Abstract
The p53-family member, p73, plays a key role in the development of the central nervous system (CNS), in senescence, and in tumor formation. The role of p73 in neuronal differentiation is complex and involves several downstream pathways. Indeed, in the last few years, we have learnt that TAp73 directly or indirectly regulates several genes involved in neural biology. In particular, TAp73 is involved in the maintenance of neural stem/progenitor cell self-renewal and differentiation throughout the regulation of SOX-2, Hey-2, TRIM32 and Notch. In addition, TAp73 is also implicated in the regulation of the differentiation and function of postmitotic neurons by regulating the expression of p75NTR and GLS2 (glutamine metabolism). Further still, the regulation of miR-34a by TAp73 indicates that microRNAs can also participate in this multifunctional role of p73 in adult brain physiology. However, contradictory results still exist in the relationship between p73 and brain disorders, and this remains an important area for further investigation.
Similar content being viewed by others
Abbreviations
- CNS:
-
Central nervous system
- NSC:
-
Neural stem cell
- (MBP):
-
Myelin basic protein
- NGF:
-
Nerve growth factor
- PNS:
-
Peripheral nervous system
- p75NTR :
-
p75 neurotrophin receptor
- WT:
-
Wild type
- TAp73−/−:
-
TAp73 knockout
- p73−/−:
-
p73 knockout mice
- DG:
-
Dentate gyrus
- AD:
-
Alzheimer’s disease
- Aβ:
-
β-amyloid
- NFTs:
-
Neurofibrillary tangles
References
Dotsch V, Bernassola F, Coutandin D, Candi E, Melino G (2010) p63 and p73, the ancestors of p53. Cold Spring Harb Perspect Biol 2(9):a004887. doi:10.1101/cshperspect.a004887
Montero J, Dutta C, van Bodegom D, Weinstock D, Letai A (2013) p53 regulates a non-apoptotic death induced by ROS. Cell Death Differ 20(11):1465–1474. doi:10.1038/cdd.2013.52
Fan YH, Cheng J, Vasudevan SA, Dou J, Zhang H, Patel RH, Ma IT, Rojas Y et al (2013) USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis. Cell Death Dis 4:e867. doi:10.1038/cddis.2013.400
Valentino T, Palmieri D, Vitiello M, Pierantoni GM, Fusco A, Fedele M (2013) PATZ1 interacts with p53 and regulates expression of p53-target genes enhancing apoptosis or cell survival based on the cellular context. Cell Death Dis 4:e963. doi:10.1038/cddis.2013.500
Kenzelmann Broz D, Spano Mello S, Bieging KT, Jiang D, Dusek RL, Brady CA, Sidow A, Attardi LD (2013) Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. Genes Dev 27(9):1016–1031. doi:10.1101/gad.212282.112
Qian Y, Chen X (2013) Senescence regulation by the p53 protein family. Methods Mol Biol 965:37–61. doi:10.1007/978-1-62703-239-1_3
Levine AJ, Tomasini R, McKeon FD, Mak TW, Melino G (2011) The p53 family: guardians of maternal reproduction. Nat Rev Mol Cell Biol 12(4):259–265. doi:10.1038/nrm3086
He Z, Liu H, Agostini M, Yousefi S, Perren A, Tschan MP, Mak TW, Melino G et al (2013) p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene. Cell Death Differ 20(10):1415–1424. doi:10.1038/cdd.2013.104
Alexandrova EM, Petrenko O, Nemajerova A, Romano RA, Sinha S, Moll UM (2013) DeltaNp63 regulates select routes of reprogramming via multiple mechanisms. Cell Death Differ 20(12):1698–1708. doi:10.1038/cdd.2013.122
