Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Dec;17(12):7362–7374. doi: 10.1128/mcb.17.12.7362

A dominant-negative cyclin D1 mutant prevents nuclear import of cyclin-dependent kinase 4 (CDK4) and its phosphorylation by CDK-activating kinase.

J A Diehl 1, C J Sherr 1
PMCID: PMC232592  PMID: 9372967

Abstract

Cyclins contain two characteristic cyclin folds, each consisting of five alpha-helical bundles, which are connected to one another by a short linker peptide. The first repeat makes direct contact with cyclin-dependent kinase (CDK) subunits in assembled holoenzyme complexes, whereas the second does not contribute directly to the CDK interface. Although threonine 156 in mouse cyclin D1 is predicted to lie at the carboxyl terminus of the linker peptide that separates the two cyclin folds and is buried within the cyclin subunit, mutation of this residue to alanine has profound effects on the behavior of the derived cyclin D1-CDK4 complexes. CDK4 in complexes with mutant cyclin D1 (T156A or T156E but not T156S) is not phosphorylated by recombinant CDK-activating kinase (CAK) in vitro, fails to undergo activating T-loop phosphorylation in vivo, and remains catalytically inactive and unable to phosphorylate the retinoblastoma protein. Moreover, when it is ectopically overexpressed in mammalian cells, cyclin D1 (T156A) assembles with CDK4 in the cytoplasm but is not imported into the cell nucleus. CAK phosphorylation is not required for nuclear transport of cyclin D1-CDK4 complexes, because complexes containing wild-type cyclin D1 and a CDK4 (T172A) mutant lacking the CAK phosphorylation site are efficiently imported. In contrast, enforced overexpression of the CDK inhibitor p21Cip1 together with mutant cyclin D1 (T156A)-CDK4 complexes enhanced their nuclear localization. These results suggest that cyclin D1 (T156A or T156E) forms abortive complexes with CDK4 that prevent recognition by CAK and by other cellular factors that are required for their nuclear localization. These properties enable ectopically overexpressed cyclin D1 (T156A), or a more stable T156A/T286A double mutant that is resistant to ubiquitination, to compete with endogenous cyclin D1 in mammalian cells, thereby mobilizing CDK4 into cytoplasmic, catalytically inactive complexes and dominantly inhibiting the ability of transfected NIH 3T3 fibroblasts to enter S phase.

Full Text

The Full Text of this article is available as a PDF (980.2 KB).

Selected References

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

  1. Andersen G., Busso D., Poterszman A., Hwang J. R., Wurtz J. M., Ripp R., Thierry J. C., Egly J. M., Moras D. The structure of cyclin H: common mode of kinase activation and specific features. EMBO J. 1997 Mar 3;16(5):958–967. doi: 10.1093/emboj/16.5.958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baldin V., Lukas J., Marcote M. J., Pagano M., Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993 May;7(5):812–821. doi: 10.1101/gad.7.5.812. [DOI] [PubMed] [Google Scholar]
  3. Bram R. J., Crabtree G. R. Calcium signalling in T cells stimulated by a cyclophilin B-binding protein. Nature. 1994 Sep 22;371(6495):355–358. doi: 10.1038/371355a0. [DOI] [PubMed] [Google Scholar]
  4. Brugarolas J., Chandrasekaran C., Gordon J. I., Beach D., Jacks T., Hannon G. J. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 1995 Oct 12;377(6549):552–557. doi: 10.1038/377552a0. [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. Cismowski M. J., Laff G. M., Solomon M. J., Reed S. I. KIN28 encodes a C-terminal domain kinase that controls mRNA transcription in Saccharomyces cerevisiae but lacks cyclin-dependent kinase-activating kinase (CAK) activity. Mol Cell Biol. 1995 Jun;15(6):2983–2992. doi: 10.1128/mcb.15.6.2983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Connell-Crowley L., Harper J. W., Goodrich D. W. Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Mol Biol Cell. 1997 Feb;8(2):287–301. doi: 10.1091/mbc.8.2.287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. De Bondt H. L., Rosenblatt J., Jancarik J., Jones H. D., Morgan D. O., Kim S. H. Crystal structure of cyclin-dependent kinase 2. Nature. 1993 Jun 17;363(6430):595–602. doi: 10.1038/363595a0. [DOI] [PubMed] [Google Scholar]
