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J. Biol. Chem., Vol. 282, Issue 38, 27713-27720, September 21, 2007

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Signaling Pathways Regulating TC21-induced Tumorigenesis^*

Mete Erdogan, Ambra Pozzi^¶, Neil Bhowmick^||, Harold L Moses, and Roy Zent^¶**1

From the Departments of Cancer Biology, Medicine, ^**Cell and Developmental Biology, and ^||Urologic Surgery, Vanderbilt University Medical Center and the ^¶Department of Medicine, Veterans Affairs Hospital, Nashville, Tennessee 37232

TC21(R-Ras2), a Ras-related GTPase with transforming potential similar to H-, K- and N-Ras, is implicated in the pathogenesis of human cancers. Transforming growth factor (TGF-), a cytokine that plays a significant role in modulating tumorigenesis, normally prevents uncontrolled cell proliferation but paradoxically induces proliferation in H-Ras-transformed cancer cells. Although TC21 activates some pathways that mediate cellular transformation by the classical Ras proteins, the mechanisms through which TC21 induces tumor formation and how TGF- regulates TC21 transformed cells is not known. To better understand the role of TC21 in cancer progression, we overexpressed an activated G23V mutant of TC21 in a nontumorigenic murine mammary epithelial (EpH4) cell line. Mutant TC21-expressing cells were significantly more oncogenic than cells expressing activated G12V H-Ras both in vivo and in vitro. TC21-induced transformation and proliferation required activation of p38 MAPK, mTOR (the mammalian target of rapamycin), and phosphoinositide 3-kinase but not Akt/PKB. Transformation by TC21 rendered EpH4 cells insensitive to the growth inhibitory effects of TGF-, and the soft agar growth of these cells was increased upon TGF- stimulation. Despite losing responsiveness to TGF--mediated growth inhibition, both Smad-dependent and independent pathways remained intact in TC21-transformed cells. Thus, overexpression of active TC21 in EpH4 cells induces tumorigenicity through the phosphoinositide 3-kinase, p38 MAPK, and mTOR pathways, and these cells lose their sensitivity to the normal growth inhibitory role of TGF-.

Received for publication, April 11, 2007 , and in revised form, July 24, 2007.

^* This work was supported by National Institutes of Health Grants CA 085492 and CA 102162 (to H. L. M.), RO1-DK 69921 (to R. Z.), and RO1-CA94849 and RO1-DK074359 (to A. P.) and a Merit Award from the Department of Veterans Affairs (to R. Z.). 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.

¹ To whom correspondence should be addressed: Rm. C3210, Medical Center North, Vanderbilt University, Nashville, TN 37232. Tel.: 615-322-4632; Fax: 615-322-4690; E-mail: roy.zent{at}vanderbilt.edu.

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