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. 1996 Apr 16;93(8):3215–3220. doi: 10.1073/pnas.93.8.3215

A unique role for the Rb protein in controlling E2F accumulation during cell growth and differentiation.

M A Ikeda 1, L Jakoi 1, J R Nevins 1
PMCID: PMC39585  PMID: 8622916

Abstract

Examination of the interactions involving transcription factor E2F activity during cell growth and terminal differentiation suggests distinct roles for Rb family members in the regulation of E2F accumulation. The major species of E2F in quiescent cells is a complex containing the E2F4 product in association with the Rb-related p130 protein. As cells enter the cell cycle, this complex disappears, and there is a concomitant accumulation of free E2F activity of which E2F4 is a major component. E2F4 then associates with the Rb-related p107 protein as cells enter S phase. Rb can be found in interactions with each E2F species, including E2F4, during G1, but there appears to be a limited amount of Rb with respect to E2F, likely due to the maintenance of most Rb protein in an inactive state by phosphorylation. A contrasting circumstance can be found during the induction of HL60 cell differentiation. As these cells exit the cell cycle, active Rb protein appears to exceed E2F, as there is a marked accumulation of E2F-Rb interactions, involving all E2F species, including E2F4, which is paralleled by the conversion of Rb from a hyperphosphorylated state to a hypophosphorylated state. These results suggest that the specific ability of Rb protein to interact with each E2F species, dependent on concentration of active Rb relative to accumulation of E2F, may be critical in cell-growth decisions.

