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Progranulin Deficiency Reduces CDK4/6/pRb Activation and Survival of Human Neuroblastoma SH-SY5Y Cells

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Abstract

Null mutations in GRN are associated with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). However, the influence of progranulin (PGRN) deficiency in neurodegeneration is largely unknown. In neuroblastoma cells, silencing of GRN gene causes significantly reduced cell survival after serum withdrawal. The following observations suggest that alterations of the CDK4/6/retinoblastoma protein (pRb) pathway, secondary to changes in PI3K/Akt and ERK1/2 activation induced by PGRN deficiency, are involved in the control of serum deprivation-induced apoptosis: (i) inhibiting CDK4/6 levels or their associated kinase activity by sodium butyrate or PD332991 sensitized control SH-SY5Y cells to serum deprivation-induced apoptosis without affecting survival of PGRN-deficient cells; (ii) CDK4/6/pRb seems to be downstream of the PI3K/Akt and ERK1/2 signaling pathways since their specific inhibitors, LY294002 and PD98059, were able to decrease CDK6-associated kinase activity and induce death of control SH-SY5Y cells; (iii) PGRN-deficient cells show reduced stimulation of PI3K/Akt, ERK1/2, and CDK4/6 activities compared with control cells in the absence of serum; and (iv) supplementation of recombinant human PGRN was able to rescue survival of PGRN-deficient cells. These observations highlight the important role of PGRN-mediated stimulation of the PI3K/Akt-ERK1/2/CDK4/6/pRb pathway in determining the cell fate survival/death under serum deprivation.

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References

  1. Graff-Radford NR, Woodruff BK (2007) Frontotemporal dementia. Semin Neurol 27(1):48–57. doi:10.1055/s-2006-956755

    Article  PubMed  Google Scholar 

  2. Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002) The prevalence of frontotemporal dementia. Neurology 58(11):1615–1621

    Article  CAS  PubMed  Google Scholar 

  3. Boxer AL, Miller BL (2005) Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord 19(Suppl 1):S3–6

    Article  PubMed  Google Scholar 

  4. Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL 3rd, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the consortium for frontotemporal lobar degeneration. Acta Neuropathol 114(1):5–22. doi:10.1007/s00401-007-0237-2

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mackenzie IR, Neumann M, Cairns NJ, Munoz DG, Isaacs AM (2011) Novel types of frontotemporal lobar degeneration: beyond tau and TDP-43. J Mol Neurosci 45(3):402–408. doi:10.1007/s12031-011-9551-1

    Article  CAS  PubMed  Google Scholar 

  6. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133. doi:10.1126/science.1134108

    Article  CAS  PubMed  Google Scholar 

  7. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442(7105):916–919. doi:10.1038/nature05016

    Article  CAS  PubMed  Google Scholar 

  8. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442(7105):920–924. doi:10.1038/nature05017

    Article  CAS  PubMed  Google Scholar 

  9. Forman MS, Mackenzie IR, Cairns NJ, Swanson E, Boyer PJ, Drachman DA, Jhaveri BS, Karlawish JH, Pestronk A, Smith TW, Tu PH, Watts GD, Markesbery WR, Smith CD, Kimonis VE (2006) Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol 65(6):571–581

    Article  CAS  PubMed  Google Scholar 

  10. Gitcho MA, Bigio EH, Mishra M, Johnson N, Weintraub S, Mesulam M, Rademakers R, Chakraverty S, Cruchaga C, Morris JC, Goate AM, Cairns NJ (2009) TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy. Acta Neuropathol 118(5):633–645. doi:10.1007/s00401-009-0571-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Le Ber I, Camuzat A, Guerreiro R, Bouya-Ahmed K, Bras J, Nicolas G, Gabelle A, Didic M, De Septenville A, Millecamps S, Lenglet T, Latouche M, Kabashi E, Campion D, Hannequin D, Hardy J, Brice A (2013) SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis. JAMA neurology 70(11):1403–1410. doi:10.1001/jamaneurol.2013.3849

    PubMed  PubMed Central  Google Scholar 

  12. Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477(7363):211–215. doi:10.1038/nature10353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2):245–256. doi:10.1016/j.neuron.2011.09.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Murray ME, DeJesus-Hernandez M, Rutherford NJ, Baker M, Duara R, Graff-Radford NR, Wszolek ZK, Ferman TJ, Josephs KA, Boylan KB, Rademakers R, Dickson DW (2011) Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 122(6):673–690. doi:10.1007/s00401-011-0907-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ahmed Z, Mackenzie IR, Hutton ML, Dickson DW (2007) Progranulin in frontotemporal lobar degeneration and neuroinflammation. J Neuroinflammation 4:7. doi:10.1186/1742-2094-4-7

