HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Choi, K. S. Articles by Kim, S.-J. Search for Related Content PubMed PubMed Citation Articles by Choi, K. S. Articles by Kim, S.-J.

J Biol Chem, Vol. 274, Issue 45, 31775-31783, November 5, 1999

Cdc2 and Cdk2 Kinase Activated by Transforming Growth Factor-1 Trigger Apoptosis through the Phosphorylation of Retinoblastoma Protein in FaO Hepatoma Cells

Kyeong Sook Choi, Young Woo Eom, Yup Kang, Mahn Joon Ha^¶, Horace Rhee, Ji-Won Yoon^**, and Seong-Jin Kim

From the  Laboratory of Endocrinology and ^¶ Laboratory of Medical Genetics, Institute for Medical Sciences, Ajou University School of Medicine, 5 Wonchon-Dong, Paldal-Gu, Suwon 442-749, Korea, the  Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892-5055, and the ^** Laboratory of Viral and Immunopathogenesis of Diabetes, Department of Microbiology and Infectious Diseases, Julia McFarlance Diabetes Research Centre, Faculty of Medicine, the University of Calgary, Alberta T2N 4N1, Canada⁴

The signaling pathway leading to TGF-1-induced apoptosis was investigated using a TGF-1-sensitive hepatoma cell line, FaO. Cell cycle analysis demonstrated that the accumulation of apoptotic cells was preceded by a progressive decrease of the cell population in the G₁ phase concomitant with a slight increase of the cell population in the G₂/M phase in response to TGF-1. TGF-1 induced a transient increase in the expression of Cdc2, cyclin A, cyclin B, and cyclin D1 at an early phase of apoptosis. During TGF-1-induced apoptosis, the transient increase in cyclin-dependent kinase (Cdk) activities coincides with a dramatic increase in the hyperphosphorylated forms of RB. Treatment with roscovitine or olomoucine, inhibitors of Cdc2 and Cdk2, blocked TGF-1-induced apoptosis by inhibiting RB phosphorylation. Overexpression of Bcl-2 or adenovirus E1B 19K suppressed TGF-1-induced apoptosis by blocking the induction of Cdc2 mRNA and the subsequent activation of Cdc2 kinase, whereas activation of Cdk2 was not affected, suggesting that Cdc2 plays a more critical role in TGF-1-induced apoptosis. In conclusion, we present the evidence that Cdc2 and Cdk2 kinase activity transiently induced by TGF-1 phosphorylates RB as a physiological target in FaO cells and that RB hyperphosphorylation may trigger abrupt cell cycle progression, leading to irreversible cell death.

---

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

This article has been cited by other articles:

				T. M. Casey, T. M. Mulvey, T. A. Patnode, A. Dean, E. Zakrzewska, and K. Plaut Mammary Epithelial Cells Treated Concurrently with TGF-{alpha} and TGF-{beta} Exhibit Enhanced Proliferation and Death Experimental Biology and Medicine, September 1, 2007; 232(8): 1027 - 1040. [Abstract] [Full Text] [PDF]

				J. H. Suh, J. Huang, Y.-Y. Park, H.-A Seong, D. Kim, M. Shong, H. Ha, I.-K. Lee, K. Lee, L. Wang, et al. Orphan Nuclear Receptor Small Heterodimer Partner Inhibits Transforming Growth Factor-beta Signaling by Repressing SMAD3 Transactivation J. Biol. Chem., December 22, 2006; 281(51): 39169 - 39178. [Abstract] [Full Text] [PDF]

				K.-Y. Kim, B.-C. Kim, Z. Xu, and S.-J. Kim Mixed Lineage Kinase 3 (MLK3)-activated p38 MAP Kinase Mediates Transforming Growth Factor-{beta}-induced Apoptosis in Hepatoma Cells J. Biol. Chem., July 9, 2004; 279(28): 29478 - 29484. [Abstract] [Full Text] [PDF]

				B.-C. Kim, H. van Gelder, T. A. Kim, H.-J. Lee, K. G. Baik, H. H. Chun, D. A. Lee, K. S. Choi, and S.-J. Kim Activin Receptor-like Kinase-7 Induces Apoptosis through Activation of MAPKs in a Smad3-dependent Mechanism in Hepatoma Cells J. Biol. Chem., July 2, 2004; 279(27): 28458 - 28465. [Abstract] [Full Text] [PDF]

				P. M. Price, R. L. Safirstein, and J. Megyesi Protection of renal cells from cisplatin toxicity by cell cycle inhibitors Am J Physiol Renal Physiol, February 1, 2004; 286(2): F378 - F384. [Abstract] [Full Text] [PDF]