  9. Deng C., Zhang P., Harper J. W., Elledge S. J., Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 1995 Aug 25;82(4):675–684. doi: 10.1016/0092-8674(95)90039-x. [DOI] [PubMed] [Google Scholar]
  10. Desai D., Wessling H. C., Fisher R. P., Morgan D. O. Effects of phosphorylation by CAK on cyclin binding by CDC2 and CDK2. Mol Cell Biol. 1995 Jan;15(1):345–350. doi: 10.1128/mcb.15.1.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Devault A., Martinez A. M., Fesquet D., Labbé J. C., Morin N., Tassan J. P., Nigg E. A., Cavadore J. C., Dorée M. MAT1 ('menage à trois') a new RING finger protein subunit stabilizing cyclin H-cdk7 complexes in starfish and Xenopus CAK. EMBO J. 1995 Oct 16;14(20):5027–5036. doi: 10.1002/j.1460-2075.1995.tb00185.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Diehl J. A., Zindy F., Sherr C. J. Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev. 1997 Apr 15;11(8):957–972. doi: 10.1101/gad.11.8.957. [DOI] [PubMed] [Google Scholar]
  13. Downing J. R., Rettenmier C. W., Sherr C. J. Ligand-induced tyrosine kinase activity of the colony-stimulating factor 1 receptor in a murine macrophage cell line. Mol Cell Biol. 1988 Apr;8(4):1795–1799. doi: 10.1128/mcb.8.4.1795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ducommun B., Brambilla P., Félix M. A., Franza B. R., Jr, Karsenti E., Draetta G. cdc2 phosphorylation is required for its interaction with cyclin. EMBO J. 1991 Nov;10(11):3311–3319. doi: 10.1002/j.1460-2075.1991.tb04895.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dulić V., Kaufmann W. K., Wilson S. J., Tlsty T. D., Lees E., Harper J. W., Elledge S. J., Reed S. I. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell. 1994 Mar 25;76(6):1013–1023. doi: 10.1016/0092-8674(94)90379-4. [DOI] [PubMed] [Google Scholar]
  16. Elledge S. J., Harper J. W. Cdk inhibitors: on the threshold of checkpoints and development. Curr Opin Cell Biol. 1994 Dec;6(6):847–852. doi: 10.1016/0955-0674(94)90055-8. [DOI] [PubMed] [Google Scholar]
  17. Espinoza F. H., Farrell A., Erdjument-Bromage H., Tempst P., Morgan D. O. A cyclin-dependent kinase-activating kinase (CAK) in budding yeast unrelated to vertebrate CAK. Science. 1996 Sep 20;273(5282):1714–1717. doi: 10.1126/science.273.5282.1714. [DOI] [PubMed] [Google Scholar]
  18. Ewen M. E., Sluss H. K., Sherr C. J., Matsushime H., Kato J., Livingston D. M. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell. 1993 May 7;73(3):487–497. doi: 10.1016/0092-8674(93)90136-e. [DOI] [PubMed] [Google Scholar]
  19. Feaver W. J., Svejstrup J. Q., Henry N. L., Kornberg R. D. Relationship of CDK-activating kinase and RNA polymerase II CTD kinase TFIIH/TFIIK. Cell. 1994 Dec 16;79(6):1103–1109. doi: 10.1016/0092-8674(94)90040-x. [DOI] [PubMed] [Google Scholar]
  20. Filmus J., Robles A. I., Shi W., Wong M. J., Colombo L. L., Conti C. J. Induction of cyclin D1 overexpression by activated ras. Oncogene. 1994 Dec;9(12):3627–3633. [PubMed] [Google Scholar]
  21. Firpo E. J., Koff A., Solomon M. J., Roberts J. M. Inactivation of a Cdk2 inhibitor during interleukin 2-induced proliferation of human T lymphocytes. Mol Cell Biol. 1994 Jul;14(7):4889–4901. doi: 10.1128/mcb.14.7.4889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Fisher R. P., Jin P., Chamberlin H. M., Morgan D. O. Alternative mechanisms of CAK assembly require an assembly factor or an activating kinase. Cell. 1995 Oct 6;83(1):47–57. doi: 10.1016/0092-8674(95)90233-3. [DOI] [PubMed] [Google Scholar]
  23. Fisher R. P., Morgan D. O. A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. Cell. 1994 Aug 26;78(4):713–724. doi: 10.1016/0092-8674(94)90535-5. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Gu Y., Turck C. W., Morgan D. O. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature. 1993 Dec 16;366(6456):707–710. doi: 10.1038/366707a0. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Hall M., Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res. 1996;68:67–108. doi: 10.1016/s0065-230x(08)60352-8. [DOI] [PubMed] [Google Scholar]
