• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Oct 1, 1993; 90(19): 9075–9079.
PMCID: PMC47504

Mice with reduced levels of p53 protein exhibit the testicular giant-cell degenerative syndrome.

Abstract

Transgenic mice which carry hybrid p53 promoter-chloramphenicol acetyltransferase (CAT) transgenes were found to express CAT enzymatic activity predominantly in the testes. Endogenous levels of p53 mRNA and protein were lower than in the nontransgenic control mice. The various p53 promoter-CAT transgenic mice exhibited in their testes multinucleated giant cells, a degenerative syndrome resulting presumably from the inability of the tetraploid primary spermatocytes to complete meiotic division. The giant-cell degenerative syndrome was also observed in some genetic strains of homozygous p53 null mice. In view of the hypothesis that p53 plays a role in DNA repair mechanisms, it is tempting to speculate that the physiological function of p53 that is specifically expressed in the meiotic pachytene phase of spermatogenesis is to allow adequate time for the DNA reshuffling and repair events which occur at this phase to be properly completed. Primary spermatocytes which have reduced p53 levels are probably impaired with respect to DNA repair, thus leading to the development of genetically defective giant cells that do not mature.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.8M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Lane DP, Benchimol S. p53: oncogene or anti-oncogene? Genes Dev. 1990 Jan;4(1):1–8. [PubMed]
  • Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. [PubMed]
  • Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. [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]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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, Rotter V. Alterations in tumor development in vivo mediated by expression of wild type or mutant p53 proteins. Cancer Res. 1991 Oct 1;51(19):5232–5237. [PubMed]
  • Kastan MB, Radin AI, Kuerbitz SJ, Onyekwere O, Wolkow CA, Civin CI, Stone KD, Woo T, Ravindranath Y, Craig RW. Levels of p53 protein increase with maturation in human hematopoietic cells. Cancer Res. 1991 Aug 15;51(16):4279–4286. [PubMed]
  • Rotter V, Boss MA, Baltimore D. Increased concentration of an apparently identical cellular protein in cells transformed by either Abelson murine leukemia virus or other transforming agents. J Virol. 1981 Apr;38(1):336–346. [PMC free article] [PubMed]
  • Rogel A, Popliker M, Webb CG, Oren M. p53 cellular tumor antigen: analysis of mRNA levels in normal adult tissues, embryos, and tumors. Mol Cell Biol. 1985 Oct;5(10):2851–2855. [PMC free article] [PubMed]
  • Mora PT, Chandrasekaran K, McFarland VW. An embryo protein induced by SV40 virus transformation of mouse cells. Nature. 1980 Dec 25;288(5792):722–724. [PubMed]
  • Schmid P, Lorenz A, Hameister H, Montenarh M. Expression of p53 during mouse embryogenesis. Development. 1991 Nov;113(3):857–865. [PubMed]
  • Almon E, Goldfinger N, Kapon A, Schwartz D, Levine AJ, Rotter V. Testicular tissue-specific expression of the p53 suppressor gene. Dev Biol. 1993 Mar;156(1):107–116. [PubMed]
  • Schwartz D, Goldfinger N, Rotter V. Expression of p53 protein in spermatogenesis is confined to the tetraploid pachytene primary spermatocytes. Oncogene. 1993 Jun;8(6):1487–1494. [PubMed]
  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Jr, Butel JS, Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. [PubMed]
  • Ronen D, Rotter V, Reisman D. Expression from the murine p53 promoter is mediated by factor binding to a downstream helix-loop-helix recognition motif. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4128–4132. [PMC free article] [PubMed]
  • Reisman D, Rotter V. Two promoters that map to 5'-sequences of the human p53 gene are differentially regulated during terminal differentiation of human myeloid leukemic cells. Oncogene. 1989 Aug;4(8):945–953. [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]
