• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of molcellbPermissionsJournals.ASM.orgJournalMCB ArticleJournal InfoAuthorsReviewers
Mol Cell Biol. Sep 1996; 16(9): 5178–5185.
PMCID: PMC231518

p53 plays a regulatory role in differentiation and apoptosis of central nervous system-associated cells.

Abstract

This study demonstrated the involvement of the tumor suppressor protein p53 in differentiation and programmed cell death of neurons and oligodendrocytes, two cell types that leave the mitotic cycle early in development and undergo massive-scale cell death as the nervous system matures. We found that primary cultures of rat oligodendrocytes and neurons, as well as of the neuronal PC12 pheochromocytoma cell line, constitutively express the p53 protein. At critical points in the maturation of these cells in vitro, the subcellular localization of p53 changes: during differentiation it appears mainly in the nucleus, whereas in mature differentiated cells it is present mainly in the cytoplasm. These subcellular changes were correlated with changes in levels of immunoprecipitated p53. Infection of cells with a recombinant retrovirus encoding a C-terminal p53 miniprotein (p53 DD), previously shown to act as a dominant negative inhibitor of endogenous wild-type p53 activity, inhibited the differentiation of oligodendrocytes and of PC12 cells and protected neurons from spontaneous apoptotic death. These findings suggest that p53, upon receiving appropriate signals, is recruited into the nucleus, where it plays a regulatory role in directing primary neurons', oligodendrocytes, and PC12 cells toward either differentiation or apoptosis in vitro.