  28. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  29. Harper J. W., Elledge S. J., Keyomarsi K., Dynlacht B., Tsai L. H., Zhang P., Dobrowolski S., Bai C., Connell-Crowley L., Swindell E. Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell. 1995 Apr;6(4):387–400. doi: 10.1091/mbc.6.4.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hatakeyama M., Brill J. A., Fink G. R., Weinberg R. A. Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev. 1994 Aug 1;8(15):1759–1771. doi: 10.1101/gad.8.15.1759. [DOI] [PubMed] [Google Scholar]
  31. Higashi H., Suzuki-Takahashi I., Saitoh S., Segawa K., Taya Y., Okuyama A., Nishimura S., Kitagawa M. Cyclin-dependent kinase-2 (Cdk2) forms an inactive complex with cyclin D1 since Cdk2 associated with cyclin D1 is not phosphorylated by Cdk7-cyclin-H. Eur J Biochem. 1996 Apr 15;237(2):460–467. doi: 10.1111/j.1432-1033.1996.0460k.x. [DOI] [PubMed] [Google Scholar]
  32. Hinds P. W., Mittnacht S., Dulic V., Arnold A., Reed S. I., Weinberg R. A. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell. 1992 Sep 18;70(6):993–1006. doi: 10.1016/0092-8674(92)90249-c. [DOI] [PubMed] [Google Scholar]
  33. Hirai H., Roussel M. F., Kato J. Y., Ashmun R. A., Sherr C. J. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol. 1995 May;15(5):2672–2681. doi: 10.1128/mcb.15.5.2672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Iavarone A., Massagué J. Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15. Nature. 1997 May 22;387(6631):417–422. doi: 10.1038/387417a0. [DOI] [PubMed] [Google Scholar]
  35. Inaba T., Inukai T., Yoshihara T., Seyschab H., Ashmun R. A., Canman C. E., Laken S. J., Kastan M. B., Look A. T. Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor. Nature. 1996 Aug 8;382(6591):541–544. doi: 10.1038/382541a0. [DOI] [PubMed] [Google Scholar]
  36. Jeffrey P. D., Russo A. A., Polyak K., Gibbs E., Hurwitz J., Massagué J., Pavletich N. P. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature. 1995 Jul 27;376(6538):313–320. doi: 10.1038/376313a0. [DOI] [PubMed] [Google Scholar]
  37. Jiang W., Kahn S. M., Zhou P., Zhang Y. J., Cacace A. M., Infante A. S., Doi S., Santella R. M., Weinstein I. B. Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene. 1993 Dec;8(12):3447–3457. [PubMed] [Google Scholar]
  38. Kaldis P., Sutton A., Solomon M. J. The Cdk-activating kinase (CAK) from budding yeast. Cell. 1996 Aug 23;86(4):553–564. doi: 10.1016/s0092-8674(00)80129-4. [DOI] [PubMed] [Google Scholar]
  39. Kamps M. P. Determination of phosphoamino acid composition by acid hydrolysis of protein blotted to Immobilon. Methods Enzymol. 1991;201:21–27. doi: 10.1016/0076-6879(91)01005-m. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Kato J. Y., Matsuoka M., Strom D. K., Sherr C. J. Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase. Mol Cell Biol. 1994 Apr;14(4):2713–2721. doi: 10.1128/mcb.14.4.2713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kim K. K., Chamberlin H. M., Morgan D. O., Kim S. H. Three-dimensional structure of human cyclin H, a positive regulator of the CDK-activating kinase. Nat Struct Biol. 1996 Oct;3(10):849–855. doi: 10.1038/nsb1096-849. [DOI] [PubMed] [Google Scholar]
  43. Koh J., Enders G. H., Dynlacht B. D., Harlow E. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature. 1995 Jun 8;375(6531):506–510. doi: 10.1038/375506a0. [DOI] [PubMed] [Google Scholar]
  44. 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]
  45. Krek W., Xu G., Livingston D. M. Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint. Cell. 1995 Dec 29;83(7):1149–1158. doi: 10.1016/0092-8674(95)90141-8. [DOI] [PubMed] [Google Scholar]
  46. Krude T., Jackman M., Pines J., Laskey R. A. Cyclin/Cdk-dependent initiation of DNA replication in a human cell-free system. Cell. 1997 Jan 10;88(1):109–119. doi: 10.1016/s0092-8674(00)81863-2. [DOI] [PubMed] [Google Scholar]