				K. Plaut, A. J. Dean, T. A. Patnode, and T. M. Casey Effect of Transforming Growth Factor-beta (TGF-{beta}) on Mammary Development J Dairy Sci, July 1, 2003; 86(13_suppl): E16 - 27. [Abstract] [Full Text] [PDF]

				S. Wang, M. G. Hasham, I. Isordia-Salas, A. Y. Tsygankov, R. W. Colman, and Y.-L. Guo Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems: Upregulation of Cdc2 and cyclin A during apoptosis of endothelial cells induced by cleaved high-molecular-weight kininogen Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1917 - H1923. [Abstract] [Full Text] [PDF]

				L. M. Schang Cyclin-dependent kinases as cellular targets for antiviral drugs J. Antimicrob. Chemother., December 1, 2002; 50(6): 779 - 792. [Abstract] [Full Text] [PDF]

				C. Bowen, M. Birrer, and E. P. Gelmann Retinoblastoma Protein-mediated Apoptosis After gamma -Irradiation J. Biol. Chem., November 15, 2002; 277(47): 44969 - 44979. [Abstract] [Full Text] [PDF]

				B.-C. Kim, H.-T. Kim, M. Mamura, I. S. Ambudkar, K.-S. Choi, and S.-J. Kim Tumor Necrosis Factor Induces Apoptosis in Hepatoma Cells by Increasing Ca2+ Release from the Endoplasmic Reticulum and Suppressing Bcl-2 Expression J. Biol. Chem., August 23, 2002; 277(35): 31381 - 31389. [Abstract] [Full Text] [PDF]

				T. Sandal, C. Stapnes, H. Kleivdal, L. Hedin, and S. O. Doskeland A Novel, Extraneuronal Role for Cyclin-dependent Protein Kinase 5 (CDK5). MODULATION OF cAMP-INDUCED APOPTOSIS IN RAT LEUKEMIA CELLS J. Biol. Chem., May 31, 2002; 277(23): 20783 - 20793. [Abstract] [Full Text] [PDF]

				B.-C. Kim, M. Mamura, K. S. Choi, B. Calabretta, and S.-J. Kim Transforming Growth Factor {beta}1 Induces Apoptosis through Cleavage of BAD in a Smad3-Dependent Mechanism in FaO Hepatoma Cells Mol. Cell. Biol., March 1, 2002; 22(5): 1369 - 1378. [Abstract] [Full Text] [PDF]

				M. Fedele, S. Battista, G. Manfioletti, C. M. Croce, V. Giancotti, and A. Fusco Role of the high mobility group A proteins in human lipomas Carcinogenesis, October 1, 2001; 22(10): 1583 - 1591. [Abstract] [Full Text] [PDF]

				S. Wolff, P. A. Harper, J. M. Y. Wong, V. Mostert, Y. Wang, and J. Abel Cell-Specific Regulation of Human Aryl Hydrocarbon Receptor Expression by Transforming Growth Factor-{beta}1 Mol. Pharmacol., April 1, 2001; 59(4): 716 - 724. [Abstract] [Full Text]

				F. Diana, R. Sgarra, G. Manfioletti, A. Rustighi, D. Poletto, M. T. Sciortino, A. Mastino, and V. Giancotti A Link between Apoptosis and Degree of Phosphorylation of High Mobility Group A1a Protein in Leukemic Cells J. Biol. Chem., March 30, 2001; 276(14): 11354 - 11361. [Abstract] [Full Text] [PDF]

				M. M. Ahmed, R. A. Alcock, D. Chendil, S. Dey, A. Das, K. Venkatasubbarao, M. Mohiuddin, L. Sun, W. E. Strodel, and J. W. Freeman Restoration of Transforming Growth Factor-beta Signaling Enhances Radiosensitivity by Altering the Bcl-2/Bax Ratio in the p53 Mutant Pancreatic Cancer Cell Line MIA PaCa-2 J. Biol. Chem., January 11, 2002; 277(3): 2234 - 2246. [Abstract] [Full Text] [PDF]

				J. Yu, S. Tian, L. Metheny-Barlow, L.-J. Chew, A. J. Hayes, H. Pan, G.-L. Yu, and L.-Y. Li Modulation of Endothelial Cell Growth Arrest and Apoptosis by Vascular Endothelial Growth Inhibitor Circ. Res., December 7, 2001; 89(12): 1161 - 1167. [Abstract] [Full Text] [PDF]