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Selected References

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

  1. Bandara L. R., Lam E. W., Sørensen T. S., Zamanian M., Girling R., La Thangue N. B. DP-1: a cell cycle-regulated and phosphorylated component of transcription factor DRTF1/E2F which is functionally important for recognition by pRb and the adenovirus E4 orf 6/7 protein. EMBO J. 1994 Jul 1;13(13):3104–3114. doi: 10.1002/j.1460-2075.1994.tb06609.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beijersbergen R. L., Kerkhoven R. M., Zhu L., Carlée L., Voorhoeve P. M., Bernards R. E2F-4, a new member of the E2F gene family, has oncogenic activity and associates with p107 in vivo. Genes Dev. 1994 Nov 15;8(22):2680–2690. doi: 10.1101/gad.8.22.2680. [DOI] [PubMed] [Google Scholar]
  3. Blake M. C., Azizkhan J. C. Transcription factor E2F is required for efficient expression of the hamster dihydrofolate reductase gene in vitro and in vivo. Mol Cell Biol. 1989 Nov;9(11):4994–5002. doi: 10.1128/mcb.9.11.4994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cao L., Faha B., Dembski M., Tsai L. H., Harlow E., Dyson N. Independent binding of the retinoblastoma protein and p107 to the transcription factor E2F. Nature. 1992 Jan 9;355(6356):176–179. doi: 10.1038/355176a0. [DOI] [PubMed] [Google Scholar]
  5. Chen P. L., Scully P., Shew J. Y., Wang J. Y., Lee W. H. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell. 1989 Sep 22;58(6):1193–1198. doi: 10.1016/0092-8674(89)90517-5. [DOI] [PubMed] [Google Scholar]
  6. Cobrinik D., Whyte P., Peeper D. S., Jacks T., Weinberg R. A. Cell cycle-specific association of E2F with the p130 E1A-binding protein. Genes Dev. 1993 Dec;7(12A):2392–2404. doi: 10.1101/gad.7.12a.2392. [DOI] [PubMed] [Google Scholar]
  7. Devoto S. H., Mudryj M., Pines J., Hunter T., Nevins J. R. A cyclin A-protein kinase complex possesses sequence-specific DNA binding activity: p33cdk2 is a component of the E2F-cyclin A complex. Cell. 1992 Jan 10;68(1):167–176. doi: 10.1016/0092-8674(92)90215-x. [DOI] [PubMed] [Google Scholar]
  8. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dyson N., Dembski M., Fattaey A., Ngwu C., Ewen M., Helin K. Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1. J Virol. 1993 Dec;67(12):7641–7647. doi: 10.1128/jvi.67.12.7641-7647.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ewen M. E., Xing Y. G., Lawrence J. B., Livingston D. M. Molecular cloning, chromosomal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein. Cell. 1991 Sep 20;66(6):1155–1164. doi: 10.1016/0092-8674(91)90038-z. [DOI] [PubMed] [Google Scholar]
  11. Ginsberg D., Vairo G., Chittenden T., Xiao Z. X., Xu G., Wydner K. L., DeCaprio J. A., Lawrence J. B., Livingston D. M. E2F-4, a new member of the E2F transcription factor family, interacts with p107. Genes Dev. 1994 Nov 15;8(22):2665–2679. doi: 10.1101/gad.8.22.2665. [DOI] [PubMed] [Google Scholar]
  12. Hannon G. J., Demetrick D., Beach D. Isolation of the Rb-related p130 through its interaction with CDK2 and cyclins. Genes Dev. 1993 Dec;7(12A):2378–2391. doi: 10.1101/gad.7.12a.2378. [DOI] [PubMed] [Google Scholar]
  13. Helin K., Ed H. The retinoblastoma protein as a transcriptional repressor. Trends Cell Biol. 1993 Feb;3(2):43–46. doi: 10.1016/0962-8924(93)90150-y. [DOI] [PubMed] [Google Scholar]
  14. Hiebert S. W., Chellappan S. P., Horowitz J. M., Nevins J. R. The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F. Genes Dev. 1992 Feb;6(2):177–185. doi: 10.1101/gad.6.2.177. [DOI] [PubMed] [Google Scholar]
  15. Hiebert S. W. Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression. Mol Cell Biol. 1993 Jun;13(6):3384–3391. doi: 10.1128/mcb.13.6.3384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ikeda M. A., Nevins J. R. Identification of distinct roles for separate E1A domains in disruption of E2F complexes. Mol Cell Biol. 1993 Nov;13(11):7029–7035. doi: 10.1128/mcb.13.11.7029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ivey-Hoyle M., Conroy R., Huber H. E., Goodhart P. J., Oliff A., Heimbrook D. C. Cloning and characterization of E2F-2, a novel protein with the biochemical properties of transcription factor E2F. Mol Cell Biol. 1993 Dec;13(12):7802–7812. doi: 10.1128/mcb.13.12.7802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. La Thangue N. B. DRTF1/E2F: an expanding family of heterodimeric transcription factors implicated in cell-cycle control. Trends Biochem Sci. 1994 Mar;19(3):108–114. doi: 10.1016/0968-0004(94)90202-x. [DOI] [PubMed] [Google Scholar]
  19. Lees J. A., Saito M., Vidal M., Valentine M., Look T., Harlow E., Dyson N., Helin K. The retinoblastoma protein binds to a family of E2F transcription factors. Mol Cell Biol. 1993 Dec;13(12):7813–7825. doi: 10.1128/mcb.13.12.7813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Li Y., Graham C., Lacy S., Duncan A. M., Whyte P. The adenovirus E1A-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. Genes Dev. 1993 Dec;7(12A):2366–2377. doi: 10.1101/gad.7.12a.2366. [DOI] [PubMed] [Google Scholar]
  21. Lukas J., Bartkova J., Rohde M., Strauss M., Bartek J. Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity. Mol Cell Biol. 1995 May;15(5):2600–2611. doi: 10.1128/mcb.15.5.2600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mayol X., Graña X., Baldi A., Sang N., Hu Q., Giordano A. Cloning of a new member of the retinoblastoma gene family (pRb2) which binds to the E1A transforming domain. Oncogene. 1993 Sep;8(9):2561–2566. [PubMed] [Google Scholar]
  23. Mudryj M., Devoto S. H., Hiebert S. W., Hunter T., Pines J., Nevins J. R. Cell cycle regulation of the E2F transcription factor involves an interaction with cyclin A. Cell. 1991 Jun 28;65(7):1243–1253. doi: 10.1016/0092-8674(91)90019-u. [DOI] [PubMed] [Google Scholar]
  24. Nevins J. R. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science. 1992 Oct 16;258(5081):424–429. doi: 10.1126/science.1411535. [DOI] [PubMed] [Google Scholar]
  25. Qian Y., Luckey C., Horton L., Esser M., Templeton D. J. Biological function of the retinoblastoma protein requires distinct domains for hyperphosphorylation and transcription factor binding. Mol Cell Biol. 1992 Dec;12(12):5363–5372. doi: 10.1128/mcb.12.12.5363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Qin X. Q., Chittenden T., Livingston D. M., Kaelin W. G., Jr Identification of a growth suppression domain within the retinoblastoma gene product. Genes Dev. 1992 Jun;6(6):953–964. doi: 10.1101/gad.6.6.953. [DOI] [PubMed] [Google Scholar]
  27. Sardet C., Vidal M., Cobrinik D., Geng Y., Onufryk C., Chen A., Weinberg R. A. E2F-4 and E2F-5, two members of the E2F family, are expressed in the early phases of the cell cycle. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2403–2407. doi: 10.1073/pnas.92.6.2403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Shin E. K., Shin A., Paulding C., Schaffhausen B., Yee A. S. Multiple change in E2F function and regulation occur upon muscle differentiation. Mol Cell Biol. 1995 Apr;15(4):2252–2262. doi: 10.1128/mcb.15.4.2252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Vairo G., Livingston D. M., Ginsberg D. Functional interaction between E2F-4 and p130: evidence for distinct mechanisms underlying growth suppression by different retinoblastoma protein family members. Genes Dev. 1995 Apr 1;9(7):869–881. doi: 10.1101/gad.9.7.869. [DOI] [PubMed] [Google Scholar]
  30. Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]

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