an essential role in the pathogenesis of both cancer and neurodegenerative disorders. Pharmacological targeting of important cell cycle regulatory molecules like the application of CDK inhibitors, PARP inhibitors, checkpoint kinase inhibitors, and microtubule inhibitors holds great promise for treating various human cancers and can be repurposed for different neurodegenerative disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

No datasets were generated or analyzed during the current study.

Abbreviations

6-OHDA:

6-Hydroxydopamine

AML:

Acute myeloid leukemia

ALS:

Amyotrophic lateral sclerosis

APC/C:

Anaphase-promoting complex

APP-BP1:

Amyloid precursor protein-binding protein 1

ATM:

Ataxia telangiectasia mutated

ATR:

Ataxia telangiectasia and Rad3-related

BDNF:

Brain-derived growth factor

CDKs:

Cyclin-dependent kinase inhibitors

CHK:

Checkpoint kinase

CNS:

Central nervous system

CREB:

C-AMP response element-binding protein

CRND:

Cell cycle–related neuronal cell death

CRL:

Cullin-RING E3 ligases

DG:

Dentate gyrus

DSBs:

Double-strand breaks

DSBR:

DNA double-strand break repair

EC:

Entorhinal cortex

FALS:

Familial, autosomal dominant disorder

GAK:

Cyclin G–associated protein kinase

GDC:

Genomic Data Commons

GSK-3β:

Glycogen synthase kinase-3 beta

HD:

Huntington’s disease

HIF-1:

Hypoxia-inducible factor-1

HNSCC:

Head and neck squamous cell carcinoma

HR:

Homologous recombination

HTT:

Huntingtin

JNK:

C-Jun amino-terminal kinases

LRRK2:

Leucine-rich repeat kinase 2

MAPK:

Mitogen-activated protein kinase

MCD:

Mitotic cell death

MCL:

Mantle cell lymphoma

MDM2:

Murine double minute 2

MnSOD:

Manganese superoxide dismutase

NDDs:

Neurodegenerative disorders

NER:

Nucleotide excision repair

NHEJ:

Non-homologous end-joining

NGF:

Nerve growth factor

NSCLC:

Non-small cell lung cancers

NT:

Neurotrophin

ORC:

Origin recognition complex

PARP:

Poly(ADP-ribose) polymerase

PHD:

Pyrolyl hydroxylase

PI3K-PKB/Akt/mTOR:

Phosphoinositide-3-kinase–protein kinase B and the mammalian target of rapamycin

PIP3:

Phosphatidylinositol-3,4,5-triphosphate

PTEN:

Phosphatase and tensin homolog

Rb:

Retinoblastoma

ROS:

Reactive oxygen species

RTK:

Receptor tyrosine kinases

SAC:

Spindle assembly checkpoint

SAPKs:

Stress-activated MAP kinases

SCF:

SKP1-cullin-1-F-box

Shh:

Sonic hedgehog

SOD1:

Superoxide dismutase

SSBR:

Single-strand break repair

TS:

Template-switch

TLS:

Translesion synthesis

TRIM:

Tripartite motif

UPS:

Ubiquitin-proteasome system

References

  1. Vermeulen K, Van Bockstaele DR, Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36:131. https://doi.org/10.1046/J.1365-2184.2003.00266.X

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lui A, Vanleuven J, Perekopskiy D, et al (2022) FDA-approved kinase inhibitors in preclinical and clinical trials for neurological disorders. Pharmaceuticals 15:. https://doi.org/10.3390/PH15121546

  3. Nandakumar S, Rozich E, Buttitta L (2021) Cell cycle re-entry in the nervous system: from polyploidy to neurodegeneration. Front. Cell Dev, Biol

    Google Scholar 

  4. Sarsour EH, Kumar MG, Chaudhuri L et al (2009) Redox control of the cell cycle in health and disease. Antioxidants Redox Signal 11:2985–3011

    Article  CAS  Google Scholar 

  5. Branzei D (2008) Foiani M (2008) Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 94(9):297–308. https://doi.org/10.1038/nrm2351

    Article  CAS  Google Scholar 

  6. López-Sánchez N, Frade JM (2002) Control of the cell cycle by neurotrophins: lessons from the p75 neurotrophin receptor. Histol Histopathol 17:1227–1237. https://doi.org/10.14670/HH-17.1227

    Article  PubMed  Google Scholar 

  7. Bassermann F, Eichner R, Pagano M (2014) The ubiquitin proteasome system — implications for cell cycle control and the targeted treatment of cancer. Biochim Biophys Acta - Mol Cell Res 1843:150–162. https://doi.org/10.1016/J.BBAMCR.2013.02.028

    Article  CAS  Google Scholar 

  8. Zhivotovsky B, Orrenius S (2010) Cell cycle and cell death in disease: past, present and future. J Intern Med 268:395–409. https://doi.org/10.1111/j.1365-2796.2010.02282.x

    Article  CAS  PubMed  Google Scholar 

  9. Scorah J, McGowan CH (2010) Regulation of cell cycle progression. In: Handbook of cell signaling. Academic Press, pp 2545-2553. https://doi.org/10.1016/B978-0-12-374145-5.00302-8

  10. Coudreuse D, Nurse P (2010) Driving the cell cycle with a minimal CDK control network. Nature 468:1074–1080. https://doi.org/10.1038/nature09543

    Article  CAS  PubMed  Google Scholar 

  11. Barnum KJ, O’Connell MJ (2014) Cell cycle regulation by checkpoints. Methods Mol, Biol, p 1170

    Google Scholar 

  12. Chen X, Stauffer S, Chen Y, Dong J (2016) Ajuba phosphorylation by CDK1 promotes cell proliferation and tumorigenesis *. J Biol Chem 291:14761–14772. https://doi.org/10.1074/JBC.M116.722751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bonni AHK & Azad (2008) Cdk1-FOXO1: a mitotic signal takes center stage in post-mitotic neurons. Cell Cycle 7:3819–3822. https://doi.org/10.4161/CC.7.24.7215

    Article  Google Scholar 

  14. Vincent I, Jicha G, Rosado M, Dickson DW (1997) Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer’s disease brain. J Neurosci 17:3588–3598. https://doi.org/10.1523/jneurosci.17-10-03588.1997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gopinathan L, Tan SLW, Padmakumar VC et al (2014) Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis. Cancer Res 74:3870–3879. https://doi.org/10.1158/0008-5472.CAN-13-3440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee KH, Lee S-J, Lee HJ et al (2017) Amyloid β1–42 (Aβ1–42) induces the CDK2-mediated phosphorylation of Tau through the activation of the mTORC1 signaling pathway while promoting neuronal cell death. Front Mol Neurosci 0:229. https://doi.org/10.3389/FNMOL.2017.00229

    Article  Google Scholar 

  17. Gao X, Leone GW, Wang H (2020) Cyclin D-CDK4/6 functions in cancer. Adv Cancer Res 148:147–169. https://doi.org/10.1016/BS.ACR.2020.02.002

    Article  CAS  PubMed  Google Scholar 

  18. Tsujioka Y, Takahashi M, Tsuboi Y et al (1999) Localization and expression of cdc2 and cdk4 in Alzheimer brain tissue. Dement Geriatr Cogn Disord 10:192–198. https://doi.org/10.1159/000017119

    Article  CAS  PubMed  Google Scholar 

  19. Rao HV, Thirumangalakudi L, Desmond P, Grammas P (2007) Cyclin D1, cdk4, and Bim are involved in thrombin-induced apoptosis in cultured cortical neurons. J Neurochem 101:498–505. https://doi.org/10.1111/j.1471-4159.2006.04389.x

