Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Oct 1;89(19):9210–9214. doi: 10.1073/pnas.89.19.9210

Growth arrest induced by wild-type p53 protein blocks cells prior to or near the restriction point in late G1 phase.

D Lin 1, M T Shields 1, S J Ullrich 1, E Appella 1, W E Mercer 1
PMCID: PMC50095  PMID: 1409626

Abstract

Conditional expression of wild-type (wt) p53 protein in a glioblastoma tumor cell line has been shown to be growth inhibitory. We have now more precisely localized the position in the cell cycle where growth arrest occurs. We show that growth arrest occurs prior to or near the restriction point in late G1 phase of the cell cycle. The effect of wt p53 protein on the expression of four immediate-early genes (c-FOS, c-JUN, JUN-B, and c-MYC), one delayed-early gene (ornithine decarboxylase), and two late-G1/S-phase genes (B-MYB and DNA polymerase alpha) was also examined. Of this subset of growth response genes, only the expression of B-MYB and DNA polymerase alpha was significantly repressed. The possibility that decreased expression of B-MYB may be an important component of growth arrest mediated by wt p53 protein is discussed.

Full text

PDF
9214

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anfossi G., Gewirtz A. M., Calabretta B. An oligomer complementary to c-myb-encoded mRNA inhibits proliferation of human myeloid leukemia cell lines. Proc Natl Acad Sci U S A. 1989 May;86(9):3379–3383. doi: 10.1073/pnas.86.9.3379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ashihara T., Traganos F., Baserga R., Darzynkiewicz Z. A comparison of cell cycle-related changes in postmitotic and quiescent AF8 cells as measured by cytofluorometry after acridine orange staining. Cancer Res. 1978 Aug;38(8):2514–2518. [PubMed] [Google Scholar]
  3. Baker S. J., Markowitz S., Fearon E. R., Willson J. K., Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science. 1990 Aug 24;249(4971):912–915. doi: 10.1126/science.2144057. [DOI] [PubMed] [Google Scholar]
  4. Bohmann D., Bos T. J., Admon A., Nishimura T., Vogt P. K., Tjian R. Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science. 1987 Dec 4;238(4832):1386–1392. doi: 10.1126/science.2825349. [DOI] [PubMed] [Google Scholar]
  5. Calabretta B., Kaczmarek L., Selleri L., Torelli G., Ming P. M., Ming S. C., Mercer W. E. Growth-dependent expression of human Mr 53,000 tumor antigen messenger RNA in normal and neoplastic cells. Cancer Res. 1986 Nov;46(11):5738–5742. [PubMed] [Google Scholar]
  6. Calabretta B., Mercer W. E. TPA-induction of c-fos mRNA during the cell cycle of WI-38 human fibroblasts. Biochem Biophys Res Commun. 1987 Sep 15;147(2):716–723. doi: 10.1016/0006-291x(87)90989-2. [DOI] [PubMed] [Google Scholar]
  7. 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. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. Darzynkiewicz Z., Evenson D. P., Staiano-Coico L., Sharpless T. K., Melamed M. L. Correlation between cell cycle duration and RNA content. J Cell Physiol. 1979 Sep;100(3):425–438. doi: 10.1002/jcp.1041000306. [DOI] [PubMed] [Google Scholar]
  9. Denhardt D. T., Edwards D. R., Parfett C. L. Gene expression during the mammalian cell cycle. Biochim Biophys Acta. 1986 Oct 28;865(2):83–125. doi: 10.1016/0304-419x(86)90024-7. [DOI] [PubMed] [Google Scholar]
  10. Diller L., Kassel J., Nelson C. E., Gryka M. A., Litwak G., Gebhardt M., Bressac B., Ozturk M., Baker S. J., Vogelstein B. p53 functions as a cell cycle control protein in osteosarcomas. Mol Cell Biol. 1990 Nov;10(11):5772–5781. doi: 10.1128/mcb.10.11.5772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eliyahu D., Michalovitz D., Eliyahu S., Pinhasi-Kimhi O., Oren M. Wild-type p53 can inhibit oncogene-mediated focus formation. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8763–8767. doi: 10.1073/pnas.86.22.8763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  13. Finlay C. A., Hinds P. W., Levine A. J. The p53 proto-oncogene can act as a suppressor of transformation. Cell. 1989 Jun 30;57(7):1083–1093. doi: 10.1016/0092-8674(89)90045-7. [DOI] [PubMed] [Google Scholar]
  14. Gewirtz A. M., Anfossi G., Venturelli D., Valpreda S., Sims R., Calabretta B. G1/S transition in normal human T-lymphocytes requires the nuclear protein encoded by c-myb. Science. 1989 Jul 14;245(4914):180–183. doi: 10.1126/science.2665077. [DOI] [PubMed] [Google Scholar]
  15. Gewirtz A. M., Calabretta B. A c-myb antisense oligodeoxynucleotide inhibits normal human hematopoiesis in vitro. Science. 1988 Dec 2;242(4883):1303–1306. doi: 10.1126/science.2461588. [DOI] [PubMed] [Google Scholar]
  16. Ginsberg D., Mechta F., Yaniv M., Oren M. Wild-type p53 can down-modulate the activity of various promoters. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):9979–9983. doi: 10.1073/pnas.88.22.9979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jaskulski D., Gatti C., Travali S., Calabretta B., Baserga R. Regulation of the proliferating cell nuclear antigen cyclin and thymidine kinase mRNA levels by growth factors. J Biol Chem. 1988 Jul 25;263(21):10175–10179. [PubMed] [Google Scholar]