Molchadsky A, Ezra O, Amendola PG, Krantz D, Kogan-Sakin I, Buganim Y, Rivlin N, Goldfinger N et al (2013) p53 is required for brown adipogenic differentiation and has a protective role against diet-induced obesity. Cell Death Differ 20(5):774–783. doi:10.1038/cdd.2013.9
Candi E, Agostini M, Melino G, Bernassola F (2014) How the TP53 family proteins TP63 and TP73 contribute to tumorigenesis: regulators and effectors. Hum Mutat 35(6):702–714. doi:10.1002/humu.22523
Levrero M, De Laurenzi V, Costanzo A, Gong J, Wang JY, Melino G (2000) The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci 113(Pt 10):1661–1670
Rai TS, Adams PD (2013) Lessons from senescence: chromatin maintenance in non-proliferating cells. Biochim Biophys Acta 1819(3–4):322–331
Wiman KG (2013) p53 talks to PARP: the increasing complexity of p53-induced cell death. Cell Death Differ 20(11):1438–1439. doi:10.1038/cdd.2013.111
Huang Q, Yu L, Levine AJ, Nussinov R, Ma B (2014) Dipeptide analysis of p53 mutations and evolution of p53 family proteins. Biochim Biophys Acta 1844(1 Pt B):198–206. doi:10.1016/j.bbapap.2013.04.002
Mello SS, Attardi LD (2013) Not all p53 gain-of-function mutants are created equal. Cell Death Differ 20(7):855–857. doi:10.1038/cdd.2013.53
Hanel W, Marchenko N, Xu S, Yu SX, Weng W, Moll U (2013) Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis. Cell Death Differ 20(7):898–909. doi:10.1038/cdd.2013.17
Wang W, Cheng B, Miao L, Mei Y, Wu M (2013) Mutant p53-R273H gains new function in sustained activation of EGFR signaling via suppressing miR-27a expression. Cell Death Dis 4:e574. doi:10.1038/cddis.2013.97
Chen YC, Chan JY, Chiu YL, Liu ST, Lozano G, Wang SL, Ho CL, Huang SM (2013) Grail as a molecular determinant for the functions of the tumor suppressor p53 in tumorigenesis. Cell Death Differ 20(5):732–743. doi:10.1038/cdd.2013.1
Vanbokhoven H, Melino G, Candi E, Declercq W (2011) p63, a story of mice and men. J Investig Dermatol 131(6):1196–1207. doi:10.1038/jid.2011.84
Candi E, Cipollone R, di Val R, Cervo P, Gonfloni S, Melino G, Knight R (2008) p63 in epithelial development. Cell Mol Life Sci CMLS 65(20):3126–3133. doi:10.1007/s00018-008-8119-x
Chari NS, Romano RA, Koster MI, Jaks V, Roop D, Flores ER, Teglund S, Sinha S et al (2013) Interaction between the TP63 and SHH pathways is an important determinant of epidermal homeostasis. Cell Death Differ 20(8):1080–1088. doi:10.1038/cdd.2013.41
Masse I, Barbollat-Boutrand L, Molina M, Berthier-Vergnes O, Joly-Tonetti N, Martin MT, Caron de Fromentel C, Kanitakis J et al (2012) Functional interplay between p63 and p53 controls RUNX1 function in the transition from proliferation to differentiation in human keratinocytes. Cell Death Dis 3:e318. doi:10.1038/cddis.2012.62
Rufini A, Barlattani A, Docimo R, Velletri T, Niklison-Chirou MV, Agostini M, Melino G (2011) p63 in tooth development. Biochem Pharmacol 82(10):1256–1261. doi:10.1016/j.bcp.2011.07.068
Paradis MR, Raj MT, Boughner JC (2013) Jaw growth in the absence of teeth: the developmental morphology of edentulous mandibles using the p63 mouse mutant. Evol Dev 15(4):268–279. doi:10.1111/ede.12026
Rouleau M, Medawar A, Hamon L, Shivtiel S, Wolchinsky Z, Zhou H, De Rosa L, Candi E et al (2011) TAp63 is important for cardiac differentiation of embryonic stem cells and heart development. Stem Cells 29(11):1672–1683. doi:10.1002/stem.723