  47. LaBaer J., Garrett M. D., Stevenson L. F., Slingerland J. M., Sandhu C., Chou H. S., Fattaey A., Harlow E. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 1997 Apr 1;11(7):847–862. doi: 10.1101/gad.11.7.847. [DOI] [PubMed] [Google Scholar]
  48. Li J., Meyer A. N., Donoghue D. J. Nuclear localization of cyclin B1 mediates its biological activity and is regulated by phosphorylation. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):502–507. doi: 10.1073/pnas.94.2.502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Li Y., Jenkins C. W., Nichols M. A., Xiong Y. Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. Oncogene. 1994 Aug;9(8):2261–2268. [PubMed] [Google Scholar]
  50. Liu J. J., Chao J. R., Jiang M. C., Ng S. Y., Yen J. J., Yang-Yen H. F. Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells. Mol Cell Biol. 1995 Jul;15(7):3654–3663. doi: 10.1128/mcb.15.7.3654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Lovec H., Sewing A., Lucibello F. C., Müller R., Möröy T. Oncogenic activity of cyclin D1 revealed through cooperation with Ha-ras: link between cell cycle control and malignant transformation. Oncogene. 1994 Jan;9(1):323–326. [PubMed] [Google Scholar]
  52. 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]
  53. Lukas J., Herzinger T., Hansen K., Moroni M. C., Resnitzky D., Helin K., Reed S. I., Bartek J. Cyclin E-induced S phase without activation of the pRb/E2F pathway. Genes Dev. 1997 Jun 1;11(11):1479–1492. doi: 10.1101/gad.11.11.1479. [DOI] [PubMed] [Google Scholar]
  54. Lukas J., Müller H., Bartkova J., Spitkovsky D., Kjerulff A. A., Jansen-Dürr P., Strauss M., Bartek J. DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1. J Cell Biol. 1994 May;125(3):625–638. doi: 10.1083/jcb.125.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Lukas J., Parry D., Aagaard L., Mann D. J., Bartkova J., Strauss M., Peters G., Bartek J. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995 Jun 8;375(6531):503–506. doi: 10.1038/375503a0. [DOI] [PubMed] [Google Scholar]
  56. Macleod K. F., Sherry N., Hannon G., Beach D., Tokino T., Kinzler K., Vogelstein B., Jacks T. p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev. 1995 Apr 15;9(8):935–944. doi: 10.1101/gad.9.8.935. [DOI] [PubMed] [Google Scholar]
  57. Mantel C., Luo Z., Canfield J., Braun S., Deng C., Broxmeyer H. E. Involvement of p21cip-1 and p27kip-1 in the molecular mechanisms of steel factor-induced proliferative synergy in vitro and of p21cip-1 in the maintenance of stem/progenitor cells in vivo. Blood. 1996 Nov 15;88(10):3710–3719. [PubMed] [Google Scholar]
  58. Matsuoka M., Kato J. Y., Fisher R. P., Morgan D. O., Sherr C. J. Activation of cyclin-dependent kinase 4 (cdk4) by mouse MO15-associated kinase. Mol Cell Biol. 1994 Nov;14(11):7265–7275. doi: 10.1128/mcb.14.11.7265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Matsushime H., Quelle D. E., Shurtleff S. A., Shibuya M., Sherr C. J., Kato J. Y. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol. 1994 Mar;14(3):2066–2076. doi: 10.1128/mcb.14.3.2066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Matsushime H., Roussel M. F., Ashmun R. A., Sherr C. J. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell. 1991 May 17;65(4):701–713. doi: 10.1016/0092-8674(91)90101-4. [DOI] [PubMed] [Google Scholar]
  61. Medema R. H., Herrera R. E., Lam F., Weinberg R. A. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6289–6293. doi: 10.1073/pnas.92.14.6289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Meyerson M., Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994 Mar;14(3):2077–2086. doi: 10.1128/mcb.14.3.2077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Michieli P., Chedid M., Lin D., Pierce J. H., Mercer W. E., Givol D. Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 1994 Jul 1;54(13):3391–3395. [PubMed] [Google Scholar]
  64. Morgan D. O. Principles of CDK regulation. Nature. 1995 Mar 9;374(6518):131–134. doi: 10.1038/374131a0. [DOI] [PubMed] [Google Scholar]
