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

J. Biol. Chem., Vol. 279, Issue 38, 40237-40244, September 17, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/38/40237    most recent M401665200v1 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 Wang, J. Articles by Brattain, M. G. Search for Related Content PubMed PubMed Citation Articles by Wang, J. Articles by Brattain, M. G. Social Bookmarking                      What's this?

Autocrine and Exogenous Transforming Growth Factor Control Cell Cycle Inhibition through Pathways with Different Sensitivity^*

Jing Wang, Natalia Sergina¶||, Tien C. Ko**, Jiangeng Gong¶, and Michael G. Brattain

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14226, the ^¶Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, and the ^**Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77555

Human colon carcinoma cells HCT116 that lack transforming growth factor (TGF-) type II receptor (RII) demonstrated restoration of autocrine TGF- activity upon reexpression of RII without restoring inhibitory responses to exogenous TGF- treatment. RII transfectants (designated RII Cl 37) had a longer lag phase relative to NEO-transfected control cells (designated NEO pool) before entering exponential growth in tissue culture. The prolonged growth arrest of RII Cl 37 cells was associated with markedly reduced cyclin-dependent kinase (CDK)2 activity. Our results demonstrate that p21 induction by autocrine TGF- is responsible for reduced CDK2 activity, which at least partially contributes to prolonged growth arrest and reduced cell proliferation in RII Cl 37 cells. In contrast to RII transfectants, HCT116 cells transfected with chromosome 3 (designated HCT116Ch3), which bears the RII gene, restored the response to exogenous TGF- as well as autocrine TGF- activity. Autocrine TGF- activity in HCT116Ch3 cells induced p21 expression as seen in RII Cl 37 cells; however, in addition to autocrine activity, HCT116Ch3 cells responded to exogenous TGF- as decreased CDK4 expression and reduced pRb phosphorylation mediated a TGF- inhibitory response in these cells. These results indicate that autocrine TGF- regulates the cell cycle through a pathway different from exogenous TGF- in the sense that p21 is a more sensitive effector of the TGF- signaling pathway, which can be induced and saturated by autocrine TGF-, whereas CDK4 inhibition is a less sensitive effector, which can only be activated by high levels of exogenous TGF-

Received for publication, February 15, 2004 , and in revised form, July 14, 2004.

^* This work was supported by National Institutes of Health Grants CA38173 and CA50457 (to M. G. B.) and by National Institutes of Health Comprehensive Cancer Center Grant 16056 (to Roswell Park Cancer Institute). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The first two authors contributed equally to this work.

^|| Present address: Dept. of Microbiology, University of Virginia, 1300 Jefferson Park Ave., Charlottesville, VA 22908.

Present address: Diversa Corp., 4955 Directors Place, San Diego, CA 92121.

To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, GCDC, Elm and Carlton Sts., Buffalo, NY 14226. Tel.: 716-845-3044; Fax: 716-845-8857; E-mail: michael.brattain{at}roswellpark.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Wang, L. Yang, J. Yang, K. Kuropatwinski, W. Wang, X.-Q. Liu, J. Hauser, and M. G. Brattain Transforming Growth Factor {beta} Induces Apoptosis through Repressing the Phosphoinositide 3-Kinase/AKT/Survivin Pathway in Colon Cancer Cells Cancer Res., May 1, 2008; 68(9): 3152 - 3160. [Abstract] [Full Text] [PDF]

				Y. Carrier, J. Yuan, V. K. Kuchroo, and H. L. Weiner Th3 Cells in Peripheral Tolerance. I. Induction of Foxp3-Positive Regulatory T Cells by Th3 Cells Derived from TGF-beta T Cell-Transgenic Mice J. Immunol., January 1, 2007; 178(1): 179 - 185. [Abstract] [Full Text] [PDF]