Paris M, Rouleau M, Puceat M, Aberdam D (2012) Regulation of skin aging and heart development by TAp63. Cell Death Differ 19(2):186–193. doi:10.1038/cdd.2011.181
Barrow LL, van Bokhoven H, Daack-Hirsch S, Andersen T, van Beersum SE, Gorlin R, Murray JC (2002) Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. J Med Genet 39(8):559–566
Ferone G, Mollo MR, Thomason HA, Antonini D, Zhou H, Ambrosio R, De Rosa L, Salvatore D et al (2013) p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome. Hum Mol Genet 22(3):531–543. doi:10.1093/hmg/dds464
Ferone G, Thomason HA, Antonini D, De Rosa L, Hu B, Gemei M, Zhou H, Ambrosio R et al (2012) Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome. EMBO Mol Med 4(3):192–205. doi:10.1002/emmm.201100199
Wilhelm MT, Rufini A, Wetzel MK, Tsuchihara K, Inoue S, Tomasini R, Itie-Youten A, Wakeham A et al (2010) Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA damage response pathway. Genes Dev 24(6):549–560. doi:10.1101/gad.1873910
Rufini A, Agostini M, Grespi F, Tomasini R, Sayan BS, Niklison-Chirou MV, Conforti F, Velletri T et al (2011) p73 in cancer. Genes Cancer 2(4):491–502. doi:10.1177/1947601911408890
Liu T, Roh SE, Woo JA, Ryu H, Kang DE (2013) Cooperative role of RanBP9 and P73 in mitochondria-mediated apoptosis. Cell Death Dis 4:e476. doi:10.1038/cddis.2012.203
Tomasini R, Tsuchihara K, Wilhelm M, Fujitani M, Rufini A, Cheung CC, Khan F, Itie-Youten A et al (2008) TAp73 knockout shows genomic instability with infertility and tumor suppressor functions. Genes Dev 22(19):2677–2691. doi:10.1101/gad.1695308
Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H et al (2000) p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404(6773):99–103. doi:10.1038/35003607
Niklison-Chirou MV, Steinert JR, Agostini M, Knight RA, Dinsdale D, Cattaneo A, Mak TW, Melino G (2013) TAp73 knockout mice show morphological and functional nervous system defects associated with loss of p75 neurotrophin receptor. Proc Natl Acad Sci U S A 110(47):18952–18957. doi:10.1073/pnas.1221172110
Killick R, Niklison-Chirou M, Tomasini R, Bano D, Rufini A, Grespi F, Velletri T, Tucci P et al (2011) p73: a multifunctional protein in neurobiology. Mol Neurobiol 43(2):139–146. doi:10.1007/s12035-011-8172-6
Inoue S, Tomasini R, Rufini A, Elia AJ, Agostini M, Amelio I, Cescon D, Dinsdale D et al (2014) TAp73 is required for spermatogenesis and the maintenance of male fertility. Proc Natl Acad Sci U S A 111(5):1843–1848. doi:10.1073/pnas.1323416111
Seeliger MA, Moll UM (2013) p73—constitutively open for business. Cell Death Differ 20(8):972–973. doi:10.1038/cdd.2013.56
Luh LM, Kehrloesser S, Deutsch GB, Gebel J, Coutandin D, Schafer B, Agostini M, Melino G et al (2013) Analysis of the oligomeric state and transactivation potential of TAp73alpha. Cell Death Differ 20(8):1008–1016. doi:10.1038/cdd.2013.23
Flores ER, Lozano G (2012) The p53 family grows old. Genes Dev 26(18):1997–2000. doi:10.1101/gad.202648.112
Fricker M, Papadia S, Hardingham GE, Tolkovsky AM (2010) Implication of TAp73 in the p53-independent pathway of Puma induction and Puma-dependent apoptosis in primary cortical neurons. J Neurochem 114(3):772–783. doi:10.1111/j.1471-4159.2010.06804.x
Buhlmann S, Putzer BM (2008) DNp73 a matter of cancer: mechanisms and clinical implications. Biochim Biophys Acta 1785(2):207–216. doi:10.1016/j.bbcan.2008.01.002