    Article  PubMed  PubMed Central  Google Scholar 

  16. Coppola G, Karydas A, Rademakers R, Wang Q, Baker M, Hutton M, Miller BL, Geschwind DH (2008) Gene expression study on peripheral blood identifies progranulin mutations. Ann Neurol 64(1):92–96. doi:10.1002/ana.21397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gijselinck I, Van Broeckhoven C, Cruts M (2008) Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update. Hum Mutat 29(12):1373–1386. doi:10.1002/humu.20785

    Article  CAS  PubMed  Google Scholar 

  18. Bhandari V, Bateman A (1992) Structure and chromosomal location of the human granulin gene. Biochem Biophys Res Commun 188(1):57–63

    Article  CAS  PubMed  Google Scholar 

  19. Daniel R, He Z, Carmichael KP, Halper J, Bateman A (2000) Cellular localization of gene expression for progranulin. J Histochem Cytochem J Histochem Soc 48(7):999–1009

    Article  CAS  Google Scholar 

  20. Petkau TL, Neal SJ, Orban PC, MacDonald JL, Hill AM, Lu G, Feldman HH, Mackenzie IR, Leavitt BR (2010) Progranulin expression in the developing and adult murine brain. J Comp Neurol 518(19):3931–3947. doi:10.1002/cne.22430

    Article  PubMed  Google Scholar 

  21. Eriksen JL, Mackenzie IR (2008) Progranulin: normal function and role in neurodegeneration. J Neurochem 104(2):287–297. doi:10.1111/j.1471-4159.2007.04968.x

    CAS  PubMed  Google Scholar 

  22. Van Damme P, Van Hoecke A, Lambrechts D, Vanacker P, Bogaert E, van Swieten J, Carmeliet P, Van Den Bosch L, Robberecht W (2008) Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol 181(1):37–41. doi:10.1083/jcb.200712039

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hu F, Padukkavidana T, Vaegter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM (2010) Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68(4):654–667. doi:10.1016/j.neuron.2010.09.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gao X, Joselin AP, Wang L, Kar A, Ray P, Bateman A, Goate AM, Wu JY (2010) Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3beta. Protein & cell 1(6):552–562. doi:10.1007/s13238-010-0067-1

    Article  CAS  Google Scholar 

  25. Guo A, Tapia L, Bamji SX, Cynader MS, Jia W (2010) Progranulin deficiency leads to enhanced cell vulnerability and TDP-43 translocation in primary neuronal cultures. Brain Res 1366:1–8. doi:10.1016/j.brainres.2010.09.099

    Article  CAS  PubMed  Google Scholar 

  26. Kleinberger G, Wils H, Ponsaerts P, Joris G, Timmermans JP, Van Broeckhoven C, Kumar-Singh S (2010) Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures. J Neurochem 115(3):735–747. doi:10.1111/j.1471-4159.2010.06961.x

    Article  CAS  PubMed  Google Scholar 

  27. Ghoshal N, Dearborn JT, Wozniak DF, Cairns NJ (2012) Core features of frontotemporal dementia recapitulated in progranulin knockout mice. Neurobiol Dis 45(1):395–408. doi:10.1016/j.nbd.2011.08.029

    Article  CAS  PubMed  Google Scholar 

  28. Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, Ma X, Ma Y, Iadecola C, Beal MF, Nathan C, Ding A (2010) Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 207(1):117–128. doi:10.1084/jem.20091568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Alquezar C, Esteras N, Alzualde A, Moreno F, Ayuso MS, Lopez De Munain A, Martin-Requero A (2012) Inactivation of CDK/pRb pathway normalizes survival pattern of lymphoblasts expressing the FTLD-progranulin mutation c.709-1G>A. PLoS One 7(5):37057. doi:10.1371/journal.pone.0037057

    Article  Google Scholar 

  30. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T, Munshi N, Treon SP, Anderson KC (2002) Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood 99(11):4079–4086

    Article  CAS  PubMed  Google Scholar 

  31. Samali A, Cai J, Zhivotovsky B, Jones DP, Orrenius S (1999) Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells. The EMBO J 18(8):2040–2048. doi:10.1093/emboj/18.8.2040

    Article  CAS  PubMed  Google Scholar 

  32. Bedner E, Smolewski P, Amstad P, Darzynkiewicz Z (2000) Activation of caspases measured in situ by binding of fluorochrome-labeled inhibitors of caspases (FLICA): correlation with DNA fragmentation. Exp Cell Res 259(1):308–313. doi:10.1006/excr.2000.4955