  65. Morgan D. O. Under arrest at atomic resolution. Nature. 1996 Jul 25;382(6589):295–296. doi: 10.1038/382295a0. [DOI] [PubMed] [Google Scholar]
  66. Mäkelä T. P., Tassan J. P., Nigg E. A., Frutiger S., Hughes G. J., Weinberg R. A. A cyclin associated with the CDK-activating kinase MO15. Nature. 1994 Sep 15;371(6494):254–257. doi: 10.1038/371254a0. [DOI] [PubMed] [Google Scholar]
  67. Nigg E. A. The substrates of the cdc2 kinase. Semin Cell Biol. 1991 Aug;2(4):261–270. [PubMed] [Google Scholar]
  68. Noda A., Ning Y., Venable S. F., Pereira-Smith O. M., Smith J. R. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res. 1994 Mar;211(1):90–98. doi: 10.1006/excr.1994.1063. [DOI] [PubMed] [Google Scholar]
  69. 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]
  70. 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]
  71. 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]
  72. Pagano M., Theodoras A. M., Tam S. W., Draetta G. F. Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Genes Dev. 1994 Jul 15;8(14):1627–1639. doi: 10.1101/gad.8.14.1627. [DOI] [PubMed] [Google Scholar]
  73. Pines J., Hunter T. Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-dependent nuclear transport. J Cell Biol. 1991 Oct;115(1):1–17. doi: 10.1083/jcb.115.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Pines J., Hunter T. The differential localization of human cyclins A and B is due to a cytoplasmic retention signal in cyclin B. EMBO J. 1994 Aug 15;13(16):3772–3781. doi: 10.1002/j.1460-2075.1994.tb06688.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Poon R. Y., Yamashita K., Adamczewski J. P., Hunt T., Shuttleworth J. The cdc2-related protein p40MO15 is the catalytic subunit of a protein kinase that can activate p33cdk2 and p34cdc2. EMBO J. 1993 Aug;12(8):3123–3132. doi: 10.1002/j.1460-2075.1993.tb05981.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Quelle D. E., Ashmun R. A., Shurtleff S. A., Kato J. Y., Bar-Sagi D., Roussel M. F., Sherr C. J. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev. 1993 Aug;7(8):1559–1571. doi: 10.1101/gad.7.8.1559. [DOI] [PubMed] [Google Scholar]
  77. 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]
  78. Rettenmier C. W., Chen J. H., Roussel M. F., Sherr C. J. The product of the c-fms proto-oncogene: a glycoprotein with associated tyrosine kinase activity. Science. 1985 Apr 19;228(4697):320–322. doi: 10.1126/science.2580348. [DOI] [PubMed] [Google Scholar]
  79. Roy R., Adamczewski J. P., Seroz T., Vermeulen W., Tassan J. P., Schaeffer L., Nigg E. A., Hoeijmakers J. H., Egly J. M. The MO15 cell cycle kinase is associated with the TFIIH transcription-DNA repair factor. Cell. 1994 Dec 16;79(6):1093–1101. doi: 10.1016/0092-8674(94)90039-6. [DOI] [PubMed] [Google Scholar]
  80. 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]
  81. Russo A. A., Jeffrey P. D., Pavletich N. P. Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat Struct Biol. 1996 Aug;3(8):696–700. doi: 10.1038/nsb0896-696. [DOI] [PubMed] [Google Scholar]
  82. Serizawa H., Mäkelä T. P., Conaway J. W., Conaway R. C., Weinberg R. A., Young R. A. Association of Cdk-activating kinase subunits with transcription factor TFIIH. Nature. 1995 Mar 16;374(6519):280–282. doi: 10.1038/374280a0. [DOI] [PubMed] [Google Scholar]
  83. Serrano M., Gómez-Lahoz E., DePinho R. A., Beach D., Bar-Sagi D. Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Science. 1995 Jan 13;267(5195):249–252. doi: 10.1126/science.7809631. [DOI] [PubMed] [Google Scholar]
  84. Sheaff R. J., Groudine M., Gordon M., Roberts J. M., Clurman B. E. Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev. 1997 Jun 1;11(11):1464–1478. doi: 10.1101/gad.11.11.1464. [DOI] [PubMed] [Google Scholar]
  85. Sheikh M. S., Li X. S., Chen J. C., Shao Z. M., Ordonez J. V., Fontana J. A. Mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma: role of p53-dependent and independent signal transduction pathways. Oncogene. 1994 Dec;9(12):3407–3415. [PubMed] [Google Scholar]