Grespi F, Amelio I, Tucci P, Annicchiarico-Petruzzelli M, Melino G (2012) Tissue-specific expression of p73 C-terminal isoforms in mice. Cell Cycle 11(23):4474–4483. doi:10.4161/cc.22787
Tomasini R, Secq V, Pouyet L, Thakur AK, Wilhelm M, Nigri J, Vasseur S, Berthezene P et al (2013) TAp73 is required for macrophage-mediated innate immunity and the resolution of inflammatory responses. Cell Death Differ 20(2):293–301. doi:10.1038/cdd.2012.123
Marcel V, Petit I, Murray-Zmijewski F, Goullet de Rugy T, Fernandes K, Meuray V, Diot A, Lane DP et al (2012) Diverse p63 and p73 isoforms regulate Delta133p53 expression through modulation of the internal TP53 promoter activity. Cell Death Differ 19(5):816–826. doi:10.1038/cdd.2011.152
Meyer G, Perez-Garcia CG, Abraham H, Caput D (2002) Expression of p73 and reelin in the developing human cortex. J Neurosci Off J Soc Neurosci 22(12):4973–4986
Pozniak CD, Barnabe-Heider F, Rymar VV, Lee AF, Sadikot AF, Miller FD (2002) p73 is required for survival and maintenance of CNS neurons. J Neurosci Off J Soc Neurosci 22(22):9800–9809
Pozniak CD, Radinovic S, Yang A, McKeon F, Kaplan DR, Miller FD (2000) An anti-apoptotic role for the p53 family member, p73, during developmental neuron death. Science 289(5477):304–306
Tissir F, Ravni A, Achouri Y, Riethmacher D, Meyer G, Goffinet AM (2009) DeltaNp73 regulates neuronal survival in vivo. Proc Natl Acad Sci U S A 106(39):16871–16876. doi:10.1073/pnas.0903191106
Thompson CL, Pathak SD, Jeromin A, Ng LL, MacPherson CR, Mortrud MT, Cusick A, Riley ZL et al (2008) Genomic anatomy of the hippocampus. Neuron 60(6):1010–1021. doi:10.1016/j.neuron.2008.12.008
Talos F, Abraham A, Vaseva AV, Holembowski L, Tsirka SE, Scheel A, Bode D, Dobbelstein M et al (2010) p73 is an essential regulator of neural stem cell maintenance in embryonal and adult CNS neurogenesis. Cell Death Differ 17(12):1816–1829. doi:10.1038/cdd.2010.131
Deacon RM (2006) Burrowing in rodents: a sensitive method for detecting behavioral dysfunction. Nat Protoc 1(1):118–121. doi:10.1038/nprot.2006.19
Elder GA, Ragnauth A, Dorr N, Franciosi S, Schmeidler J, Haroutunian V, Buxbaum JD (2008) Increased locomotor activity in mice lacking the low-density lipoprotein receptor. Behav Brain Res 191(2):256–265. doi:10.1016/j.bbr.2008.03.036
Wetzel MK, Naska S, Laliberte CL, Rymar VV, Fujitani M, Biernaskie JA, Cole CJ, Lerch JP et al (2008) p73 regulates neurodegeneration and phospho-tau accumulation during aging and Alzheimer’s disease. Neuron 59(5):708–721. doi:10.1016/j.neuron.2008.07.021
Agostini M, Tucci P, Killick R, Candi E, Sayan BS, di Val R, Cervo P, Nicotera P et al (2011) Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets. Proc Natl Acad Sci U S A 108(52):21093–21098. doi:10.1073/pnas.1112061109
De Laurenzi V, Raschella G, Barcaroli D, Annicchiarico-Petruzzelli M, Ranalli M, Catani MV, Tanno B, Costanzo A et al (2000) Induction of neuronal differentiation by p73 in a neuroblastoma cell line. J Biol Chem 275(20):15226–15231
Billon N, Terrinoni A, Jolicoeur C, McCarthy A, Richardson WD, Melino G, Raff M (2004) Roles for p53 and p73 during oligodendrocyte development. Development 131(6):1211–1220. doi:10.1242/dev.01035
Kole AJ, Annis RP, Deshmukh M (2013) Mature neurons: equipped for survival. Cell Death Dis 4:e689. doi:10.1038/cddis.2013.220
Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250. doi:10.1146/annurev.neuro.28.051804.101459
Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132(4):645–660. doi:10.1016/j.cell.2008.01.033
Yadirgi G, Marino S (2009) Adult neural stem cells and their role in brain pathology. J Pathol 217(2):242–253. doi:10.1002/path.2480
Meletis K, Wirta V, Hede SM, Nister M, Lundeberg J, Frisen J (2006) p53 suppresses the self-renewal of adult neural stem cells. Development 133(2):363–369. doi:10.1242/dev.02208
Dugani CB, Paquin A, Fujitani M, Kaplan DR, Miller FD (2009) p63 antagonizes p53 to promote the survival of embryonic neural precursor cells. J Neurosci Off J Soc Neurosci 29(20):6710–6721. doi:10.1523/JNEUROSCI.5878-08.2009
Hadjal Y, Hadadeh O, Yazidi CE, Barruet E, Binetruy B (2013) A p38MAPK-p53 cascade regulates mesodermal differentiation and neurogenesis of embryonic stem cells. Cell Death Dis 4:e737. doi:10.1038/cddis.2013.246
Agostini M, Tucci P, Chen H, Knight RA, Bano D, Nicotera P, McKeon F, Melino G (2010) p73 regulates maintenance of neural stem cell. Biochem Biophys Res Commun 403(1):13–17. doi:10.1016/j.bbrc.2010.10.087
Fujitani M, Cancino GI, Dugani CB, Weaver IC, Gauthier-Fisher A, Paquin A, Mak TW, Wojtowicz MJ et al (2010) TAp73 acts via the bHLH Hey2 to promote long-term maintenance of neural precursors. Curr Biol CB 20(22):2058–2065. doi:10.1016/j.cub.2010.10.029
Gonzalez-Cano L, Herreros-Villanueva M, Fernandez-Alonso R, Ayuso-Sacido A, Meyer G, Garcia-Verdugo JM, Silva A, Marques MM et al (2010) p73 deficiency results in impaired self renewal and premature neuronal differentiation of mouse neural progenitors independently of p53. Cell Death Dis 1:e109. doi:10.1038/cddis.2010.87
Fatt MP, Cancino GI, Miller FD, Kaplan DR (2014) p63 and p73 coordinate p53 function to determine the balance between survival, cell death, and senescence in adult neural precursor cells. Cell Death Differ 21(10):1546–1559. doi:10.1038/cdd.2014.61
Molofsky AV, Pardal R, Morrison SJ (2004) Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol 16(6):700–707. doi:10.1016/j.ceb.2004.09.004
Hooper C, Tavassoli M, Chapple JP, Uwanogho D, Goodyear R, Melino G, Lovestone S, Killick R (2006) TAp73 isoforms antagonize Notch signalling in SH-SY5Y neuroblastomas and in primary neurones. J Neurochem 99(3):989–999. doi:10.1111/j.1471-4159.2006.04142.x
Favaro R, Valotta M, Ferri AL, Latorre E, Mariani J, Giachino C, Lancini C, Tosetti V et al (2009) Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat Neurosci 12(10):1248–1256. doi:10.1038/nn.2397
Agostini M, Tucci P, Steinert JR, Shalom-Feuerstein R, Rouleau M, Aberdam D, Forsythe ID, Young KW et al (2011) microRNA-34a regulates neurite outgrowth, spinal morphology, and function. Proc Natl Acad Sci U S A 108(52):21099–21104. doi:10.1073/pnas.1112063108
Aranha MM, Santos DM, Sola S, Steer CJ, Rodrigues CM (2011) miR-34a regulates mouse neural stem cell differentiation. PLoS One 6(8):e21396. doi:10.1371/journal.pone.0021396
Tarantino C, Paolella G, Cozzuto L, Minopoli G, Pastore L, Parisi S, Russo T (2010) miRNA 34a, 100, and 137 modulate differentiation of mouse embryonic stem cells. FASEB J Off Publ Fed Am Soc Exp Biol 24(9):3255–3263. doi:10.1096/fj.09-152207
Miyabayashi T, Teo JL, Yamamoto M, McMillan M, Nguyen C, Kahn M (2007) Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency. Proc Natl Acad Sci U S A 104(13):5668–5673. doi:10.1073/pnas.0701331104
Sampath P, Pritchard DK, Pabon L, Reinecke H, Schwartz SM, Morris DR, Murry CE (2008) A hierarchical network controls protein translation during murine embryonic stem cell self-renewal and differentiation. Cell Stem Cell 2(5):448–460. doi:10.1016/j.stem.2008.03.013
Hashimi ST, Fulcher JA, Chang MH, Gov L, Wang S, Lee B (2009) MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation. Blood 114(2):404–414. doi:10.1182/blood-2008-09-179150
Collu GM, Hidalgo-Sastre A, Brennan K (2014) Wnt-Notch signalling crosstalk in development and disease. Cell Mol Life Sci CMLS 71(18):3553–3567. doi:10.1007/s00018-014-1644-x
Ueda Y, Hijikata M, Takagi S, Takada R, Takada S, Chiba T, Shimotohno K (2001) p73beta, a variant of p73, enhances Wnt/beta-catenin signaling in Saos-2 cells. Biochem Biophys Res Commun 283(2):327–333. doi:10.1006/bbrc.2001.4788
Hillje AL, Pavlou MA, Beckmann E, Worlitzer MM, Bahnassawy L, Lewejohann L, Palm T, Schwamborn JC (2013) TRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation. Cell Death Dis 4:e976. doi:10.1038/cddis.2013.487
Schwamborn JC, Berezikov E, Knoblich JA (2009) The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors. Cell 136(5):913–925. doi:10.1016/j.cell.2008.12.024
Gonzalez-Cano L, Hillje AL, Fuertes-Alvarez S, Marques MM, Blanch A, Ian RW, Irwin MS, Schwamborn JC et al (2013) Regulatory feedback loop between TP73 and TRIM32. Cell Death Dis 4:e704. doi:10.1038/cddis.2013.224
Alexandrova EM, Talos F, Moll UM (2013) p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation. Cell Death Differ 20(2):368. doi:10.1038/cdd.2012.134
de la Torre-Ubieta L, Bonni A (2011) Transcriptional regulation of neuronal polarity and morphogenesis in the mammalian brain. Neuron 72(1):22–40. doi:10.1016/j.neuron.2011.09.018
Chao MV, Bothwell M (2002) Neurotrophins: to cleave or not to cleave. Neuron 33(1):9–12
Zampieri N, Chao MV (2004) Structural biology. The p75 NGF receptor exposed. Science 304(5672):833–834. doi:10.1126/science.1098110
Arevalo JC, Chao MV (2005) Axonal growth: where neurotrophins meet Wnts. Curr Opin Cell Biol 17(2):112–115. doi:10.1016/j.ceb.2005.01.004
Tiveron C, Fasulo L, Capsoni S, Malerba F, Marinelli S, Paoletti F, Piccinin S, Scardigli R et al (2013) ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice. Cell Death Differ 20(8):1017–1030. doi:10.1038/cdd.2013.22
Chen Y, Zeng J, Cen L, Chen Y, Wang X, Yao G, Wang W, Qi W et al (2009) Multiple roles of the p75 neurotrophin receptor in the nervous system. J Int Med Res 37(2):281–288
Hempstead BL (2002) The many faces of p75NTR. Curr Opin Neurobiol 12(3):260–267
Brito V, Puigdellivol M, Giralt A, del Toro D, Alberch J, Gines S (2013) Imbalance of p75(NTR)/TrkB protein expression in Huntington’s disease: implication for neuroprotective therapies. Cell Death Dis 4:e595. doi:10.1038/cddis.2013.116
Hu Y, Lee X, Shao Z, Apicco D, Huang G, Gong BJ, Pepinsky RB, Mi S (2013) A DR6/p75(NTR) complex is responsible for beta-amyloid-induced cortical neuron death. Cell Death Dis 4:e579. doi:10.1038/cddis.2013.110
Blochl A, Blumenstein L, Ahmadian MR (2004) Inactivation and activation of Ras by the neurotrophin receptor p75. Eur J Neurosci 20(9):2321–2335. doi:10.1111/j.1460-9568.2004.03692.x
Song MS, Posse de Chaves EI (2003) Inhibition of rat sympathetic neuron apoptosis by ceramide. Role of p75NTR in ceramide generation. Neuropharmacology 45(8):1130–1150
Xue L, Murray JH, Tolkovsky AM (2000) The Ras/phosphatidylinositol 3-kinase and Ras/ERK pathways function as independent survival modules each of which inhibits a distinct apoptotic signaling pathway in sympathetic neurons. J Biol Chem 275(12):8817–8824
Roux PP, Bhakar AL, Kennedy TE, Barker PA (2001) The p75 neurotrophin receptor activates Akt (protein kinase B) through a phosphatidylinositol 3-kinase-dependent pathway. J Biol Chem 276(25):23097–23104. doi:10.1074/jbc.M011520200
Yeiser EC, Rutkoski NJ, Naito A, Inoue J, Carter BD (2004) Neurotrophin signaling through the p75 receptor is deficient in traf6−/− mice. J Neurosci Off J Soc Neurosci 24(46):10521–10529. doi:10.1523/JNEUROSCI.1390-04.2004
Harrington AW, Kim JY, Yoon SO (2002) Activation of Rac GTPase by p75 is necessary for c-jun N-terminal kinase-mediated apoptosis. J Neurosci Off J Soc Neurosci 22(1):156–166
Carter BD, Kaltschmidt C, Kaltschmidt B, Offenhauser N, Bohm-Matthaei R, Baeuerle PA, Barde YA (1996) Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science 272(5261):542–545
Cosgaya JM, Chan JR, Shooter EM (2002) The neurotrophin receptor p75NTR as a positive modulator of myelination. Science 298(5596):1245–1248. doi:10.1126/science.1076595
Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao MV, Jaenisch R (1992) Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69(5):737–749
Uesugi N, Kimura Y, Yamashita T (2013) Suppression of the p75 receptor signal attenuates the effect of ephrin-B3 and promotes axonal regeneration of the injured optic nerve. Cell Death Dis 4:e557. doi:10.1038/cddis.2013.83
Kosik KS (2006) The neuronal microRNA system. Nat Rev Neurosci 7(12):911–920. doi:10.1038/nrn2037
Volvert ML, Rogister F, Moonen G, Malgrange B, Nguyen L (2012) MicroRNAs tune cerebral cortical neurogenesis. Cell Death Differ 19(10):1573–1581. doi:10.1038/cdd.2012.96
Wei JS, Song YK, Durinck S, Chen QR, Cheuk AT, Tsang P, Zhang Q, Thiele CJ et al (2008) The MYCN oncogene is a direct target of miR-34a. Oncogene 27(39):5204–5213. doi:10.1038/onc.2008.154
Velletri T, Romeo F, Tucci P, Peschiaroli A, Annicchiarico-Petruzzelli M, Niklison-Chirou MV, Amelio I, Knight RA, Mak TW, Melino G, Agostini M (2013) GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation. Cell Cycle 12(22)
De Strooper B (2010) Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol Rev 90(2):465–494. doi:10.1152/physrev.00023.2009
Palavicini JP, Wang H, Bianchi E, Xu S, Rao JS, Kang DE, Lakshmana MK (2013) RanBP9 aggravates synaptic damage in the mouse brain and is inversely correlated to spinophilin levels in Alzheimer’s brain synaptosomes. Cell Death Dis 4:e667. doi:10.1038/cddis.2013.183
Grolla AA, Sim JA, Lim D, Rodriguez JJ, Genazzani AA, Verkhratsky A (2013) Amyloid-beta and Alzheimer’s disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions. Cell Death Dis 4:e623. doi:10.1038/cddis.2013.145
Ittner LM, Gotz J (2011) Amyloid-beta and tau—a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 12(2):65–72. doi:10.1038/nrn2967
Herrup K (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18(6):794–799. doi:10.1038/nn.4017
Musiek ES, Holtzman DM (2015) Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat Neurosci 18(6):800–806. doi:10.1038/nn.4018