    Article  CAS  PubMed  Google Scholar 

  20. Pozo K, Bibb JA (2016) The emerging role of Cdk5 in cancer. Trends in Cancer 2(10):606–618

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gupta KK, Singh SK (2019) Cdk5: A main culprit in neurodegeneration. Int J Neurosci 129:1192–1197. https://doi.org/10.1080/00207454.2019.1645142

    Article  PubMed  Google Scholar 

  22. Avraham E, Rott R, Liani E et al (2007) Phosphorylation of Parkin by the cyclin-dependent kinase 5 at the linker region modulates its ubiquitin-ligase activity and aggregation. J Biol Chem 282:12842–12850. https://doi.org/10.1074/jbc.M608243200

    Article  CAS  PubMed  Google Scholar 

  23. Bk B, Skuntz S, Prochazkova M et al (2019) Overexpression of the Cdk5 inhibitory peptide in motor neurons rescue of amyotrophic lateral sclerosis phenotype in a mouse model. Hum Mol Genet 28:3175–3187. https://doi.org/10.1093/hmg/ddz118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Luo S, Vacher C, Davies JE, Rubinsztein DC (2005) Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J Cell Biol 169:647–656. https://doi.org/10.1083/jcb.200412071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yam CH, Fung TK, Poon RYC (2002) Cyclin A in cell cycle control and cancer. Cell Mol Life Sci 59:1317–1326. https://doi.org/10.1007/S00018-002-8510-Y

    Article  CAS  PubMed  Google Scholar 

  26. Oka T, Kubo T, Enokido Y, Hatanaka H (1996) Expression of cyclin A decreases during neuronal apoptosis in cultured rat cerebellar granule neurons. Dev Brain Res 97:96–106. https://doi.org/10.1016/S0165-3806(96)00138-1

    Article  CAS  Google Scholar 

  27. Ye C, Wang J, Wu P et al (2017) Prognostic role of cyclin B1 in solid tumors: a meta-analysis. Oncotarget 8:2224. https://doi.org/10.18632/ONCOTARGET.13653

    Article  PubMed  Google Scholar 

  28. Lee SS, Kim YM, Junn E et al (2003) Cell cycle aberrations by α-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies. Neurobiol Aging 24:687–696. https://doi.org/10.1016/S0197-4580(02)00196-3

    Article  CAS  PubMed  Google Scholar 

  29. Stamatakos M, Palla V, Karaiskos I, et al (2010) Cell cyclins: triggering elements of cancer or not? World J Surg Oncol 8:. https://doi.org/10.1186/1477-7819-8-111

  30. Hoozemans JJM, Brückner MK, Rozemuller AJM et al (2002) Cyclin D1 and cyclin E are co-localized with cyclo-oxygenase 2 (COX-2) in pyramidal neurons in Alzheimer disease temporal cortex. J Neuropathol Exp Neurol 61:678–688. https://doi.org/10.1093/JNEN/61.8.678

    Article  CAS  PubMed  Google Scholar 

  31. Atabay KD, Karabay A (2012) Pin1 inhibition activates cyclin D and produces neurodegenerative pathology. J Neurochem. https://doi.org/10.1111/j.1471-4159.2011.07259.x

    Article  PubMed  Google Scholar 

  32. Keyomarsi K, Herliczek TW (1997) The role of cyclin E in cell proliferation, development and cancer. Prog Cell Cycle Res 3:171–191

    Article  CAS  PubMed  Google Scholar 

  33. Galper J, Rayner SL, Hogan AL et al (2017) Cyclin F: A component of an E3 ubiquitin ligase complex with roles in neurodegeneration and cancer. Int J Biochem Cell Biol 89:216–220. https://doi.org/10.1016/J.BIOCEL.2017.06.011

    Article  CAS  PubMed  Google Scholar 

  34. Lee A, Rayner SL, Gwee SSL et al (2018) Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy. Cell Mol Life Sci 75:335–354. https://doi.org/10.1007/S00018-017-2632-8

    Article  CAS  PubMed  Google Scholar 

  35. Zhang Y, Hunter T (2014) Roles of Chk1 in cell biology and cancer therapy. Int J Cancer 134:1013–1023. https://doi.org/10.1002/IJC.28226

    Article  CAS  PubMed  Google Scholar 

  36. Ye W, Blain SW (2011) Chk1 has an essential role in the survival of differentiated cortical neurons in the absence of DNA damage. Apoptosis 16:449–459. https://doi.org/10.1007/S10495-011-0579-Z

    Article  CAS  PubMed  Google Scholar 

  37. Mendoza J, Sekiya M, Taniguchi T et al (2013) Global analysis of phosphorylation of tau by the checkpoint kinases Chk1 and Chk2 in vitro. J Proteome Res 12:2654–2665. https://doi.org/10.1021/pr400008f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Iijima-Ando K, Zhao L, Gatt A et al (2010) A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration. Hum Mol Genet 19:1930–1938. https://doi.org/10.1093/HMG/DDQ068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stolz A, Ertych N, Bastians H (2011) Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability. Clin Cancer Res 17:401–405. https://doi.org/10.1158/1078-0432.CCR-10-1215

    Article  CAS  PubMed  Google Scholar 

  40. Liu Z, Sun Q, Wang X (2017) PLK1, A potential target for cancer therapy. Transl Oncol 10:22. https://doi.org/10.1016/J.TRANON.2016.10.003

    Article  PubMed  Google Scholar 

  41. Song B, Davis K, Liu XS et al (2011) Inhibition of Polo-like kinase 1 reduces beta-amyloid-induced neuronal cell death in Alzheimer’s disease. Aging (Albany NY) 3:846–851. https://doi.org/10.18632/aging.100382

    Article  CAS  PubMed  Google Scholar 

  42. di Rorà AGL, Cerchione C, Martinelli G (2020) Simonetti G (2020) A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target. J Hematol Oncol 131(13):1–17. https://doi.org/10.1186/S13045-020-00959-2

    Article  Google Scholar 

  43. Tomashevski A, Husseman J, Jin LW et al (2001) Constitutive wee1 activity in adult brain neurons with M phase-type alterations in Alzheimer neurodegeneration. J Alzheimer’s Dis 3:195–207. https://doi.org/10.3233/JAD-2001-3205

    Article  CAS  Google Scholar 

  44. Alvarado-Ortiz E, de la Cruz-López KG, Becerril-Rico J et al (2020) Mutant p53 gain-of-function: role in cancer development, progression, and therapeutic approaches. Front Cell Dev Biol 8:607670. https://doi.org/10.3389/FCELL.2020.607670

    Article  PubMed  Google Scholar 

  45. Thakur A, Siedlak SL, James SL et al (2008) Retinoblastoma protein phosphorylation at multiple sites is associated with neurofibrillary pathology in Alzheimer disease. Int J Clin Exp Pathol 1:134

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen HZ, Tsai SY, Leone G (2009) Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer 9:785–797. https://doi.org/10.1038/NRC2696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Verdaguer E, de Arriba SG, Clemens A et al (2007) Implication of the transcription factor E2F–1 in the modulation of neuronal apoptosis. Biomed Pharmacother 61:390–399. https://doi.org/10.1016/J.BIOPHA.2006.11.001

    Article  CAS  PubMed  Google Scholar 

  48. Ranganathan S, Bowser R (2010) p53 and cell cycle proteins participate in spinal motor neuron cell death in ALS. Open Pathol J 4:11–22. https://doi.org/10.2174/1874375701004010011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hou H, Sun D (2019) Zhang X (2019) The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors. Cancer Cell Int 191(19):1–8. https://doi.org/10.1186/S12935-019-0937-4

    Article  CAS  Google Scholar 

  50. Esteras N, Alquézar C, Bermejo-Pareja F et al (2013) Downregulation of extracellular signal-regulated kinase 1/2 activity by calmodulin KII modulates p21Cip1 levels and survival of immortalized lymphocytes from Alzheimer’s disease patients. Neurobiol Aging 34:1090–1100. https://doi.org/10.1016/J.NEUROBIOLAGING.2012.10.014

    Article  CAS  PubMed  Google Scholar 

  51. Lee SJ, Kim DC, Choi BH et al (2006) Regulation of p53 by activated protein kinase C-delta during nitric oxide-induced dopaminergic cell death. J Biol Chem 281:2215–2224. https://doi.org/10.1074/JBC.M509509200

    Article  CAS  PubMed  Google Scholar 

  52. Sadeghi H, Golalipour M, Yamchi A et al (2018) CDC25A pathway toward tumorigenesis: Molecular targets of CDC25A in cell-cycle regulation. J Cell Biochem 120:2919–2928. https://doi.org/10.1002/JCB.26838

    Article  PubMed  Google Scholar 

  53. Ding X-L, Husseman J, Tomashevski A et al (2000) The cell cycle Cdc25A tyrosine phosphatase is activated in degenerating postmitotic neurons in Alzheimer’s disease. Am J Pathol 157:1983–1990. https://doi.org/10.1016/S0002-9440(10)64837-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen Y-C, Hsieh H-H, Chang H-C et al (2021) CDC25B induces cellular senescence and correlates with tumor suppression in a p53-dependent manner. J Biol Chem 296:100564–100565. https://doi.org/10.1016/J.JBC.2021.100564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Vincent I, Bu B, Hudson K et al (2001) Constitutive Cdc25B tyrosine phosphatase activity in adult brain neurons with M phase-type alterations in Alzheimer’s disease. Neuroscience 105:639–650. https://doi.org/10.1016/S0306-4522(01)00219-6

    Article  CAS  PubMed  Google Scholar 

  56. Liggett WH, Sidransky D (1998) Role of the p16 tumor suppressor gene in cancer. J Clin Oncol 16:1197–1206. https://doi.org/10.1200/JCO.1998.16.3.1197

    Article  CAS  PubMed  Google Scholar 

  57. Arendt T, Rödel L, Gärtner U, Holzer M (1996) Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer’s disease. NeuroReport 7:3047–3049. https://doi.org/10.1097/00001756-199611250-00050

    Article  CAS  PubMed  Google Scholar 

  58. Feddersen RM, Ehlenfeldt R, Yunis WS et al (1992) Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40 T antigen transgenic mice. Neuron 9:955–966. https://doi.org/10.1016/0896-6273(92)90247-B

    Article  CAS  PubMed  Google Scholar 

  59. Tsai KY, Hu Y, Macleod KF et al (1998) Mutation of E2f–1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell 2:293–304. https://doi.org/10.1016/S1097-2765(00)80274-9

    Article  CAS  PubMed  Google Scholar 

  60. Freeman RS, Estus S, Johnson EM (1994) Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of cyclin D1 during programmed cell death. Neuron 12:343–355. https://doi.org/10.1016/0896-6273(94)90276-3

    Article  CAS  PubMed  Google Scholar 

  61. Frade JM (2000) Unscheduled re-entry into the cell cycle induced by NGF precedes cell death in nascent retinal neurones. J Cell Sci 113:1139–1148. https://doi.org/10.1242/jcs.113.7.1139

    Article  CAS  PubMed  Google Scholar 

  62. Lombardi D, Lasagni L (2016) Cell-cycle alterations in post-mitotic cells and cell death by mitotic catastrophe. Cell Biol - New Insights. https://doi.org/10.5772/61783

    Article  Google Scholar 

  63. Thome KC, Dhar SK, Quintana DG et al (2000) Subsets of human origin recognition complex (ORC) subunits are expressed in non-proliferating cells and associate with non-ORC proteins. J Biol Chem 275:35233–35241. https://doi.org/10.1074/jbc.M005765200

    Article  CAS  PubMed  Google Scholar 

  64. Frank CL, Tsai LH (2009) Alternative functions of core cell cycle regulators in neuronal migration, neuronal maturation, and synaptic plasticity. Neuron 62:312–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. López-Sánchez N, Frade JM (2013) Genetic evidence for p75NTR-dependent tetraploidy in cortical projection neurons from adult mice. J Neurosci 33:7488–7500. https://doi.org/10.1523/JNEUROSCI.3849-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yuan Z, Becker EBE, Merlo P et al (2008) Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science 319:1665–1668. https://doi.org/10.1126/science.1152337

    Article  CAS  PubMed  Google Scholar 

  67. Konishi Y, Lehtinen M, Donovan N, Bonni A (2002) Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Mol Cell 9:1005–1016. https://doi.org/10.1016/S1097-2765(02)00524-5

    Article  CAS  PubMed  Google Scholar 

  68. Marlier Q, D’aes T, Verteneuil S et al (2020) Core cell cycle machinery is crucially involved in both life and death of post-mitotic neurons. Cell Mol Life Sci 77:4553–4571

    Article  CAS  PubMed  Google Scholar 

  69. Nandakumar S, Rozich E, Buttitta L (2021) Cell cycle re-entry in the nervous system: from polyploidy to neurodegeneration. Front Cell Dev Biol 9:1511. https://doi.org/10.3389/FCELL.2021.698661/BIBTEX

    Article  Google Scholar 

  70. Hammond EM, Dorie MJ, Giaccia AJ (2003) ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. J Biol Chem 278:12207–12213. https://doi.org/10.1074/jbc.M212360200

    Article  CAS  PubMed  Google Scholar 

  71. Patterson JC, Joughin BA, van de Kooij B et al (2019) ROS and oxidative stress are elevated in mitosis during asynchronous cell cycle progression and are exacerbated by mitotic arrest. Cell Syst 8:163-167.e2. https://doi.org/10.1016/j.cels.2019.01.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Langley B, Ratan RR (2004) Oxidative stress-induced death in the nervous system: Cell cycle dependent or independent? J Neurosci Res 77:621–629

    Article  CAS  PubMed  Google Scholar 

  73. Schwartz EI, Smilenov LB, Price MA et al (2007) Cell cycle activation in postmitotic neurons is essential for DNA repair. Cell Cycle 6:318–329. https://doi.org/10.4161/cc.6.3.3752

    Article  CAS  PubMed  Google Scholar 

  74. Gómez-Crisóstomo NP, Rodríguez Martínez E, Rivas-Arancibia S (2014) Oxidative stress activates the transcription factors FoxO 1a and FoxO 3a in the hippocampus of rats exposed to low doses of ozone. Oxid Med Cell Longev 2014:. https://doi.org/10.1155/2014/805764

  75. Bianco MR, Berbenni M, Amara F et al (2011) Cross-talk between cell cycle induction and mitochondrial dysfunction during oxidative stress and nerve growth factor withdrawal in differentiated PC12 cells. J Neurosci Res 89:1302–1315

    Article  CAS  PubMed  Google Scholar 

  76. Ortmann B, Druker J, Rocha S (2014) Cell cycle progression in response to oxygen levels. Cell Mol Life Sci 71:3569–3582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chao HX, Poovey CE, Privette AA et al (2017) DNA damage checkpoint dynamics drive cell cycle phase transitions. bioRxiv 8:14728

    Google Scholar 

  78. Takata M, Sasaki MS, Sonoda E et al (1998) Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J 17:5497–5508. https://doi.org/10.1093/emboj/17.18.5497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Mills KD, Ferguson DO, Alt FW (2003) The role of DNA breaks in genomic instability and tumorigenesis. Immunol Rev 194:77–95. https://doi.org/10.1034/j.1600-065X.2003.00060.x

    Article  CAS  PubMed  Google Scholar 

  80. Suberbielle E, Djukic B, Evans M, et al (2015) DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nat Commun 6:. https://doi.org/10.1038/ncomms9897

  81. Konopka A, Atkin JD (2022) DNA damage, defective dna repair, and neurodegeneration in amyotrophic lateral sclerosis. Front Aging Neurosci 14:279

    Article  Google Scholar 

  82. Descamps S, Toillon RA, Adriaenssens E et al (2001) Nerve growth factor stimulates proliferation and survival of human breast cancer cells through two distinct signaling pathways. J Biol Chem 276:17864–17870. https://doi.org/10.1074/jbc.M010499200

    Article  CAS  PubMed  Google Scholar 

  83. Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73:2424–2428. https://doi.org/10.1073/pnas.73.7.2424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Khwaja F, Tabassum A, Allen J, Djakiew D (2006) The p75NTR tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells. Biochem Biophys Res Commun 341:1184–1192. https://doi.org/10.1016/j.bbrc.2006.01.073

    Article  CAS  PubMed  Google Scholar 

  85. Ikeda T, Puro DG (1994) Nerve growth factor: a mitogenic signal for retinal müller glial cells. Brain Res 649:260–264. https://doi.org/10.1016/0006-8993(94)91072-3

    Article  CAS  PubMed  Google Scholar 

  86. Boutahar N, Reynaud E, Lassabliere F, Borg J (2010) Brain-derived neurotrophic factor inhibits cell cycle reentry but not endoplasmic reticulum stress in cultured neurons following oxidative or excitotoxic stress. J Neurosci Res 88:2263–2271. https://doi.org/10.1002/jnr.22384

    Article  CAS  PubMed  Google Scholar 

  87. Fasanaro P, Capogrossi MC, Martelli F (2010) Regulation of the endothelial cell cycle by the ubiquitin-proteasome system. Cardiovasc Res 85:272–280

    Article  CAS  PubMed  Google Scholar 

  88. Jin J, Shirogane T, Xu L et al (2003) SCFβ-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev 17:3062–3074. https://doi.org/10.1101/gad.1157503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Barford D (2011) Structure, function and mechanism of the anaphase promoting complex (APC/C). Q Rev Biophys 44:153–190

    Article  CAS  PubMed  Google Scholar 

  90. Venuto S, Merla G (2019) E3 Ubiquitin Ligase TRIM Proteins. Cell Cycle and Mitosis Cells 8:510. https://doi.org/10.3390/cells8050510

    Article  CAS  PubMed  Google Scholar 

  91. Mulvaney KM, Matson JP, Siesser PF et al (2016) Identification and characterization of MCM3 as a kelch-like ECH-associated protein 1 (KEAP1) substrate. J Biol Chem 291:23719–23733. https://doi.org/10.1074/jbc.M116.729418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Uruno A, Yamamoto M (2023) The KEAP1-NRF2 System and Neurodegenerative Diseases. https://home.liebertpub.com/ars 38:974–988. https://doi.org/10.1089/ARS.2023.0234

  93. Kishi T, Ikeda A, Koyama N et al (2008) A refined two-hybrid system reveals that SCFCdc4-dependent degradation of Swi5 contributes to the regulatory mechanism of S-phase entry. Proc Natl Acad Sci U S A 105:14497–14502. https://doi.org/10.1073/pnas.0806253105

    Article  PubMed  PubMed Central  Google Scholar 

  94. Bornstein G, Bloom J, Sitry-Shevah D et al (2003) Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem 278:25752–25757. https://doi.org/10.1074/jbc.M301774200

    Article  CAS  PubMed  Google Scholar 

  95. Alessandrini A, Chiaur DS, Pagano M (1997) Regulation of the cyclin-dependent kinase inhibitor p27 by degradation and phosphorylation. Leukemia 11:342–345

    Article  CAS  PubMed  Google Scholar 

  96. Kamura T, Hara T, Kotoshiba S et al (2003) Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation. Proc Natl Acad Sci U S A 100:10231–10236. https://doi.org/10.1073/pnas.1831009100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Boix-Perales H, Horan I, Wise H, et al (2007) The E3 ubiquitin ligase skp2 regulates neural differentiation independent from the cell cycle. Neural Dev 2:. https://doi.org/10.1186/1749-8104-2-27

  98. Mimura S, Komata M, Kishi T et al (2009) SCFDia2 regulates DNA replication forks during S-phase in budding yeast. EMBO J 28:3693–3705. https://doi.org/10.1038/emboj.2009.320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Strohmaier H, Spruck CH, Kaiser P et al (2001) Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 413:316–322. https://doi.org/10.1038/35095076

    Article  CAS  PubMed  Google Scholar 

  100. Ang XL, Seeburg DP, Sheng M, Harper JW (2008) Regulation of Postsynaptic RapGAP SPAR by Polo-like Kinase 2 and the SCFβ-TRCP Ubiquitin Ligase in Hippocampal Neurons. J Biol Chem 283:29424. https://doi.org/10.1074/JBC.M802475200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Thomas Y, Coux O, Baldin V (2010) βTrCP-dependent degradation of CDC25B phosphatase at the metaphase-anaphase transition is a pre-requisite for correct mitotic exit. Cell Cycle 9:4338–4350. https://doi.org/10.4161/cc.9.21.13593

    Article  CAS  PubMed  Google Scholar 

  102. Liu Q, Tang Y, Chen L et al (2016) E3 Ligase SCFβTrCP-induced DYRK1A Protein Degradation Is Essential for Cell Cycle Progression in HEK293 Cells*. J Biol Chem 291:26399–26409. https://doi.org/10.1074/JBC.M116.717553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Li DZ, Liu SF, Zhu L et al (2017) FBXW8-dependent degradation of MRFAP1 in anaphase controls mitotic cell death. Oncotarget 8:97178–97186. https://doi.org/10.18632/oncotarget.21843

    Article  PubMed  PubMed Central  Google Scholar 

  104. Bassermann F, Von Klitzing C, Münch S et al (2005) NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry. Cell. https://doi.org/10.1016/j.cell.2005.04.034

    Article  PubMed  Google Scholar 

  105. Koepp DM, Schaefer LK, Ye X et al (2001) Phosphorylation-dependent ubiquitination of cyctin E by the SCFFbw7 ubiquitin ligase. Science 294:173–177. https://doi.org/10.1126/science.1065203

    Article  CAS  PubMed  Google Scholar 

  106. Gomez-Pastor R, Burchfiel ET, Neef DW et al (2017) (2017) Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease. Nat Commun 81(8):1–17. https://doi.org/10.1038/ncomms14405

    Article  CAS  Google Scholar 

  107. Li M, Zhang P (2009) The function of APC/CCdh1 in cell cycle and beyond. Cell Div 4:2. https://doi.org/10.1186/1747-1028-4-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Park HJ, Costa RH, Lau LF et al (2008) Anaphase-Promoting Complex/Cyclosome-Cdh1-Mediated Proteolysis of the Forkhead Box M1 Transcription Factor Is Critical for Regulated Entry into S Phase. Mol Cell Biol 28:5162–5171. https://doi.org/10.1128/mcb.00387-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Almeida A (2012) Regulation of APC/C-Cdh1 and Its Function in Neuronal Survival. Mol Neurobiol 46:547–554. https://doi.org/10.1007/s12035-012-8309-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Beck J, Maerki S, Posch M et al (2013) Ubiquitylation-dependent localization of PLK1 in mitosis. Nat Cell Biol 15:430–439. https://doi.org/10.1038/ncb2695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kong X, Shu X, Wang J, et al (2022) Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development. Dev 149:. https://doi.org/10.1242/DEV.201286/VIDEO-1

  112. Fang G, Hongtao Y, Kirschner MW (1998) Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1. Mol Cell 2:163–171. https://doi.org/10.1016/S1097-2765(00)80126-4

    Article  CAS  PubMed  Google Scholar 

  113. Senga T, Sivaprasad U, Zhu W et al (2006) PCNA is a cofactor for CDT1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination. J Biol Chem 281:6246–6252. https://doi.org/10.1074/jbc.M512705200

    Article  CAS  PubMed  Google Scholar 

  114. Patrón LA, Nagatomo K, Eves DT et al (2019) Cul4 ubiquitin ligase cofactor DCAF12 promotes neurotransmitter release and homeostatic plasticity. J Cell Biol 218:993–1010. https://doi.org/10.1083/JCB.201805099

    Article  PubMed  PubMed Central  Google Scholar 

  115. Lin DI, Barbash O, Kumar KGS et al (2006) Phosphorylation-Dependent Ubiquitination of Cyclin D1 by the SCFFBX4-αB Crystallin Complex. Mol Cell 24:355–366. https://doi.org/10.1016/j.molcel.2006.09.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lehman NL, Verschuren EW, Hsu JY et al (2006) Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells. Cell Cycle 5:1569–1573. https://doi.org/10.4161/cc.5.14.2925

    Article  CAS  PubMed  Google Scholar 

  117. Malureanu L, Jeganathan KB, Jin F et al (2010) Cdc20 hypomorphic mice fail to counteract de novo synthesis of cyclin B1 in mitosis. J Cell Biol 191:313–329. https://doi.org/10.1083/jcb.201003090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Huang HC, Shi J, Orth JD, Mitchison TJ (2009) Evidence that Mitotic Exit Is a Better Cancer Therapeutic Target Than Spindle Assembly. Cancer Cell 16:347–358. https://doi.org/10.1016/j.ccr.2009.08.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Dang F, Nie L, Wei W (2021) Ubiquitin signaling in cell cycle control and tumorigenesis. Cell Death Differ 28:427–438

    Article  CAS  PubMed  Google Scholar 

  120. Staropoli JF, Abeliovich A (2005) The ubiquitin-proteasome pathway is necessary for maintenance of the postmitotic status of neurons. J Mol Neurosci 27:175–183. https://doi.org/10.1385/JMN:27:2:175

    Article  CAS  PubMed  Google Scholar 

  121. Chauhan M, Modi PK, Sharma P (2020) Aberrant activation of neuronal cell cycle caused by dysregulation of ubiquitin ligase Itch results in neurodegeneration. Cell Death Dis 11:1–13. https://doi.org/10.1038/s41419-020-2647-1

    Article  CAS  Google Scholar 

  122. Staropoli JF, McDermott C, Martinat C et al (2003) Parkin Is a Component of an SCF-like Ubiquitin Ligase Complex and Protects Postmitotic Neurons from Kainate Excitotoxicity. Neuron 37:735–749. https://doi.org/10.1016/S0896-6273(03)00084-9

    Article  CAS  PubMed  Google Scholar 

  123. Almeida A, Bolaños JP, Moreno S (2005) Cdh1/Hct1-APC is essential for the survival of postmitotic neurons. J Neurosci 25:8115–8121. https://doi.org/10.1523/JNEUROSCI.1143-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Malumbres M, Barbacid M (2001) To cycle or not to cycle: A critical decision in cancer. Nat Rev Cancer 1:222–231. https://doi.org/10.1038/35106065

    Article  CAS  PubMed  Google Scholar 

  125. Hamilton E, Infante JR (2016) Targeting CDK4/6 in patients with cancer. Cancer Treat Rev 45:129–138

    Article  CAS  PubMed  Google Scholar 

  126. Wölfel T, Hauer M, Schneider J et al (1995) A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269:1281–1284. https://doi.org/10.1126/science.7652577

    Article  PubMed  Google Scholar 

  127. Qie S, Diehl JA (2016) Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med 94:1313–1326

    Article  CAS  PubMed  Google Scholar 

  128. Teixeira LK, Wang X, Li Y et al (2015) Cyclin e deregulation promotes loss of specific genomic regions. Curr Biol 25:1327–1333. https://doi.org/10.1016/j.cub.2015.03.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Keck JM, Summers MK, Tedesco D et al (2007) Cyclin E overexpression impairs progression through mitosis by inhibiting APCCdh1. J Cell Biol 178:371–385. https://doi.org/10.1083/jcb.200703202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Menon DR, Luo Y, Arcaroli JJ et al (2018) CDK1 interacts with SOX2 and promotes tumor initiation in human melanoma. Cancer Res 78:6561–6574. https://doi.org/10.1158/0008-5472.CAN-18-0330

    Article  CAS  PubMed Central  Google Scholar 

  131. Otto T, Sicinski P (2017) Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer 17:93–115. https://doi.org/10.1038/NRC.2016.138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ozono E, Yamaoka S, Ohtani K (2013) To grow, stop or die? – Novel tumor-suppressive mechanism regulated by the transcription factor E2F. In: Future aspects of tumor suppressor gene. InTech. https://doi.org/10.5772/54510

  133. Pandey N, Vinod PK (2022) Model scenarios for cell cycle re-entry in Alzheimer’s disease. iScience 25:. https://doi.org/10.1016/J.ISCI.2022.104543

  134. van Leeuwen LAG, Hoozemans JJM (2015) Physiological and pathophysiological functions of cell cycle proteins in post-mitotic neurons: implications for Alzheimer’s disease. Acta Neuropathol 129:511–525. https://doi.org/10.1007/S00401-015-1382-7

    Article  PubMed  PubMed Central  Google Scholar 

  135. Ueberham U, Arendt T (2005) The expression of cell cycle proteins in neurons and its relevance for Alzheimer’s disease. Curr Drug Targets CNS Neurol Disord 4:293–306

    Article  CAS  PubMed  Google Scholar 

  136. Hernández-Ortega K, Ferrera P, Arias C (2007) Sequential expression of cell-cycle regulators and Alzheimer’s disease-related proteins in entorhinal cortex after hippocampal excitotoxic damage. J Neurosci Res 85:1744–1751. https://doi.org/10.1002/jnr.21301

    Article  CAS  PubMed  Google Scholar 

  137. Der CS, Yang JL, Lin YC et al (2020) Emerging Roles of Inhibitor of Differentiation-1 in Alzheimer’s Disease: Cell Cycle Reentry and Beyond. Cells 9(7):1746

    Article  Google Scholar 

  138. Chen Y, McPhie DL, Hirschberg J, Neve RL (2000) The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons. J Biol Chem 275:8929–8935. https://doi.org/10.1074/jbc.275.12.8929

    Article  CAS  PubMed  Google Scholar 

  139. Höglinger GU, Breunig JJ, Depboylu C et al (2007) The pRb/E2F cell-cycle pathway mediates cell death in Parkinson’s disease. Proc Natl Acad Sci U S A 104:3585–3590. https://doi.org/10.1073/pnas.0611671104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Smith PD, Crocker SJ, Jackson-Lewis V et al (2003) Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.2232515100

    Article  PubMed  PubMed Central  Google Scholar 

  141. Alves Da Costa C, Paitel E, Vincent B, Checler F (2002) α-synuclein lowers p53-dependent apoptotic response of neuronal cells: Abolishment by 6-hydroxydopamine and implication for Parkinson’s disease. J Biol Chem 277:50980–50984. https://doi.org/10.1074/jbc.M207825200

    Article  CAS  PubMed  Google Scholar 

  142. Wolfrum P, Fietz A, Schnichels S, Hurst J (2022) The function of p53 and its role in Alzheimer’s and Parkinson’s disease compared to age-related macular degeneration. Front, Neurosci

    Book  Google Scholar 

  143. Lee SB, Kim JJ, Nam HJ et al (2015) Parkin Regulates Mitosis and Genomic Stability through Cdc20/Cdh1. Mol Cell 60:21–34. https://doi.org/10.1016/j.molcel.2015.08.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. López-Grueso MJ, Padilla CA, Bárcena JA, Requejo-Aguilar R (2020) Parkinson´s related protein DJ-1 is involved in aberrant cell cyclere-entry through Cdk5. https://doi.org/10.21203/rs.2.22860/v1

  145. Pelegrí C, Duran-Vilaregut J, del Valle J et al (2008) Cell cycle activation in striatal neurons from Huntington’s disease patients and rats treated with 3-nitropropionic acid. Int J Dev Neurosci 26:665–671. https://doi.org/10.1016/j.ijdevneu.2008.07.016

    Article  CAS  PubMed  Google Scholar 

  146. Feng Z, Jin S, Zupnick A et al (2006) p53 tumor suppressor protein regulates the levels of huntingtin gene expression. Oncogene 25:1–7. https://doi.org/10.1038/sj.onc.1209021

    Article  CAS  PubMed  Google Scholar 

  147. Godin JD, Colombo K, Molina-Calavita M et al (2010) Huntingtin Is Required for Mitotic Spindle Orientation and Mammalian Neurogenesis. Neuron 67:392–406. https://doi.org/10.1016/j.neuron.2010.06.027

    Article  CAS  PubMed  Google Scholar 

  148. Trinh E, Boutillier AL, Loeffler JP (2001) Regulation of the retinoblastoma-dependent Mdm2 and E2F–1 signaling pathways during neuronal apoptosis. Mol Cell Neurosci 17:342–353. https://doi.org/10.1006/mcne.2000.0928

    Article  CAS  PubMed  Google Scholar 

  149. Bajaj NP, Al-Sarraj ST, Anderson V, Kibble M, Leigh N, Miller CC (1998) Cyclin-dependent kinase-5 is associated with lipofuscin in motor neurones in amyotrophic lateral sclerosis. Neurosci Lett 245(1):45–48. https://doi.org/10.1016/s0304-3940(98)00176-1

    Article  CAS  PubMed  Google Scholar 

  150. Cova E, Ghiroldi A, Guareschi S et al (2010) G93A SOD1 alters cell cycle in a cellular model of Amyotrophic Lateral Sclerosis. Cell Signal 22:1477–1484. https://doi.org/10.1016/j.cellsig.2010.05.016

    Article  CAS  PubMed  Google Scholar 

  151. Cross DAE, Alessi DR, Cohen P et al (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789. https://doi.org/10.1038/378785a0

    Article  CAS  PubMed  Google Scholar 

  152. Kandel ES, Skeen J, Majewski N et al (2002) Activation of Akt/Protein Kinase B Overcomes a G2/M Cell Cycle Checkpoint Induced by DNA Damage. Mol Cell Biol 22:7831–7841. https://doi.org/10.1128/mcb.22.22.7831-7841.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Chang F, Lee JT, Navolanic PM et al (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia 17:590–603. https://doi.org/10.1038/sj.leu.2402824

    Article  CAS  PubMed  Google Scholar 

  154. Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14:381–395

    Article  CAS  PubMed  Google Scholar 

  155. Kurose K, Gilley K, Matsumoto S et al (2002) Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 32:355–357. https://doi.org/10.1038/ng1013

    Article  CAS  PubMed  Google Scholar 

  156. Pei JJ, Hugon J (2008) mTOR-dependent signalling in Alzheimer’s disease. J Cell Mol Med 12:2525–2532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Norambuena A, Wallrabe H, McMahon L et al (2017) mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer’s disease. Alzheimer’s Dement 13:152–167. https://doi.org/10.1016/j.jalz.2016.08.015

    Article  Google Scholar 

  158. Murata H, Sakaguchi M, Jin Y et al (2011) A new cytosolic pathway from a Parkinson disease-associated kinase, BRPK/PINK1: Activation of AKT via MTORC2. J Biol Chem 286:7182–7189. https://doi.org/10.1074/jbc.M110.179390

    Article  CAS  PubMed  Google Scholar 

  159. Albanese C, Johnson J, Watanabe G et al (1995) Transforming p21(ras) mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 270:23589–23597. https://doi.org/10.1074/jbc.270.40.23589

    Article  CAS  PubMed  Google Scholar 

  160. Matsushime H, Quelle DE, Shurtleff SA et al (1994) D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol 14:2066–2076. https://doi.org/10.1128/mcb.14.3.2066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Kawada M, Yamagoe S, Murakami Y et al (1997) Induction of p27Kip1 degradation and anchorage independence by Ras through the MAP kinase signaling pathway. Oncogene 15:629–637. https://doi.org/10.1038/sj.onc.1201228

    Article  CAS  PubMed  Google Scholar 

  162. Gutierrez GJ, Tsuji T, Cross JV et al (2010) JNK-mediated phosphorylation of Cdc25C regulates cell cycle entry and G2/M DNA damage checkpoint. J Biol Chem 285:14217–14228. https://doi.org/10.1074/jbc.M110.121848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Gutierrez GJ, Tsuji T, Chen M et al (2010) Interplay between Cdh1 and JNK activity during the cell cycle. Nat Cell Biol 12:686–695. https://doi.org/10.1038/ncb2071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Thoms HC, Dunlop MG, Stark LA (2007) p38-mediated inactivation of cyclin D1/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells. Cancer Res 67:1660–1669. https://doi.org/10.1158/0008-5472.CAN-06-1038

    Article  CAS  PubMed  Google Scholar 

  165. Thornton TM, Rincon M (2009) Non-classical p38 map kinase functions: Cell cycle checkpoints and survival. Int J Biol Sci 5:44–52. https://doi.org/10.7150/ijbs.5.44

    Article  CAS  PubMed  Google Scholar 

  166. Guo Y, Pan W, Liu S, et al (2020) ERK/MAPK signalling pathway and tumorigenesis (Review). Exp Ther Med 1997–2007. https://doi.org/10.3892/etm.2020.8454

  167. Torii S, Yamamoto T, Tsuchiya Y, Nishida E (2006) ERK MAP kinase in G1 cell cycle progression and cancer. Cancer Sci 97:697–702. https://doi.org/10.1111/j.1349-7006.2006.00244.x

    Article  CAS  PubMed  Google Scholar 

  168. Hydbring P, Bahram F, Su Y et al (2010) Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation. Proc Natl Acad Sci U S A 107:58–63. https://doi.org/10.1073/pnas.0900121106

    Article  PubMed  Google Scholar 

  169. Urasaki Y, Fiscus RR, Le TT (2018) Detection of the Cell Cycle-Regulated Negative Feedback Phosphorylation of Mitogen-Activated Protein Kinases in Breast Carcinoma using Nanofluidic Proteomics. Sci Rep 8:. https://doi.org/10.1038/s41598-018-28335-8

  170. Modi PK, Komaravelli N, Singh N, Sharma P (2012) Interplay between MEK-ERK signaling, cyclin D1, and cyclin-dependent kinase 5 regulates cell cycle reentry and apoptosis of neurons. Mol Biol Cell 23:3722–3730. https://doi.org/10.1091/mbc.E12-02-0125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Rodriguez-Blanco J, Martín V, Herrera F et al (2008) Intracellular signaling pathways involved in post-mitotic dopaminergic PC12 cell death induced by 6-hydroxydopamine. J Neurochem 107:127–140. https://doi.org/10.1111/j.1471-4159.2008.05588.x

    Article  CAS  PubMed  Google Scholar 

  172. Zhang M, Zhang L, Hei R et al (2021) CDK inhibitors in cancer therapy, an overview of recent development. Am J Cancer Res 11:1913–1935

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Monaco E III, Vallano M (2012) Cyclin-Dependent Kinase Inhibitors: Cancer Killers to Neuronal Guardians. Curr Med Chem 10:367–379. https://doi.org/10.2174/0929867033368277

    Article  Google Scholar 

  174. Pallàs M, Canudas AM, Verdaguer E et al (2005) Inhibitors of cyclin-dependent kinases: Potential drugs for the treatment of neurodegenerative disorders? Curr Med Chem - Cent Nerv Syst Agents 5:101–109. https://doi.org/10.2174/1568015054022371

