This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ravitz, M. J. Articles by Wenner, C. E. Search for Related Content PubMed PubMed Citation Articles by Ravitz, M. J. Articles by Wenner, C. E.

Transforming Growth Factor ß-induced Activation of Cyclin E-cdk2 Kinase and Down-Regulation of p27^Kip1 in C3H 10T Mouse Fibroblasts^1,2,

Department of Biochemistry, Roswell Park Cancer Institute, Buffalo, New York 14263

Transforming growth factor (TGF-ß)-stimulated induction of DNA synthesis is preceded by the activation of cyclin E/cyclin-dependent kinase (cdk)2 kinase in late G₁ in C3H 10T mouse fibroblasts. TGF-ß has no effect on the steady-state level of cdk4, while having only a modest inductive effect on cyclin D1 expression. TGF-ß stimulation does, however, lead to the striking down-regulation of p27^Kip1 expression during G₁ in a manner consistent with the timing of cyclin E-cdk2 activation. Coimmunoprecipitation analysis reveals that the amount of p27^Kip1 in complexes with the cdk2 catalytic subunit is drastically reduced at the time in late G₁ when cyclin E-cdk2 activity is maximal. These data indicate that cyclin E-cdk2 is inhibited by p27^Kip1 in the growth-arrested state and that TGF-ß relieves this inhibition by down-regulating the steady-state level of the p27^Kip1 inhibitor protein, thus reducing the level of inhibitor present in complexes with cdk2.

¹ Presented at the American Association for Cancer Research (AACR) Special Conference on Transcriptional Control of Cell Growth and Differentiation, Chatham, MA, October 16–20, 1994. Submitted as an abstract for presentation at the AACR 86th annual meeting, Toronto, Canada, 1995.

² Work on this study was supported in part by a grant (to C. E. W.) from the United States Department of Agriculture (Proposal No. 9303647).

³ To whom requests for reprints should be addressed, at Department of Biochemistry, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263-0001.

Received 12/27/94. Accepted 2/17/95.

This article has been cited by other articles:

				M. Lynch, L. Chen, M. J. Ravitz, S. Mehtani, K. Korenblat, M. J. Pazin, and E. V. Schmidt hnRNP K Binds a Core Polypyrimidine Element in the Eukaryotic Translation Initiation Factor 4E (eIF4E) Promoter, and Its Regulation of eIF4E Contributes to Neoplastic Transformation Mol. Cell. Biol., August 1, 2005; 25(15): 6436 - 6453. [Abstract] [Full Text] [PDF]

				Y. Xiao, C. L. Monitto, K. M. Minhas, and D. Sidransky Lactoferrin Down-Regulates G1 Cyclin-Dependent Kinases during Growth Arrest of Head and Neck Cancer Cells Clin. Cancer Res., December 15, 2004; 10(24): 8683 - 8686. [Abstract] [Full Text] [PDF]

				V. Frost, S. Delikat, S. Al-Mehairi, and A. J. Sinclair Regulation of p27KIP1 in Epstein-Barr virus-immortalized lymphoblastoid cell lines involves non-apoptotic caspase cleavage J. Gen. Virol., December 1, 2001; 82(12): 3057 - 3066. [Abstract] [Full Text] [PDF]

				L. Pierelli, M. Marone, G. Bonanno, S. Mozzetti, S. Rutella, R. Morosetti, C. Rumi, S. Mancuso, G. Leone, and G. Scambia Modulation of bcl-2 and p27 in human primitive proliferating hematopoietic progenitors by autocrine TGF-beta 1 is a cell cycle-independent effect and influences their hematopoietic potential Blood, May 15, 2000; 95(10): 3001 - 3009. [Abstract] [Full Text] [PDF]

				R. H. Weiss, A. Joo, and C. Randour p21Waf1/Cip1 Is an Assembly Factor Required for Platelet-derived Growth Factor-induced Vascular Smooth Muscle Cell Proliferation J. Biol. Chem., March 31, 2000; 275(14): 10285 - 10290. [Abstract] [Full Text] [PDF]

				H. Oka, L. Jin, E. Kulig, B. W. Scheithauer, and R. V. Lloyd Pituitary Adenylate Cyclase-Activating Polypeptide Inhibits Transforming Growth Factor-{beta}1-Induced Apoptosis in a Human Pituitary Adenoma Cell Line Am. J. Pathol., December 1, 1999; 155(6): 1893 - 1900. [Abstract] [Full Text] [PDF]

				R. V. Lloyd, L. A. Erickson, L. Jin, E. Kulig, X. Qian, J. C. Cheville, and B. W. Scheithauer p27kip1: A Multifunctional Cyclin-Dependent Kinase Inhibitor with Prognostic Significance in Human Cancers Am. J. Pathol., February 1, 1999; 154(2): 313 - 323. [Abstract] [Full Text] [PDF]

				C. A. Muro-Cacho, T. Munoz-Antonia, S. Livingston, and D. Klotch Transforming Growth Factor {beta} Receptors and p27kip in Thyroid Carcinoma Arch Otolaryngol Head Neck Surg, January 1, 1999; 125(1): 76 - 81. [Abstract] [Full Text] [PDF]

				F Depoortere, J. Dumont, and P. Roger Paradoxical accumulation of the cyclin-dependent kinase inhibitor p27kip1 during the cAMP-dependent mitogenic stimulation of thyroid epithelial cells J. Cell Sci., January 7, 1996; 109(7): 1759 - 1764. [Abstract] [PDF]

				P. L. Woo, H. H. Cha, K. L. Singer, and G. L. Firestone Antagonistic Regulation of Tight Junction Dynamics by Glucocorticoids and Transforming Growth Factor-beta in Mouse Mammary Epithelial Cells J. Biol. Chem., January 5, 1996; 271(1): 404 - 412. [Abstract] [Full Text] [PDF]