Full Text

The Full Text of this article is available as a PDF (900K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Allcutt D, Berry M, Sievers J. A qualitative comparison of the reactions of retinal ganglion cell axons to optic nerve crush in neonatal and adult mice. Brain Res. 1984 Nov;318(2):231–240. [PubMed]
  • Arakawa Y, Sendtner M, Thoenen H. Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines. J Neurosci. 1990 Nov;10(11):3507–3515. [PubMed]
  • Armstrong JF, Kaufman MH, Harrison DJ, Clarke AR. High-frequency developmental abnormalities in p53-deficient mice. Curr Biol. 1995 Aug 1;5(8):931–936. [PubMed]
  • Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science. 1990 Aug 24;249(4971):912–915. [PubMed]
  • Barres BA, Hart IK, Coles HS, Burne JF, Voyvodic JT, Richardson WD, Raff MC. Cell death and control of cell survival in the oligodendrocyte lineage. Cell. 1992 Jul 10;70(1):31–46. [PubMed]
  • Barres BA, Raff MC, Gaese F, Bartke I, Dechant G, Barde YA. A crucial role for neurotrophin-3 in oligodendrocyte development. Nature. 1994 Jan 27;367(6461):371–375. [PubMed]
  • Barres BA, Schmid R, Sendnter M, Raff MC. Multiple extracellular signals are required for long-term oligodendrocyte survival. Development. 1993 May;118(1):283–295. [PubMed]
  • Bottenstein JE, Sato GH. Growth of a rat neuroblastoma cell line in serum-free supplemented medium. Proc Natl Acad Sci U S A. 1979 Jan;76(1):514–517. [PMC free article] [PubMed]
  • Buchman VL, Davies AM. Different neurotrophins are expressed and act in a developmental sequence to promote the survival of embryonic sensory neurons. Development. 1993 Jul;118(3):989–1001. [PubMed]
  • Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature. 1994 Jul 21;370(6486):220–223. [PubMed]
  • Chen PL, Chen YM, Bookstein R, Lee WH. Genetic mechanisms of tumor suppression by the human p53 gene. Science. 1990 Dec 14;250(4987):1576–1580. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Cowan WM, Fawcett JW, O'Leary DD, Stanfield BB. Regressive events in neurogenesis. Science. 1984 Sep 21;225(4668):1258–1265. [PubMed]
  • Diller L, Kassel J, Nelson CE, Gryka MA, Litwak G, Gebhardt M, Bressac B, Ozturk M, Baker SJ, Vogelstein B, et al. p53 functions as a cell cycle control protein in osteosarcomas. Mol Cell Biol. 1990 Nov;10(11):5772–5781. [PMC free article] [PubMed]
  • Donehower LA, Bradley A. The tumor suppressor p53. Biochim Biophys Acta. 1993 Aug 23;1155(2):181–205. [PubMed]
  • Dugaiczyk A, Haron JA, Stone EM, Dennison OE, Rothblum KN, Schwartz RJ. Cloning and sequencing of a deoxyribonucleic acid copy of glyceraldehyde-3-phosphate dehydrogenase messenger ribonucleic acid isolated from chicken muscle. Biochemistry. 1983 Mar 29;22(7):1605–1613. [PubMed]
  • Duguid JR, Bohmont CW, Liu NG, Tourtellotte WW. Changes in brain gene expression shared by scrapie and Alzheimer disease. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7260–7264. [PMC free article] [PubMed]
  • Eizenberg O, Faber-Elman A, Gottlieb E, Oren M, Rotter V, Schwartz M. Direct involvement of p53 in programmed cell death of oligodendrocytes. EMBO J. 1995 Mar 15;14(6):1136–1144. [PMC free article] [PubMed]
  • Feinberg AP, Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. [PubMed]
  • Feinstein E, Gale RP, Reed J, Canaani E. Expression of the normal p53 gene induces differentiation of K562 cells. Oncogene. 1992 Sep;7(9):1853–1857. [PubMed]
  • Ferrer I, Tortosa A, Condom E, Blanco R, Macaya A, Planas A. Increased expression of bcl-2 immunoreactivity in the developing cerebral cortex of the rat. Neurosci Lett. 1994 Sep 26;179(1-2):13–16. [PubMed]
  • Gannon JV, Lane DP. Protein synthesis required to anchor a mutant p53 protein which is temperature-sensitive for nuclear transport. Nature. 1991 Feb 28;349(6312):802–806. [PubMed]
  • Garcia-Valenzuela E, Gorczyca W, Darzynkiewicz Z, Sharma SC. Apoptosis in adult retinal ganglion cells after axotomy. J Neurobiol. 1994 Apr;25(4):431–438. [PubMed]
  • Ginsberg D, Michael-Michalovitz D, Ginsberg D, Oren M. Induction of growth arrest by a temperature-sensitive p53 mutant is correlated with increased nuclear localization and decreased stability of the protein. Mol Cell Biol. 1991 Jan;11(1):582–585. [PMC free article] [PubMed]
  • Gottlieb E, Haffner R, von Rüden T, Wagner EF, Oren M. Down-regulation of wild-type p53 activity interferes with apoptosis of IL-3-dependent hematopoietic cells following IL-3 withdrawal. EMBO J. 1994 Mar 15;13(6):1368–1374. [PMC free article] [PubMed]
  • Grafstein B, Ingoglia NA. Intracranial transection of the optic nerve in adult mice: preliminary observations. Exp Neurol. 1982 May;76(2):318–330. [PubMed]
  • Harlow E, Crawford LV, Pim DC, Williamson NM. Monoclonal antibodies specific for simian virus 40 tumor antigens. J Virol. 1981 Sep;39(3):861–869. [PMC free article] [PubMed]
  • Hartwell L. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell. 1992 Nov 13;71(4):543–546. [PubMed]
  • Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science. 1989 Nov 3;246(4930):629–634. [PubMed]
  • Haupt Y, Rowan S, Shaulian E, Vousden KH, Oren M. Induction of apoptosis in HeLa cells by trans-activation-deficient p53. Genes Dev. 1995 Sep 1;9(17):2170–2183. [PubMed]
  • Johnson GD, Davidson RS, McNamee KC, Russell G, Goodwin D, Holborow EJ. Fading of immunofluorescence during microscopy: a study of the phenomenon and its remedy. J Immunol Methods. 1982 Dec 17;55(2):231–242. [PubMed]
  • Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, Valentine JS, Ord T, Bredesen DE. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993 Nov 19;262(5137):1274–1277. [PubMed]
  • Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991 Dec 1;51(23 Pt 1):6304–6311. [PubMed]
  • Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol. 1993 Dec;4(6):327–332. [PubMed]
  • Krajewski S, Mai JK, Krajewska M, Sikorska M, Mossakowski MJ, Reed JC. Upregulation of bax protein levels in neurons following cerebral ischemia. J Neurosci. 1995 Oct;15(10):6364–6376. [PubMed]
  • Lane DP. Worrying about p53. Curr Biol. 1992 Nov;2(11):581–583. [PubMed]
  • Lehrach H, Diamond D, Wozney JM, Boedtker H. RNA molecular weight determinations by gel electrophoresis under denaturing conditions, a critical reexamination. Biochemistry. 1977 Oct 18;16(21):4743–4751. [PubMed]
  • Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992 Sep 18;70(6):923–935. [PubMed]
  • Louis JC, Magal E, Takayama S, Varon S. CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science. 1993 Jan 29;259(5095):689–692. [PubMed]
  • Mah SP, Zhong LT, Liu Y, Roghani A, Edwards RH, Bredesen DE. The protooncogene bcl-2 inhibits apoptosis in PC12 cells. J Neurochem. 1993 Mar;60(3):1183–1186. [PubMed]
  • Maltzman W, Oren M, Levine AJ. The structural relationships between 54,000-molecular-weight cellular tumor antigens detected in viral- and nonviral-transformed cells. Virology. 1981 Jul 15;112(1):145–156. [PubMed]
  • Martinez J, Georgoff I, Martinez J, Levine AJ. Cellular localization and cell cycle regulation by a temperature-sensitive p53 protein. Genes Dev. 1991 Feb;5(2):151–159. [PubMed]
  • McCarthy KD, de Vellis J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol. 1980 Jun;85(3):890–902. [PMC free article] [PubMed]
  • McKinnon RD, Matsui T, Dubois-Dalcq M, Aaronson SA. FGF modulates the PDGF-driven pathway of oligodendrocyte development. Neuron. 1990 Nov;5(5):603–614. [PubMed]
  • Mercer WE, Amin M, Sauve GJ, Appella E, Ullrich SJ, Romano JW. Wild type human p53 is antiproliferative in SV40-transformed hamster cells. Oncogene. 1990 Jul;5(7):973–980. [PubMed]
  • Mercer WE, Shields MT, Amin M, Sauve GJ, Appella E, Romano JW, Ullrich SJ. Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6166–6170. [PMC free article] [PubMed]
  • Merry DE, Veis DJ, Hickey WF, Korsmeyer SJ. bcl-2 protein expression is widespread in the developing nervous system and retained in the adult PNS. Development. 1994 Feb;120(2):301–311. [PubMed]
  • Michalovitz D, Halevy O, Oren M. Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell. 1990 Aug 24;62(4):671–680. [PubMed]
  • Misantone LJ, Gershenbaum M, Murray M. Viability of retinal ganglion cells after optic nerve crush in adult rats. J Neurocytol. 1984 Jun;13(3):449–465. [PubMed]
  • Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994 Jun;9(6):1799–1805. [PubMed]
  • Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995 Jan 27;80(2):293–299. [PubMed]
  • Moll UM, LaQuaglia M, Bénard J, Riou G. Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4407–4411. [PMC free article] [PubMed]
  • Moll UM, Riou G, Levine AJ. Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7262–7266. [PMC free article] [PubMed]
  • Noble M, Murray K, Stroobant P, Waterfield MD, Riddle P. Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature. 1988 Jun 9;333(6173):560–562. [PubMed]
  • Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. [PubMed]
  • Oppenheim RW. Cell death during development of the nervous system. Annu Rev Neurosci. 1991;14:453–501. [PubMed]
  • Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995 Apr;36(5):774–786. [PubMed]
  • Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival: lessons from the nervous system. Science. 1993 Oct 29;262(5134):695–700. [PubMed]
  • Raff MC, Miller RH, Noble M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature. 1983 Jun 2;303(5916):390–396. [PubMed]
  • Reed M, Wang Y, Mayr G, Anderson ME, Schwedes JF, Tegtmeyer P. p53 domains: suppression, transformation, and transactivation. Gene Expr. 1993;3(1):95–107. [PubMed]
  • Richardson WD, Pringle N, Mosley MJ, Westermark B, Dubois-Dalcq M. A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell. 1988 Apr 22;53(2):309–319. [PubMed]
  • Rodriguez M, Scheithauer BW, Forbes G, Kelly PJ. Oligodendrocyte injury is an early event in lesions of multiple sclerosis. Mayo Clin Proc. 1993 Jul;68(7):627–636. [PubMed]
  • Sah VP, Attardi LD, Mulligan GJ, Williams BO, Bronson RT, Jacks T. A subset of p53-deficient embryos exhibit exencephaly. Nat Genet. 1995 Jun;10(2):175–180. [PubMed]
  • Sakhi S, Bruce A, Sun N, Tocco G, Baudry M, Schreiber SS. p53 induction is associated with neuronal damage in the central nervous system. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7525–7529. [PMC free article] [PubMed]
  • Selvakumaran M, Lin HK, Miyashita T, Wang HG, Krajewski S, Reed JC, Hoffman B, Liebermann D. Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. Oncogene. 1994 Jun;9(6):1791–1798. [PubMed]
  • Shaulian E, Zauberman A, Ginsberg D, Oren M. Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding. Mol Cell Biol. 1992 Dec;12(12):5581–5592. [PMC free article] [PubMed]
  • Shaulsky G, Ben-Ze'ev A, Rotter V. Subcellular distribution of the p53 protein during the cell cycle of Balb/c 3T3 cells. Oncogene. 1990 Nov;5(11):1707–1711. [PubMed]
  • Shaulsky G, Goldfinger N, Ben-Ze'ev A, Rotter V. Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol Cell Biol. 1990 Dec;10(12):6565–6577. [PMC free article] [PubMed]
  • Shaulsky G, Goldfinger N, Peled A, Rotter V. Involvement of wild-type p53 in pre-B-cell differentiation in vitro. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8982–8986. [PMC free article] [PubMed]
  • Shaulsky G, Goldfinger N, Tosky MS, Levine AJ, Rotter V. Nuclear localization is essential for the activity of p53 protein. Oncogene. 1991 Nov;6(11):2055–2065. [PubMed]
  • Shaw P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J. Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4495–4499. [PMC free article] [PubMed]
  • Temple S, Raff MC. Clonal analysis of oligodendrocyte development in culture: evidence for a developmental clock that counts cell divisions. Cell. 1986 Mar 14;44(5):773–779. [PubMed]
  • Vantini G, Skaper SD. Neurotrophic factors: from physiology to pharmacology? Pharmacol Res. 1992 Jul-Aug;26(1):1–15. [PubMed]
  • Wagner AJ, Kokontis JM, Hay N. Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes Dev. 1994 Dec 1;8(23):2817–2830. [PubMed]
  • Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature. 1991 Jul 25;352(6333):345–347. [PubMed]
  • Zhong LT, Sarafian T, Kane DJ, Charles AC, Mah SP, Edwards RH, Bredesen DE. bcl-2 inhibits death of central neural cells induced by multiple agents. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4533–4537. [PMC free article] [PubMed]

Articles from Molecular and Cellular Biology are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...