    Article  CAS  PubMed  Google Scholar 

  33. Gerasimovskaya EV, Tucker DA, Weiser-Evans M, Wenzlau JM, Klemm DJ, Banks M, Stenmark KR (2005) Extracellular ATP-induced proliferation of adventitial fibroblasts requires phosphoinositide 3-kinase, Akt, mammalian target of rapamycin, and p70 S6 kinase signaling pathways. J Biol Chem 280(3):1838–1848. doi:10.1074/jbc.M409466200

    Article  CAS  PubMed  Google Scholar 

  34. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD (2001) Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17:615–675. doi:10.1146/annurev.cellbio.17.1.615

    Article  CAS  PubMed  Google Scholar 

  35. Meloche S, Pouyssegur J (2007) The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 26(22):3227–3239. doi:10.1038/sj.onc.1210414

    Article  CAS  PubMed  Google Scholar 

  36. Thomas CY, Chouinard M, Cox M, Parsons S, Stallings-Mann M, Garcia R, Jove R, Wharen R (2003) Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells. Int j cancer J Int du cancer 104(1):19–27. doi:10.1002/ijc.10880

    Article  CAS  Google Scholar 

  37. Machado-Neto JA, Favaro P, Lazarini M, Costa FF, Olalla Saad ST, Traina F (2011) Knockdown of insulin receptor substrate 1 reduces proliferation and downregulates Akt/mTOR and MAPK pathways in K562 cells2. Biochim Biophys Acta 1813(8):1404–1411. doi:10.1016/j.bbamcr.2011.04.002

    Article  CAS  PubMed  Google Scholar 

  38. Alquezar C, Esteras N, Bartolome F, Merino JJ, Alzualde A, Lopez de Munain A, Martin-Requero A (2012) Alteration in cell cycle-related proteins in lymphoblasts from carriers of the c.709-1G > A PGRN mutation associated with FTLD-TDP dementia. Neurobiol Aging 33(2):429 e427-420

  39. Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer’s disease: the two-hit hypothesis. The Lancet Neurol 3(4):219–26. doi:10.1016/s1474-4422(4)00707-0

    Article  CAS  PubMed  Google Scholar 

  40. Zhu X, Lee HG, Perry G, Smith MA (2007) Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta 1772(4):494–502. doi:10.1016/j.bbadis.2006.10.014

    Article  CAS  PubMed  Google Scholar 

  41. Menu E, Garcia J, Huang X, Di Liberto M, Toogood PL, Chen I, Vanderkerken K, Chen-Kiang S (2008) A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. Cancer Res 68(14):5519–5523. doi:10.1158/0008-5472.can-07-6404

    Article  CAS  PubMed  Google Scholar 

  42. Li B, He H, Tao BB, Zhao ZY, Hu GH, Luo C, Chen JX, Ding XH, Sheng P, Dong Y, Zhang L, Lu YC (2012) Knockdown of CDK6 enhances glioma sensitivity to chemotherapy. Oncol Rep 28(3):909–914. doi:10.3892/or.2012.1884

    CAS  PubMed  Google Scholar 

  43. Feddersen RM, Clark HB, Yunis WS, Orr HT (1995) In vivo viability of postmitotic Purkinje neurons requires pRb family member function. Mol Cell Neurosci 6(2):153–167. doi:10.1006/mcne.1995.1014

    Article  CAS  PubMed  Google Scholar 

  44. White E (1994) Tumour biology. p53, guardian of Rb. Nature 371(6492):21–22. doi:10.1038/371021a0

    Article  CAS  PubMed  Google Scholar 

  45. Greene LA, Liu DX, Troy CM, Biswas SC (2007) Cell cycle molecules define a pathway required for neuron death in development and disease. Biochim Biophys Acta 1772(4):392–401. doi:10.1016/j.bbadis.2006.12.003

    Article  CAS  PubMed  Google Scholar 

  46. Nguyen MD, Mushynski WE, Julien JP (2002) Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death Differ 9(12):1294–1306. doi:10.1038/sj.cdd.4401108

    Article  CAS  PubMed  Google Scholar 

  47. Chen XC, Chen LM, Zhu YG, Fang F, Zhou YC, Zhao CH (2003) Involvement of CDK4, pRB, and E2F1 in ginsenoside Rg1 protecting rat cortical neurons from beta-amyloid-induced apoptosis. Acta Pharmacol Sin 24(12):1259–1264