  86. 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]
  87. Sherr C. J. Mammalian G1 cyclins. Cell. 1993 Jun 18;73(6):1059–1065. doi: 10.1016/0092-8674(93)90636-5. [DOI] [PubMed] [Google Scholar]
  88. Sherr C. J., Roberts J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995 May 15;9(10):1149–1163. doi: 10.1101/gad.9.10.1149. [DOI] [PubMed] [Google Scholar]
  89. Shiekhattar R., Mermelstein F., Fisher R. P., Drapkin R., Dynlacht B., Wessling H. C., Morgan D. O., Reinberg D. Cdk-activating kinase complex is a component of human transcription factor TFIIH. Nature. 1995 Mar 16;374(6519):283–287. doi: 10.1038/374283a0. [DOI] [PubMed] [Google Scholar]
  90. Solomon M. J., Harper J. W., Shuttleworth J. CAK, the p34cdc2 activating kinase, contains a protein identical or closely related to p40MO15. EMBO J. 1993 Aug;12(8):3133–3142. doi: 10.1002/j.1460-2075.1993.tb05982.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Solomon M. J., Lee T., Kirschner M. W. Role of phosphorylation in p34cdc2 activation: identification of an activating kinase. Mol Biol Cell. 1992 Jan;3(1):13–27. doi: 10.1091/mbc.3.1.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Tassan J. P., Schultz S. J., Bartek J., Nigg E. A. Cell cycle analysis of the activity, subcellular localization, and subunit composition of human CAK (CDK-activating kinase). J Cell Biol. 1994 Oct;127(2):467–478. doi: 10.1083/jcb.127.2.467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Terada Y., Tatsuka M., Jinno S., Okayama H. Requirement for tyrosine phosphorylation of Cdk4 in G1 arrest induced by ultraviolet irradiation. Nature. 1995 Jul 27;376(6538):358–362. doi: 10.1038/376358a0. [DOI] [PubMed] [Google Scholar]
  94. Thuret J. Y., Valay J. G., Faye G., Mann C. Civ1 (CAK in vivo), a novel Cdk-activating kinase. Cell. 1996 Aug 23;86(4):565–576. doi: 10.1016/s0092-8674(00)80130-0. [DOI] [PubMed] [Google Scholar]
  95. Uchimaru K., Endo K., Fujinuma H., Zukerberg L., Arnold A., Motokura T. Oncogenic collaboration of the cyclin D1 (PRAD1, bcl-1) gene with a mutated p53 and an activated ras oncogene in neoplastic transformation. Jpn J Cancer Res. 1996 May;87(5):459–465. doi: 10.1111/j.1349-7006.1996.tb00246.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Vallance S. J., Lee H. M., Roussel M. F., Shurtleff S. A., Kato J. Y., Strom D. K., Sherr C. J. Monoclonal antibodies to mammalian D-type G1 cyclins. Hybridoma. 1994 Feb;13(1):37–44. doi: 10.1089/hyb.1994.13.37. [DOI] [PubMed] [Google Scholar]
  97. Walker D. H., Maller J. L. Role for cyclin A in the dependence of mitosis on completion of DNA replication. Nature. 1991 Nov 28;354(6351):314–317. doi: 10.1038/354314a0. [DOI] [PubMed] [Google Scholar]
  98. 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]
  99. Winston J. T., Coats S. R., Wang Y. Z., Pledger W. J. Regulation of the cell cycle machinery by oncogenic ras. Oncogene. 1996 Jan 4;12(1):127–134. [PubMed] [Google Scholar]
  100. Xiong Y., Hannon G. J., Zhang H., Casso D., Kobayashi R., Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993 Dec 16;366(6456):701–704. doi: 10.1038/366701a0. [DOI] [PubMed] [Google Scholar]
  101. Xiong Y., Zhang H., Beach D. D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell. 1992 Oct 30;71(3):505–514. doi: 10.1016/0092-8674(92)90518-h. [DOI] [PubMed] [Google Scholar]
  102. Xiong Y., Zhang H., Beach D. Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev. 1993 Aug;7(8):1572–1583. doi: 10.1101/gad.7.8.1572. [DOI] [PubMed] [Google Scholar]
  103. Zhang H., Hannon G. J., Beach D. p21-containing cyclin kinases exist in both active and inactive states. Genes Dev. 1994 Aug 1;8(15):1750–1758. doi: 10.1101/gad.8.15.1750. [DOI] [PubMed] [Google Scholar]
  104. Zhang H., Xiong Y., Beach D. Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes. Mol Biol Cell. 1993 Sep;4(9):897–906. doi: 10.1091/mbc.4.9.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. 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]
  106. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES