P27Kip1 and P21Cip1 Are Not Required for the Formation of Active D Cyclin-cdk4 Complexes

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2003 Oct 1

PMID 14517297

Citations 41

Authors

Tapan K Bagui

Subhra Mohapatra

Eric Haura

W J Pledger

Affiliations

Soon will be listed here.

Abstract

Our studies address questions pertaining to the regulation of D cyclin-cdk4 activity, and the following results were obtained. Conditions that increased the abundance of the D cyclins also increased the abundance of enzymatically active D cyclin-cdk4 complexes in mouse embryo fibroblasts (MEFs) lacking both p27(Kip1) and p21(Cip1) (p27/p21(-/-)). Such conditions included ectopic expression of cyclin D1 and inhibition of D cyclin degradation by the proteasome inhibitor MG132. However, as determined by treatment of wild-type MEFs with MG132, maximal accumulation of D cyclin-cdk4 complexes required p27(Kip1) and p21(Cip1) and coincided with the formation of inactive D cyclin-cdk4-p27(Kip1) or -p21(Cip1) complexes. p27(Kip1) or p21(Cip1) also increased the abundance of D cyclin-cdk4 complexes and reduced amounts of cdk4 activity when ectopically expressed in p27/p21(-/-) MEFs. Lastly, increases in the stability of the D cyclins accounted for their greater abundance in wild-type MEFs than in p27/p21(-/-) MEFs. We conclude that (i) D cyclin-cdk4 complexes are formed and become active in the absence of p27(Kip1) and p21(Cip1) and (ii) p27(Kip1) and p21(Cip1) maximize the accumulation but inhibit the activity of D cyclin-cdk4 complexes. We suggest that D cyclin-cdk4 complexes are more stable when bound to p27(Kip1) or p21(Cip1) and that formation of ternary complexes also stabilizes the D cyclins.

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References

Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson I, Shimamoto A . Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1). Genes Dev. 1999; 13(22):3027-33. PMC: 317153. DOI: 10.1101/gad.13.22.3027. View

Cheng M, Olivier P, Diehl J, Fero M, Roussel M, Roberts J . The p21(Cip1) and p27(Kip1) CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J. 1999; 18(6):1571-83. PMC: 1171245. DOI: 10.1093/emboj/18.6.1571. View

Bagui T, Jackson R, Agrawal D, Pledger W . Analysis of cyclin D3-cdk4 complexes in fibroblasts expressing and lacking p27(kip1) and p21(cip1). Mol Cell Biol. 2000; 20(23):8748-57. PMC: 86501. DOI: 10.1128/MCB.20.23.8748-8757.2000. View

Olashaw N, Pledger W . Paradigms of growth control: relation to Cdk activation. Sci STKE. 2002; 2002(134):re7. DOI: 10.1126/stke.2002.134.re7. View

Sugimoto M, Martin N, Wilks D, Tamai K, Huot T, Pantoja C . Activation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1). Oncogene. 2002; 21(53):8067-74. DOI: 10.1038/sj.onc.1206019. View

Nevins J . Definition and mapping of adenovirus 2 nuclear transcription. Methods Enzymol. 1980; 65(1):768-85. DOI: 10.1016/s0076-6879(80)65072-1. View

Matsushime H, Ewen M, Strom D, Kato J, Hanks S, Roussel M . Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell. 1992; 71(2):323-34. DOI: 10.1016/0092-8674(92)90360-o. View

Quelle D, Ashmun R, Shurtleff S, Kato J, Bar-Sagi D, Roussel M . Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev. 1993; 7(8):1559-71. DOI: 10.1101/gad.7.8.1559. View

Polyak K, Kato J, Solomon M, Sherr C, Massague J, Roberts J . p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994; 8(1):9-22. DOI: 10.1101/gad.8.1.9. View

10.

Matsushime H, Quelle D, Shurtleff S, Shibuya M, Sherr C, Kato J . D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol. 1994; 14(3):2066-76. PMC: 358567. DOI: 10.1128/mcb.14.3.2066-2076.1994. View

11.

Zhang H, Hannon G, Beach D . p21-containing cyclin kinases exist in both active and inactive states. Genes Dev. 1994; 8(15):1750-8. DOI: 10.1101/gad.8.15.1750. View

12.

Schwarz J, Bassing C, Kovesdi I, Datto M, Blazing M, George S . Expression of the E2F1 transcription factor overcomes type beta transforming growth factor-mediated growth suppression. Proc Natl Acad Sci U S A. 1995; 92(2):483-7. PMC: 42765. DOI: 10.1073/pnas.92.2.483. View

13.

Chen J, Saha P, Kornbluth S, Dynlacht B, Dutta A . Cyclin-binding motifs are essential for the function of p21CIP1. Mol Cell Biol. 1996; 16(9):4673-82. PMC: 231467. DOI: 10.1128/MCB.16.9.4673. View

14.

LaBaer J, Garrett M, Stevenson L, Slingerland J, Sandhu C, Chou H . New functional activities for the p21 family of CDK inhibitors. Genes Dev. 1997; 11(7):847-62. DOI: 10.1101/gad.11.7.847. View

15.

Diehl J, Zindy F, Sherr C . Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev. 1997; 11(8):957-72. DOI: 10.1101/gad.11.8.957. View

16.

Blain S, Montalvo E, Massague J . Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2 and cyclin D2-Cdk4. J Biol Chem. 1997; 272(41):25863-72. DOI: 10.1074/jbc.272.41.25863. View

17.

Choi Y, Lee S, Nguyen P, Jang J, Lee J, Wu M . Regulation of cyclin D1 by calpain protease. J Biol Chem. 1997; 272(45):28479-84. DOI: 10.1074/jbc.272.45.28479. View

18.

Diehl J, Cheng M, Roussel M, Sherr C . Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998; 12(22):3499-511. PMC: 317244. DOI: 10.1101/gad.12.22.3499. View

19.

Germain D, Russell A, Thompson A, Hendley J . Ubiquitination of free cyclin D1 is independent of phosphorylation on threonine 286. J Biol Chem. 2000; 275(16):12074-9. DOI: 10.1074/jbc.275.16.12074. View