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. 1997 Jan;17(1):407–415. doi: 10.1128/mcb.17.1.407

p27KIP1 blocks cyclin E-dependent transactivation of cyclin A gene expression.

K Zerfass-Thome 1, A Schulze 1, W Zwerschke 1, B Vogt 1, K Helin 1, J Bartek 1, B Henglein 1, P Jansen-Dürr 1
PMCID: PMC231765  PMID: 8972221

Abstract

Cyclin E is necessary and rate limiting for the passage of mammalian cells through the G1 phase of the cell cycle. Control of cell cycle progression by cyclin E involves cdk2 kinase, which requires cyclin E for catalytic activity. Expression of cyclin E/cdk2 leads to an activation of cyclin A gene expression, as monitored by reporter gene constructs derived from the human cyclin A promoter. Promoter activation by cyclin E/cdk2 requires an E2F binding site in the cyclin A promoter. We show here that cyclin E/cdk2 kinase can directly bind to E2F/p107 complexes formed on the cyclin A promoter-derived E2F binding site, and this association is controlled by p27KIP1, most likely through direct protein-protein interaction. These observation suggest that cyclin E/cdk2 associates with E2F/p107 complexes in late G1 phase, once p27KIP1 has decreased below a critical threshold level. Since a kinase-negative mutant of cdk2 prevents promoter activation, it appears that transcriptional activation of the cyclin A gene requires an active cdk2 kinase tethered to its promoter region.