    Article  Google Scholar 

  175. Jorda EG, Verdaguer E, Canudas AM et al (2003) Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis. Neuropharmacology 45:672–683. https://doi.org/10.1016/S0028-3908(03)00204-1

    Article  CAS  PubMed  Google Scholar 

  176. Harnor S, Pickles J, Cano C et al (2017) Modulation of the DNA-Damage Response by Inhibitors of the Phosphatidylinositol 3-Kinase Related Kinase (PIKK) Family. Top Med Chem 28:189–189. https://doi.org/10.1007/7355_2017_26

    Article  CAS  Google Scholar 

  177. Ronco C, Martin AR, Demange L, Benhida R (2017) ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells. Medchemcomm 8:295. https://doi.org/10.1039/C6MD00439C

    Article  CAS  PubMed  Google Scholar 

  178. Chwastek J, Jantas D, Lasoń W (2017) The ATM kinase inhibitor KU-55933 provides neuroprotection against hydrogen peroxide-induced cell damage via a γH2AX/p-p53/caspase-3-independent mechanism: Inhibition of calpain and cathepsin D. Int J Biochem Cell Biol 87:38–53. https://doi.org/10.1016/J.BIOCEL.2017.03.015

    Article  CAS  PubMed  Google Scholar 

  179. Lu XH, Mattis VB, Wang N et al (2014) Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington’s disease. Sci Transl Med 6:268ra178. https://doi.org/10.1126/SCITRANSLMED.3010523/SUPPL_FILE/6-268RA178_SM.PDF

    Article  PubMed  Google Scholar 

  180. Bellozi PMQ, Gomes GF, de Oliveira LR et al (2019) NVP-BEZ235 (Dactolisib) Has Protective Effects in a Transgenic Mouse Model of Alzheimer’s Disease. Front Pharmacol 10:1345. https://doi.org/10.3389/fphar.2019.01345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Brunden KR, Yao Y, Potuzak JS et al (2011) The characterization of microtubule-stabilizing drugs as possible therapeutic agents for Alzheimer’s disease and related tauopathies. Pharmacol Res. https://doi.org/10.1016/j.phrs.2010.12.002

    Article  PubMed  Google Scholar 

  182. Zhang B, Maiti A, Shively S et al (2005) Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci U S A 102:227–231. https://doi.org/10.1073/PNAS.0406361102

    Article  CAS  PubMed  Google Scholar 

  183. Jordan MA (2004) Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 44(4):253–265. https://doi.org/10.1038/nrc1317

    Article  CAS  Google Scholar 

  184. Blazejewski SM, Bennison SA, Liu X (2021) Toyo-oka K (2021) High-throughput kinase inhibitor screening reveals roles for Aurora and Nuak kinases in neurite initiation and dendritic branching. Sci Reports 111(11):1–20. https://doi.org/10.1038/s41598-021-87521-3

    Article  CAS  Google Scholar 

  185. Lee JS, Lee Y, André EA et al (2019) Inhibition of Polo-like kinase 2 ameliorates pathogenesis in Alzheimer’s disease model mice. PLoS ONE 14:e0219691. https://doi.org/10.1371/JOURNAL.PONE.0219691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Weston LJ, Stackhouse TL, Spinelli KJ et al (2021) Genetic deletion of Polo-like kinase 2 reduces alpha-synuclein serine-129 phosphorylation in presynaptic terminals but not Lewy bodies. J Biol Chem 296:100273. https://doi.org/10.1016/J.JBC.2021.100273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Huszar D, Theoclitou ME, Skolnik J, Herbst R (2009) Kinesin motor proteins as targets for cancer therapy. Cancer Metastasis Rev 28:197–208. https://doi.org/10.1007/S10555-009-9185-8

    Article  CAS  PubMed  Google Scholar 

  188. Hernandez I, Luna G, Rauch JN, et al (2019) A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Sci Transl Med 11:. https://doi.org/10.1126/scitranslmed.aat3005

  189. Rose M, Burgess JT, O’Byrne K et al (2020) PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance. Front Cell Dev Biol 8:879. https://doi.org/10.3389/FCELL.2020.564601/BIBTEX

    Article  Google Scholar 

  190. Chen A (2011) PARP inhibitors: its role in treatment of cancer. Chin J Cancer 30:463. https://doi.org/10.5732/CJC.011.10111

    Article  PubMed  PubMed Central  Google Scholar 

  191. Mao K, Zhang G (2021) The role of PARP1 in neurodegenerative diseases and aging. FEBS J. https://doi.org/10.1111/FEBS.15716

    Article  PubMed  Google Scholar 

  192. Puentes LN, Lengyel-Zhand Z, Reilly SW, Mach RH (2021) Evaluation of a Low-Toxicity PARP Inhibitor as a Neuroprotective Agent for Parkinson’s Disease. Mol Neurobiol 58:3641–3652. https://doi.org/10.1007/S12035-021-02371-4

    Article  CAS  PubMed  Google Scholar 

  193. Salech F, Ponce DP, Paula-Lima AC et al (2020) Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment of Alzheimer’s Disease. Front Aging Neurosci 12:255. https://doi.org/10.3389/FNAGI.2020.00255/BIBTEX

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Brown DG, Shorter J, Wobst HJ (2019) Emerging small-molecule therapeutic approaches for amyotrophic lateral sclerosis and frontotemporal dementia. Bioorg Med Chem Lett 126942. https://doi.org/10.1016/j.bmcl.2019.126942

  195. Paldino E, Cardinale A, D’Angelo V, et al (2017) Selective Sparing of Striatal Interneurons after Poly (ADP-Ribose) Polymerase 1 Inhibition in the R6/2 Mouse Model of Huntington’s Disease. Front Neuroanat 11:. https://doi.org/10.3389/FNANA.2017.00061

  196. O’Hare MJ, Hou ST, Morris EJ et al (2000) Induction and modulation of cerebellar granule neuron death by E2F–1. J Biol Chem 275:25358–25364. https://doi.org/10.1074/jbc.M001725200

    Article  PubMed  Google Scholar 

  197. Kabadi SV, Stoica BA, Byrnes KR et al (2011) Selective CDK Inhibitor Limits Neuroinflammation and Progressive Neurodegeneration after Brain Trauma. J Cereb Blood Flow Metab 32:137–149. https://doi.org/10.1038/JCBFM.2011.117

    Article  PubMed  PubMed Central  Google Scholar 

  198. Chen Y, Hou Y, Ge R et al (2018) Protective effect of roscovitine against rotenone-induced parkinsonism. Restor Neurol Neurosci 36:629–638. https://doi.org/10.3233/RNN-180817

    Article  CAS  PubMed  Google Scholar 

  199. Mookherjee P, Johnson GVW (2001) Tau phosphorylation during apoptosis of human SH-SY5Y neuroblastoma cells. Brain Res 921:31–43. https://doi.org/10.1016/S0006-8993(01)03074-8

    Article  CAS  PubMed  Google Scholar 

  200. Wei W, Wang X, Kusiak JW (2002) Signaling events in amyloid β-peptide-induced neuronal death and insulin-like growth factor I protection. J Biol Chem 277:17649–17656. https://doi.org/10.1074/jbc.M111704200

    Article  CAS  PubMed  Google Scholar 

  201. Chung YH, Lin CW, Huang HY et al (2020) Targeting Inflammation, PHA-767491 Shows a Broad Spectrum in Protein Aggregation Diseases. J Mol Neurosci 70:1140–1152. https://doi.org/10.1007/S12031-020-01521-Y