  18. Kaczmarek L., Calabretta B., Elfenbein I. B., Mercer W. E. Cell cycle analysis of human peripheral blood T lymphocytes in long-term culture. Exp Cell Res. 1987 Nov;173(1):70–79. doi: 10.1016/0014-4827(87)90332-6. [DOI] [PubMed] [Google Scholar]
  19. Kaczmarek L. Protooncogene expression during the cell cycle. Lab Invest. 1986 Apr;54(4):365–376. [PubMed] [Google Scholar]
  20. Liu H. T., Gibson C. W., Hirschhorn R. R., Rittling S., Baserga R., Mercer W. E. Expression of thymidine kinase and dihydrofolate reductase genes in mammalian ts mutants of the cell cycle. J Biol Chem. 1985 Mar 25;260(6):3269–3274. [PubMed] [Google Scholar]
  21. Mercer W. E., Amin M., Sauve G. J., Appella E., Ullrich S. J., Romano J. W. Wild type human p53 is antiproliferative in SV40-transformed hamster cells. Oncogene. 1990 Jul;5(7):973–980. [PubMed] [Google Scholar]
  22. Mercer W. E., Baserga R. Expression of the p53 protein during the cell cycle of human peripheral blood lymphocytes. Exp Cell Res. 1985 Sep;160(1):31–46. doi: 10.1016/0014-4827(85)90233-2. [DOI] [PubMed] [Google Scholar]
  23. Mercer W. E., Shields M. T., Amin M., Sauve G. J., Appella E., Romano J. W., Ullrich S. J. 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. doi: 10.1073/pnas.87.16.6166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mercer W. E., Shields M. T., Lin D., Appella E., Ullrich S. J. Growth suppression induced by wild-type p53 protein is accompanied by selective down-regulation of proliferating-cell nuclear antigen expression. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1958–1962. doi: 10.1073/pnas.88.5.1958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mizuguchi G., Nakagoshi H., Nagase T., Nomura N., Date T., Ueno Y., Ishii S. DNA binding activity and transcriptional activator function of the human B-myb protein compared with c-MYB. J Biol Chem. 1990 Jun 5;265(16):9280–9284. [PubMed] [Google Scholar]
  26. Nakagoshi H., Nagase T., Kanei-Ishii C., Ueno Y., Ishii S. Binding of the c-myb proto-oncogene product to the simian virus 40 enhancer stimulates transcription. J Biol Chem. 1990 Feb 25;265(6):3479–3483. [PubMed] [Google Scholar]
  27. Nomura N., Takahashi M., Matsui M., Ishii S., Date T., Sasamoto S., Ishizaki R. Isolation of human cDNA clones of myb-related genes, A-myb and B-myb. Nucleic Acids Res. 1988 Dec 9;16(23):11075–11089. doi: 10.1093/nar/16.23.11075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Pardee A. B. G1 events and regulation of cell proliferation. Science. 1989 Nov 3;246(4930):603–608. doi: 10.1126/science.2683075. [DOI] [PubMed] [Google Scholar]
  29. Pardee A. B. Molecules involved in proliferation of normal and cancer cells: presidential address. Cancer Res. 1987 Mar 15;47(6):1488–1491. [PubMed] [Google Scholar]
  30. Ryder K., Lau L. F., Nathans D. A gene activated by growth factors is related to the oncogene v-jun. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1487–1491. doi: 10.1073/pnas.85.5.1487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Santhanam U., Ray A., Sehgal P. B. Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7605–7609. doi: 10.1073/pnas.88.17.7605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Talavera A., Basilico C. Temperature sensitive mutants of BHK cells affected in cell cycle progression. J Cell Physiol. 1977 Sep;92(3):425–436. doi: 10.1002/jcp.1040920310. [DOI] [PubMed] [Google Scholar]
  33. Travali S., Ferber A., Reiss K., Sell C., Koniecki J., Calabretta B., Baserga R. Effect of the myb gene product on expression of the PCNA gene in fibroblasts. Oncogene. 1991 Jun;6(6):887–894. [PubMed] [Google Scholar]
  34. Ullrich S. J., Mercer W. E., Appella E. Human wild-type p53 adopts a unique conformational and phosphorylation state in vivo during growth arrest of glioblastoma cells. Oncogene. 1992 Aug;7(8):1635–1643. [PubMed] [Google Scholar]
  35. Venturelli D., Travali S., Calabretta B. Inhibition of T-cell proliferation by a MYB antisense oligomer is accompanied by selective down-regulation of DNA polymerase alpha expression. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5963–5967. doi: 10.1073/pnas.87.15.5963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Watt R., Stanton L. W., Marcu K. B., Gallo R. C., Croce C. M., Rovera G. Nucleotide sequence of cloned cDNA of human c-myc oncogene. Nature. 1983 Jun 23;303(5919):725–728. doi: 10.1038/303725a0. [DOI] [PubMed] [Google Scholar]
  37. Weinberg R. A. Tumor suppressor genes. Science. 1991 Nov 22;254(5035):1138–1146. doi: 10.1126/science.1659741. [DOI] [PubMed] [Google Scholar]
  38. Weston K., Bishop J. M. Transcriptional activation by the v-myb oncogene and its cellular progenitor, c-myb. Cell. 1989 Jul 14;58(1):85–93. doi: 10.1016/0092-8674(89)90405-4. [DOI] [PubMed] [Google Scholar]

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

RESOURCES