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Selected References

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  1. Beijersbergen R. L., Carlée L., Kerkhoven R. M., Bernards R. Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes. Genes Dev. 1995 Jun 1;9(11):1340–1353. doi: 10.1101/gad.9.11.1340. [DOI] [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. Burggraf S., Larsen N., Woese C. R., Stetter K. O. An intron within the 16S ribosomal RNA gene of the archaeon Pyrobaculum aerophilum. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2547–2550. doi: 10.1073/pnas.90.6.2547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bártek J., Stasková Z., Draetta G., Lukás J. Molecular pathology of the cell cycle in human cancer cells. Stem Cells. 1993 May;11 (Suppl 1):51–58. doi: 10.1002/stem.5530110611. [DOI] [PubMed] [Google Scholar]
  5. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cobrinik D., Lee M. H., Hannon G., Mulligan G., Bronson R. T., Dyson N., Harlow E., Beach D., Weinberg R. A., Jacks T. Shared role of the pRB-related p130 and p107 proteins in limb development. Genes Dev. 1996 Jul 1;10(13):1633–1644. doi: 10.1101/gad.10.13.1633. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Dulić V., Lees E., Reed S. I. Association of human cyclin E with a periodic G1-S phase protein kinase. Science. 1992 Sep 25;257(5078):1958–1961. doi: 10.1126/science.1329201. [DOI] [PubMed] [Google Scholar]
  9. Dynlacht B. D., Flores O., Lees J. A., Harlow E. Differential regulation of E2F transactivation by cyclin/cdk2 complexes. Genes Dev. 1994 Aug 1;8(15):1772–1786. doi: 10.1101/gad.8.15.1772. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Fagan R., Flint K. J., Jones N. Phosphorylation of E2F-1 modulates its interaction with the retinoblastoma gene product and the adenoviral E4 19 kDa protein. Cell. 1994 Sep 9;78(5):799–811. doi: 10.1016/s0092-8674(94)90522-3. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Girard F., Strausfeld U., Fernandez A., Lamb N. J. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell. 1991 Dec 20;67(6):1169–1179. doi: 10.1016/0092-8674(91)90293-8. [DOI] [PubMed] [Google Scholar]
  14. Girling R., Partridge J. F., Bandara L. R., Burden N., Totty N. F., Hsuan J. J., La Thangue N. B. A new component of the transcription factor DRTF1/E2F. Nature. 1993 Sep 30;365(6445):468–468. doi: 10.1038/365468d0. [DOI] [PubMed] [Google Scholar]
  15. Guadagno T. M., Ohtsubo M., Roberts J. M., Assoian R. K. A link between cyclin A expression and adhesion-dependent cell cycle progression. Science. 1993 Dec 3;262(5139):1572–1575. doi: 10.1126/science.8248807. [DOI] [PubMed] [Google Scholar]
  16. Guan K. L., Jenkins C. W., Li Y., Nichols M. A., Wu X., O'Keefe C. L., Matera A. G., Xiong Y. Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev. 1994 Dec 15;8(24):2939–2952. doi: 10.1101/gad.8.24.2939. [DOI] [PubMed] [Google Scholar]
  17. Helin K., Wu C. L., Fattaey A. R., Lees J. A., Dynlacht B. D., Ngwu C., Harlow E. Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation. Genes Dev. 1993 Oct;7(10):1850–1861. doi: 10.1101/gad.7.10.1850. [DOI] [PubMed] [Google Scholar]
  18. Hengst L., Reed S. I. Translational control of p27Kip1 accumulation during the cell cycle. Science. 1996 Mar 29;271(5257):1861–1864. doi: 10.1126/science.271.5257.1861. [DOI] [PubMed] [Google Scholar]
  19. Hofmann F., Livingston D. M. Differential effects of cdk2 and cdk3 on the control of pRb and E2F function during G1 exit. Genes Dev. 1996 Apr 1;10(7):851–861. doi: 10.1101/gad.10.7.851. [DOI] [PubMed] [Google Scholar]
  20. Hunter T., Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994 Nov 18;79(4):573–582. doi: 10.1016/0092-8674(94)90543-6. [DOI] [PubMed] [Google Scholar]
  21. Johnson D. G., Ohtani K., Nevins J. R. Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. Genes Dev. 1994 Jul 1;8(13):1514–1525. doi: 10.1101/gad.8.13.1514. [DOI] [PubMed] [Google Scholar]
  22. Kato J. Y., Matsuoka M., Polyak K., Massagué J., Sherr C. J. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell. 1994 Nov 4;79(3):487–496. doi: 10.1016/0092-8674(94)90257-7. [DOI] [PubMed] [Google Scholar]
  23. Knoblich J. A., Sauer K., Jones L., Richardson H., Saint R., Lehner C. F. Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation. Cell. 1994 Apr 8;77(1):107–120. doi: 10.1016/0092-8674(94)90239-9. [DOI] [PubMed] [Google Scholar]