Crews L, Masliah E (2010) Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet 19(R1):R12–R20. doi:10.1093/hmg/ddq160
Carrillo-Mora P, Luna R, Colin-Barenque L (2014) Amyloid beta: multiple mechanisms of toxicity and only some protective effects? Oxidative Med Cell Longev 2014:795375. doi:10.1155/2014/795375
Kitamura Y, Shimohama S, Kamoshima W, Matsuoka Y, Nomura Y, Taniguchi T (1997) Changes of p53 in the brains of patients with Alzheimer’s disease. Biochem Biophys Res Commun 232(2):418–421. doi:10.1006/bbrc.1997.6301
Xu X, Yang D, Wyss-Coray T, Yan J, Gan L, Sun Y, Mucke L (1999) Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc Natl Acad Sci U S A 96(13):7547–7552
Cuesta A, Zambrano A, Royo M, Pascual A (2009) The tumour suppressor p53 regulates the expression of amyloid precursor protein (APP). Biochem J 418(3):643–650. doi:10.1042/BJ20081793
Checler F, Dunys J, Pardossi-Piquard R, Alves da Costa C (2010) p53 is regulated by and regulates members of the gamma-secretase complex. Neurodegener Dis 7(1–3):50–55. doi:10.1159/000283483
Kiko T, Nakagawa K, Tsuduki T, Furukawa K, Arai H, Miyazawa T (2014) MicroRNAs in plasma and cerebrospinal fluid as potential markers for Alzheimer’s disease. J Alzheimer’s Dis JAD 39(2):253–259. doi:10.3233/JAD-130932
Dickson JR, Kruse C, Montagna DR, Finsen B, Wolfe MS (2013) Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem 127(6):739–749. doi:10.1111/jnc.12437
Wang X, Liu P, Zhu H, Xu Y, Ma C, Dai X, Huang L, Liu Y et al (2009) miR-34a, a microRNA up-regulated in a double transgenic mouse model of Alzheimer’s disease, inhibits bcl2 translation. Brain Res Bull 80(4–5):268–273. doi:10.1016/j.brainresbull.2009.08.006
Wilson C, Henry S, Smith MA, Bowser R (2004) The p53 homologue p73 accumulates in the nucleus and localizes to neurites and neurofibrillary tangles in Alzheimer disease brain. Neuropathol Appl Neurobiol 30(1):19–29
Vardarajan B, Vergote D, Tissir F, Logue M, Yang J, Daude N, Ando K, Rogaeva E et al (2013) Role of p73 in Alzheimer disease: lack of association in mouse models or in human cohorts. Mol Neurodegener 8:10. doi:10.1186/1750-1326-8-10
Cancino GI, Miller FD, Kaplan DR (2013) p73 haploinsufficiency causes tau hyperphosphorylation and tau kinase dysregulation in mouse models of aging and Alzheimer’s disease. Neurobiol Aging 34(2):387–399. doi:10.1016/j.neurobiolaging.2012.04.010
Hooper C, Killick R, Tavassoli M, Melino G, Lovestone S (2006) TAp73alpha induces tau phosphorylation in HEK293a cells via a transcription-dependent mechanism. Neurosci Lett 401(1–2):30–34. doi:10.1016/j.neulet.2006.02.082
Plun-Favreau H, Lewis PA, Hardy J, Martins LM, Wood NW (2010) Cancer and neurodegeneration: between the devil and the deep blue sea. PLoS Genet 6(12):e1001257. doi:10.1371/journal.pgen.1001257
Acknowledgments
We thank Prof Eleonora Candi and Dr Ivano Amelio for scientific discussion. This work has been supported by the Medical Research Council, UK.
Conflict of Interest
The authors declare that they have no competing interests.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Niklison-Chirou, M.V., Killick, R., Knight, R.A. et al. How Does p73 Cause Neuronal Defects?. Mol Neurobiol 53, 4509–4520 (2016). https://doi.org/10.1007/s12035-015-9381-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-015-9381-1