    CAS  PubMed  Google Scholar 

  48. Copani A, Caraci F, Hoozemans JJ, Calafiore M, Sortino MA, Nicoletti F (2007) The nature of the cell cycle in neurons: focus on a “non-canonical” pathway of DNA replication causally related to death. Biochim Biophys Acta 1772(4):409–412. doi:10.1016/j.bbadis.2006.10.016

    Article  CAS  PubMed  Google Scholar 

  49. Hu SY, Tai CC, Li YH, Wu JL (2012) Progranulin compensates for blocked IGF-1 signaling to promote myotube hypertrophy in C2C12 myoblasts via the PI3K/Akt/mTOR pathway. FEBS Lett 586(19):3485–3492. doi:10.1016/j.febslet.2012.07.077

    Article  CAS  PubMed  Google Scholar 

  50. Zanocco-Marani T, Bateman A, Romano G, Valentinis B, He ZH, Baserga R (1999) Biological activities and signaling pathways of the granulin/epithelin precursor. Cancer Res 59(20):5331–5340

    CAS  PubMed  Google Scholar 

  51. Ryan CL, Baranowski DC, Chitramuthu BP, Malik S, Li Z, Cao M, Minotti S, Durham HD, Kay DG, Shaw CA, Bennett HP, Bateman A (2009) Progranulin is expressed within motor neurons and promotes neuronal cell survival. BMC Neurosci 10:130. doi:10.1186/1471-2202-10-130

    Article  PubMed  PubMed Central  Google Scholar 

  52. Xu J, Xilouri M, Bruban J, Shioi J, Shao Z, Papazoglou I, Vekrellis K, Robakis NK (2011) Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging 32(12):2326 e2325-2316. doi:10.1016/j.neurobiolaging.2011.06.017

  53. Cariaga-Martinez AE, Lopez-Ruiz P, Nombela-Blanco MP, Motino O, Gonzalez-Corpas A, Rodriguez-Ubreva J, Lobo MV, Cortes MA, Colas B (2013) Distinct and specific roles of AKT1 and AKT2 in androgen-sensitive and androgen-independent prostate cancer cells. Cell Signal 25(7):1586–1597. doi:10.1016/j.cellsig.2013.03.019

    Article  CAS  PubMed  Google Scholar 

  54. Santi SA, Lee H (2011) Ablation of Akt2 induces autophagy through cell cycle arrest, the downregulation of p70S6K, and the deregulation of mitochondria in MDA-MB231 cells. PLoS One 6(1):e14614. doi:10.1371/journal.pone.0014614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bossu P, Salani F, Alberici A, Archetti S, Bellelli G, Galimberti D, Scarpini E, Spalletta G, Caltagirone C, Padovani A, Borroni B (2011) Loss of function mutations in the progranulin gene are related to pro-inflammatory cytokine dysregulation in frontotemporal lobar degeneration patients. J Neuroinflammation 8:65. doi:10.1186/1742-2094-8-65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Alquezar C, Esteras N, de la Encarnacion A, Alzualde A, Moreno F, Lopez de Munain A, Martin-Requero A (2014) PGRN haploinsufficiency increased Wnt5a signaling in peripheral cells from frontotemporal lobar degeneration-progranulin mutation carriers. Neurobiol Aging 35(4):886–898. doi:10.1016/j.neurobiolaging.2013.09.021

    Article  CAS  PubMed  Google Scholar 

  57. Rosen EY, Wexler EM, Versano R, Coppola G, Gao F, Winden KD, Oldham MC, Martens LH, Zhou P, Farese RV Jr, Geschwind DH (2011) Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling. Neuron 71(6):1030–1042. doi:10.1016/j.neuron.2011.07.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work has been supported by grants from Ministerio de Economía y Competitividad (SAF2011-28603) and Fundación Ramón Areces. AdlE is supported by Fundación Ramón Areces. We thank Drs. Joselin and Wu for providing the GRN KD SH-SY5Y cells.

Author Contributions

AdlE and AMR conceived and designed the experiments. AdlE, CA, and NE performed the experiments. AMR wrote the paper. AdlE, NE, CA, and AMR read and approved the final manuscript.

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The authors declare that they have no conflicts of interest.

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de la Encarnación, A., Alquézar, C., Esteras, N. et al. Progranulin Deficiency Reduces CDK4/6/pRb Activation and Survival of Human Neuroblastoma SH-SY5Y Cells. Mol Neurobiol 52, 1714–1725 (2015). https://doi.org/10.1007/s12035-014-8965-5

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