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J. Biol. Chem., Vol. 281, Issue 12, 7765-7774, March 24, 2006

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Novel Permissive Role of Epidermal Growth Factor in Transforming Growth Factor (TGF-) Signaling and Growth Suppression

MEDIATION BY STABILIZATION OF TGF- RECEPTOR TYPE II^*

From the The Case Comprehensive Cancer Center, The Division of General Medical Sciences and the Department of Pharmacology, Case School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

Transforming growth factor (TGF-) signals through TGF- receptor serine/threonine kinases (TRI and TRII) and Smads, regulating cell growth and apoptosis. Although loss of TGF- receptor levels is strongly selected for during the progression of most cancers, tumor cells frequently escape from complete loss of TGF- receptors through unknown mechanisms. Here, we provide the first evidence that epidermal growth factor (EGF) signaling, which is generally enhanced in cancer, is permissive for regulation of gene expression and growth suppression by TGF- in LNCaP prostate adenocarcinoma cells. Our results support that these permissive effects occur through enhanced stability of TRII mRNA and reversal of TGF--mediated TRII mRNA loss. Changes in stability of TRII mRNA occur soon after EGF or TGF-1 addition (optimal within 3 h) and are independent of de novo protein synthesis or transcription. Remarkably, such loss of TRII by TGF- can be mediated by a kinase-dead TRII (K277R), as well as by other forms of this receptor harboring mutations at prominent autophosphorylation sites. Moreover, Smad3 small interfering RNA, which blocks TGF--induced AP-1 promoter activity, does not block changes in the expression of TRII by EGF or TGF-. We have also shown that changes in TRII levels by EGF are EGF receptor-kinase-dependent and are controlled by signals downstream of MEK1/2. Our findings provide invaluable insights on the role of the EGF receptor-kinase in enhancing TGF- responses during prostate carcinogenesis.

Received for publication, November 1, 2005 , and in revised form, January 13, 2006.

^* This work was supported by NCI, National Institutes of Health Grants R01CA092102 and R01CA102074. 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S6.

¹ To whom correspondence should be addressed: Case Cancer Center Research Laboratories, Wolstein Research Bldg., Rm. 3532, 2103 Cornell Rd., Cleveland, OH 44106. Tel.: 216-368-5670; Fax: 216-368-8919; E-mail: dxd49{at}case.edu.

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				K. Song, H. Wang, T. L. Krebs, S.-J. Kim, and D. Danielpour Androgenic Control of Transforming Growth Factor-{beta} Signaling in Prostate Epithelial Cells through Transcriptional Suppression of Transforming Growth Factor-{beta} Receptor II Cancer Res., October 1, 2008; 68(19): 8173 - 8182. [Abstract] [Full Text] [PDF]