  • Flanagan PM, Kelleher RJ, 3rd, Sayre MH, Tschochner H, Kornberg RD. A mediator required for activation of RNA polymerase II transcription in vitro. Nature. 1991 Apr 4;350(6317):436–438. [PubMed]
  • Giot JF, Mikaelian I, Buisson M, Manet E, Joab I, Nicolas JC, Sergeant A. Transcriptional interference between the EBV transcription factors EB1 and R: both DNA-binding and activation domains of EB1 are required. Nucleic Acids Res. 1991 Mar 25;19(6):1251–1258. [PMC free article] [PubMed]
  • Wasylyk C, Schneikert J, Wasylyk B. Oncogene v-jun modulates DNA replication. Oncogene. 1990 Jul;5(7):1055–1058. [PubMed]
  • Xiao JH, Davidson I, Matthes H, Garnier JM, Chambon P. Cloning, expression, and transcriptional properties of the human enhancer factor TEF-1. Cell. 1991 May 17;65(4):551–568. [PubMed]
  • Joyner AL, Herrup K, Auerbach BA, Davis CA, Rossant J. Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox. Science. 1991 Mar 8;251(4998):1239–1243. [PubMed]
  • Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao MV, Jaenisch R. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell. 1992 May 29;69(5):737–749. [PubMed]
  • Rudnicki MA, Braun T, Hinuma S, Jaenisch R. Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development. Cell. 1992 Oct 30;71(3):383–390. [PubMed]
  • Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991 Feb 22;64(4):693–702. [PubMed]
  • Braithwaite AW, Sturzbecher HW, Addison C, Palmer C, Rudge K, Jenkins JR. Mouse p53 inhibits SV40 origin-dependent DNA replication. Nature. 1987 Oct 1;329(6138):458–460. [PubMed]
  • Gannon JV, Lane DP. p53 and DNA polymerase alpha compete for binding to SV40 T antigen. Nature. 1987 Oct 1;329(6138):456–458. [PubMed]
  • Wang EH, Friedman PN, Prives C. The murine p53 protein blocks replication of SV40 DNA in vitro by inhibiting the initiation functions of SV40 large T antigen. Cell. 1989 May 5;57(3):379–392. [PubMed]
  • Overbeek PA, Chepelinsky AB, Khillan JS, Piatigorsky J, Westphal H. Lens-specific expression and developmental regulation of the bacterial chloramphenicol acetyltransferase gene driven by the murine alpha A-crystallin promoter in transgenic mice. Proc Natl Acad Sci U S A. 1985 Dec;82(23):7815–7819. [PMC free article] [PubMed]
  • Erickson RP, Bevilacqua A, Venta PJ, Karolyi J, Tashian RE. Ectopic expression of chloramphenicol acetyltransferase (CAT) in the cerebellum in mice transgenic for a carbonic anhydrase II promoter-CAT construct that is without apparent phenotypic effect. Mol Reprod Dev. 1990 Oct;27(2):102–109. [PubMed]
  • Grosschedl R, Weaver D, Baltimore D, Costantini F. Introduction of a mu immunoglobulin gene into the mouse germ line: specific expression in lymphoid cells and synthesis of functional antibody. Cell. 1984 Oct;38(3):647–658. [PubMed]
  • Maltzman W, Czyzyk L. UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol Cell Biol. 1984 Sep;4(9):1689–1694. [PMC free article] [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]
  • Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7491–7495. [PMC free article] [PubMed]
  • Lane DP. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. [PubMed]
  • Stubbs L, Stern H. DNA synthesis at selective sites during pachytene in mouse spermatocytes. Chromosoma. 1986;93(6):529–536. [PubMed]
  • Alcivar AA, Hake LE, Hecht NB. DNA polymerase-beta and poly(ADP)ribose polymerase mRNAs are differentially expressed during the development of male germinal cells. Biol Reprod. 1992 Feb;46(2):201–207. [PubMed]
  • Coogan TP, Rosenblum IY. DNA double-strand damage and repair following gamma-irradiation in isolated spermatogenic cells. Mutat Res. 1988 Nov;194(3):183–191. [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]
  • Friedberg EC. Yeast genes involved in DNA-repair processes: new looks on old faces. Mol Microbiol. 1991 Oct;5(10):2303–2310. [PubMed]
  • Thompson LH. Properties and applications of human DNA repair genes. Mutat Res. 1991 Apr;247(2):213–219. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...