    Article  CAS  PubMed  Google Scholar 

  202. Johnson K, Liu L, Majdzadeh N et al (2005) Inhibition of neuronal apoptosis by the cyclin-dependent kinase inhibitor GW8510: Identification of 3′ substituted indolones as a scaffold for the development of neuroprotective drugs. J Neurochem 93:538–548. https://doi.org/10.1111/J.1471-4159.2004.03004.X

    Article  CAS  PubMed  Google Scholar 

  203. Leost M, Schultz C, Link A et al (2000) Paullones are potent inhibitors of glycogen synthase kinase-3β and cyclin-dependent kinase 5/p25. Eur J Biochem 267:5983–5994. https://doi.org/10.1046/J.1432-1327.2000.01673.X

    Article  CAS  PubMed  Google Scholar 

  204. Wang Y, Hoi P, Chan J, Lee S (2014) New Perspective on the Dual Functions of Indirubins in Cancer Therapy and Neuroprotection. Anticancer Agents Med Chem 14:1213–1219. https://doi.org/10.2174/1871520614666140825112924

    Article  CAS  PubMed  Google Scholar 

  205. Shemesh OA, Spira ME (2011) Rescue of neurons from undergoing hallmark tau-induced Alzheimer’s disease cell pathologies by the antimitotic drug paclitaxel. Neurobiol Dis 43:163–175. https://doi.org/10.1016/J.NBD.2011.03.008

    Article  CAS  PubMed  Google Scholar 

  206. Zheng YL, Kesavapany S, Gravell M et al (2005) A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons. EMBO J 24:209–220. https://doi.org/10.1038/SJ.EMBOJ.7600441

    Article  CAS  PubMed  Google Scholar 

  207. Li Y, Yang DQ (2010) The ATM inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. Mol Cancer Ther 9:113–125. https://doi.org/10.1158/1535-7163.MCT-08-1189

    Article  CAS  PubMed  Google Scholar 

  208. Mansour HM, Fathi AM, El-Khatib AS, Khattab MM (2023) Kinases control of regulated cell death revealing druggable targets for Parkinson’s disease. Ageing Res, Rev

    Book  Google Scholar 

  209. Zhu Y, Mao C, Wu J et al (2014) Improved ataxia telangiectasia mutated kinase inhibitor KU60019 provides a promising treatment strategy for non-invasive breast cancer. Oncol Lett 8:2043. https://doi.org/10.3892/OL.2014.2444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Flemming A (2015) (2015) Banking on ATM. Nat Rev Drug Discov 142(14):93–93. https://doi.org/10.1038/nrd4542

    Article  CAS  Google Scholar 

  211. Bellozi PMQ, de Lima IV A, Dória JG et al (2016) Neuroprotective effects of the anticancer drug NVP-BEZ235 (dactolisib) on amyloid-β 1–42 induced neurotoxicity and memory impairment. Sci Rep. https://doi.org/10.1038/srep25226

    Article  PubMed  PubMed Central  Google Scholar 

  212. Furukawa K, Mattson MP (1995) Cytochalasins protect hippocampal neurons against amyloid beta-peptide toxicity: evidence that actin depolymerization suppresses Ca2+ influx. J Neurochem 65:1061–1068. https://doi.org/10.1046/J.1471-4159.1995.65031061.X

    Article  CAS  PubMed  Google Scholar 

  213. Zhang B, Carroll J, Trojanowski JQ et al (2012) The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci 32:3601–3611. https://doi.org/10.1523/JNEUROSCI.4922-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Brunden KR, Gardner NM, James MJ et al (2013) MT-stabilizer, dictyostatin, exhibits prolonged brain retention and activity: Potential therapeutic implications. ACS Med Chem Lett 4:886–889. https://doi.org/10.1021/ML400233E

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Das V, Miller JH (2012) Microtubule stabilization by peloruside A and paclitaxel rescues degenerating neurons from okadaic acid‐induced tau phosphorylation. undefined 35:1705–1717. https://doi.org/10.1111/J.1460-9568.2012.08084.X

  216. Tan CC, Zhang XY, Tan L, Yu JT (2018) Tauopathies: Mechanisms and Therapeutic Strategies. J Alzheimer’s Dis 61:487–508. https://doi.org/10.3233/JAD-170187

    Article  CAS  Google Scholar 

  217. McGurk L, Mojsilovic-Petrovic J, Van Deerlin VM, et al (2018) Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis. Acta Neuropathol Commun 6:. https://doi.org/10.1186/S40478-018-0586-1

  218. Mao K, Chen J, Yu H, et al (2020) Poly (ADP-ribose) polymerase 1 inhibition prevents neurodegeneration and promotes α-synuclein degradation via transcription factor EB-dependent autophagy in mutant α-synucleinA53T model of Parkinson’s disease. Aging Cell 19:. https://doi.org/10.1111/ACEL.13163

  219. Liu DZ (2017) Repurposing cancer drugs to treat neurological diseases – Src inhibitors as examples. Neural Regen Res 12:910. https://doi.org/10.4103/1673-5374.208569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Nagy Z (2007) The dysregulation of the cell cycle and the diagnosis of Alzheimer’s disease. Biochim Biophys Acta - Mol Basis Dis 1772:402–408. https://doi.org/10.1016/J.BBADIS.2006.11.001

    Article  CAS  Google Scholar 

  221. Song J, Wang S, Tan M, Jia J (2012) G1/S checkpoint proteins in peripheral blood lymphocytes are potentially diagnostic biomarkers for Alzheimer’s disease. Neurosci Lett 526:. https://doi.org/10.1016/J.NEULET.2012.08.020

  222. Joseph C, Mangani AS, Gupta V et al (2020) Cell cycle deficits in neurodegenerative disorders: Uncovering molecular mechanisms to drive innovative therapeutic development. Aging Dis 11:946–966. https://doi.org/10.14336/AD.2019.0923

    Article  PubMed  PubMed Central  Google Scholar 

  223. Yan VC, Butterfield HE, Poral AH et al (2020) Why Great Mitotic Inhibitors Make Poor Cancer Drugs. Trends in cancer 6:924–941. https://doi.org/10.1016/J.TRECAN.2020.05.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Juric V, Murphy B (2020) Cyclin-dependent kinase inhibitors in brain cancer: current state and future directions. Cancer Drug Resist 3:48–62. https://doi.org/10.20517/CDR.2019.105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Liu DZ, Ander BP (2012) Cell Cycle Inhibition without Disruption of Neurogenesis Is a Strategy for Treatment of Aberrant Cell Cycle Diseases: An Update. Sci World J 2012:13. https://doi.org/10.1100/2012/491737

    Article  CAS  Google Scholar 

  226. Herrup K (2010) The involvement of cell cycle events in the pathogenesis of Alzheimer’s disease. Alzheimer’s Res Ther 2:2–3. https://doi.org/10.1186/alzrt37

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank the senior management of Delhi Technological University (DTU) and the Department of Biotechnology (DBT), Government of India, for providing PhD fellowship to DA.

Author information

Authors and Affiliations

  1. Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly Delhi College of Engineering), Shahbad Daulatpur, Bawana Road, New Delhi, Delhi, 110042, India

    Dia Advani & Pravir Kumar

Authors
  1. Dia Advani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pravir Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

This work was conceived by Pravir Kumar. Did Advani and Pravir Kumar contributed to the design and conceptualization of the manuscript. Did Advani collected the data. Critical evaluation was done by Did Advani, and the manuscript was written by Dia Advani. Editing and supervision have been done by Pravir Kumar. Both authors read and approved the final manuscript.

Corresponding author

Correspondence to Pravir Kumar.

Ethics declarations

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Advani, D., Kumar, P. Uncovering Cell Cycle Dysregulations and Associated Mechanisms in Cancer and Neurodegenerative Disorders: A Glimpse of Hope for Repurposed Drugs. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04130-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12035-024-04130-7

Keywords

Search

Navigation