  24. Koff A., Cross F., Fisher A., Schumacher J., Leguellec K., Philippe M., Roberts J. M. Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell. 1991 Sep 20;66(6):1217–1228. doi: 10.1016/0092-8674(91)90044-y. [DOI] [PubMed] [Google Scholar]
  25. Koff A., Giordano A., Desai D., Yamashita K., Harper J. W., Elledge S., Nishimoto T., Morgan D. O., Franza B. R., Roberts J. M. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science. 1992 Sep 18;257(5077):1689–1694. doi: 10.1126/science.1388288. [DOI] [PubMed] [Google Scholar]
  26. Krek W., Ewen M. E., Shirodkar S., Arany Z., Kaelin W. G., Jr, Livingston D. M. Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell. 1994 Jul 15;78(1):161–172. doi: 10.1016/0092-8674(94)90582-7. [DOI] [PubMed] [Google Scholar]
  27. Lees E., Faha B., Dulic V., Reed S. I., Harlow E. Cyclin E/cdk2 and cyclin A/cdk2 kinases associate with p107 and E2F in a temporally distinct manner. Genes Dev. 1992 Oct;6(10):1874–1885. doi: 10.1101/gad.6.10.1874. [DOI] [PubMed] [Google Scholar]
  28. Maller J. L. Mitotic control. Curr Opin Cell Biol. 1991 Apr;3(2):269–275. doi: 10.1016/0955-0674(91)90151-n. [DOI] [PubMed] [Google Scholar]
  29. Motokura T., Bloom T., Kim H. G., Jüppner H., Ruderman J. V., Kronenberg H. M., Arnold A. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 1991 Apr 11;350(6318):512–515. doi: 10.1038/350512a0. [DOI] [PubMed] [Google Scholar]
  30. Nakayama K., Ishida N., Shirane M., Inomata A., Inoue T., Shishido N., Horii I., Loh D. Y., Nakayama K. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 1996 May 31;85(5):707–720. doi: 10.1016/s0092-8674(00)81237-4. [DOI] [PubMed] [Google Scholar]
  31. Nourse J., Firpo E., Flanagan W. M., Coats S., Polyak K., Lee M. H., Massague J., Crabtree G. R., Roberts J. M. Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature. 1994 Dec 8;372(6506):570–573. doi: 10.1038/372570a0. [DOI] [PubMed] [Google Scholar]
  32. Ohtsubo M., Theodoras A. M., Schumacher J., Roberts J. M., Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol. 1995 May;15(5):2612–2624. doi: 10.1128/mcb.15.5.2612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Pagano M., Draetta G., Jansen-Dürr P. Association of cdk2 kinase with the transcription factor E2F during S phase. Science. 1992 Feb 28;255(5048):1144–1147. doi: 10.1126/science.1312258. [DOI] [PubMed] [Google Scholar]
  34. Pagano M., Pepperkok R., Verde F., Ansorge W., Draetta G. Cyclin A is required at two points in the human cell cycle. EMBO J. 1992 Mar;11(3):961–971. doi: 10.1002/j.1460-2075.1992.tb05135.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pagano M., Tam S. W., Theodoras A. M., Beer-Romero P., Del Sal G., Chau V., Yew P. R., Draetta G. F., Rolfe M. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995 Aug 4;269(5224):682–685. doi: 10.1126/science.7624798. [DOI] [PubMed] [Google Scholar]
  36. Pines J. Cyclins and cyclin-dependent kinases: take your partners. Trends Biochem Sci. 1993 Jun;18(6):195–197. doi: 10.1016/0968-0004(93)90185-p. [DOI] [PubMed] [Google Scholar]
  37. Polyak K., Kato J. Y., Solomon M. J., Sherr C. J., Massague J., Roberts J. M., Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994 Jan;8(1):9–22. doi: 10.1101/gad.8.1.9. [DOI] [PubMed] [Google Scholar]
  38. Polyak K., Lee M. H., Erdjument-Bromage H., Koff A., Roberts J. M., Tempst P., Massagué J. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994 Jul 15;78(1):59–66. doi: 10.1016/0092-8674(94)90572-x. [DOI] [PubMed] [Google Scholar]
  39. Poon R. Y., Toyoshima H., Hunter T. Redistribution of the CDK inhibitor p27 between different cyclin.CDK complexes in the mouse fibroblast cell cycle and in cells arrested with lovastatin or ultraviolet irradiation. Mol Biol Cell. 1995 Sep;6(9):1197–1213. doi: 10.1091/mbc.6.9.1197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Resnitzky D., Gossen M., Bujard H., Reed S. I. Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. Mol Cell Biol. 1994 Mar;14(3):1669–1679. doi: 10.1128/mcb.14.3.1669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Rosenberg A. R., Zindy F., Le Deist F., Mouly H., Métézeau P., Bréchot C., Lamas E. Overexpression of human cyclin A advances entry into S phase. Oncogene. 1995 Apr 20;10(8):1501–1509. [PubMed] [Google Scholar]
  42. Russo A. A., Jeffrey P. D., Patten A. K., Massagué J., Pavletich N. P. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature. 1996 Jul 25;382(6589):325–331. doi: 10.1038/382325a0. [DOI] [PubMed] [Google Scholar]
  43. Schulze A., Zerfass K., Spitkovsky D., Henglein B., Jansen-Dürr P. Activation of the E2F transcription factor by cyclin D1 is blocked by p16INK4, the product of the putative tumor suppressor gene MTS1. Oncogene. 1994 Dec;9(12):3475–3482. [PubMed] [Google Scholar]
  44. Schulze A., Zerfass K., Spitkovsky D., Middendorp S., Bergès J., Helin K., Jansen-Dürr P., Henglein B. Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11264–11268. doi: 10.1073/pnas.92.24.11264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Serrano M., Hannon G. J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993 Dec 16;366(6456):704–707. doi: 10.1038/366704a0. [DOI] [PubMed] [Google Scholar]
  46. Sherr C. J. G1 phase progression: cycling on cue. Cell. 1994 Nov 18;79(4):551–555. doi: 10.1016/0092-8674(94)90540-1. [DOI] [PubMed] [Google Scholar]
  47. Shiyanov P., Bagchi S., Adami G., Kokontis J., Hay N., Arroyo M., Morozov A., Raychaudhuri P. p21 Disrupts the interaction between cdk2 and the E2F-p130 complex. Mol Cell Biol. 1996 Mar;16(3):737–744. doi: 10.1128/mcb.16.3.737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Stein G. H., Dulić V. Origins of G1 arrest in senescent human fibroblasts. Bioessays. 1995 Jun;17(6):537–543. doi: 10.1002/bies.950170610. [DOI] [PubMed] [Google Scholar]
  49. Toyoshima H., Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994 Jul 15;78(1):67–74. doi: 10.1016/0092-8674(94)90573-8. [DOI] [PubMed] [Google Scholar]
  50. Tsai L. H., Harlow E., Meyerson M. Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature. 1991 Sep 12;353(6340):174–177. doi: 10.1038/353174a0. [DOI] [PubMed] [Google Scholar]
  51. Wang J., Chenivesse X., Henglein B., Bréchot C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature. 1990 Feb 8;343(6258):555–557. doi: 10.1038/343555a0. [DOI] [PubMed] [Google Scholar]
  52. Wimmel A., Lucibello F. C., Sewing A., Adolph S., Müller R. Inducible acceleration of G1 progression through tetracycline-regulated expression of human cyclin E. Oncogene. 1994 Mar;9(3):995–997. [PubMed] [Google Scholar]
  53. Zerfass K., Schulze A., Spitkovsky D., Friedman V., Henglein B., Jansen-Dürr P. Sequential activation of cyclin E and cyclin A gene expression by human papillomavirus type 16 E7 through sequences necessary for transformation. J Virol. 1995 Oct;69(10):6389–6399. doi: 10.1128/jvi.69.10.6389-6399.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Zerfass K., Spitkovsky D., Schulze A., Joswig S., Henglein B., Jansen-Dürr P. Adenovirus E1A activates cyclin A gene transcription in the absence of growth factors through interaction with p107. J Virol. 1996 Apr;70(4):2637–2642. doi: 10.1128/jvi.70.4.2637-2642.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Zhu L., Enders G., Lees J. A., Beijersbergen R. L., Bernards R., Harlow E. The pRB-related protein p107 contains two growth suppression domains: independent interactions with E2F and cyclin/cdk complexes. EMBO J. 1995 May 1;14(9):1904–1913. doi: 10.1002/j.1460-2075.1995.tb07182.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Zhu L., Harlow E., Dynlacht B. D. p107 uses a p21CIP1-related domain to bind cyclin/cdk2 and regulate interactions with E2F. Genes Dev. 1995 Jul 15;9(14):1740–1752. doi: 10.1101/gad.9.14.1740. [DOI] [PubMed] [Google Scholar]
  57. Zindy F., Lamas E., Chenivesse X., Sobczak J., Wang J., Fesquet D., Henglein B., Bréchot C. Cyclin A is required in S phase in normal epithelial cells. Biochem Biophys Res Commun. 1992 Feb 14;182(3):1144–1154. doi: 10.1016/0006-291x(92)91851-g. [DOI] [PubMed] [Google Scholar]
  58. Zwicker J., Lucibello F. C., Wolfraim L. A., Gross C., Truss M., Engeland K., Müller R. Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression. EMBO J. 1995 Sep 15;14(18):4514–4522. doi: 10.1002/j.1460-2075.1995.tb00130.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. van den Heuvel S., Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993 Dec 24;262(5142):2050–2054. doi: 10.1126/science.8266103. [DOI] [PubMed] [Google Scholar]

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