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J. Biol. Chem., Vol. 279, Issue 35, 36287-36292, August 27, 2004

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Differential Activation of Smads in HeLa and SiHa Cells That Differ in Their Response to Transforming Growth Factor-^*

Tessy T. Maliekal, Ruby John Anto, and Devarajan Karunagaran

From the Division of Cancer Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, Kerala 695 014, India

We assessed the responsiveness of six human cervical cancer cell lines to transforming growth factor (TGF)- with p3TP-lux reporter assay and found that HeLa and SiHa cells were highly responsive to TGF-. However, when pSBE4-BV/Luc reporter with four Smad binding elements was used, only the SiHa, not the HeLa, cells showed Smad activation. Smad DNA binding activity was relatively more in SiHa than in HeLa cells upon TGF- treatment, and the active complex contained Smad 2 and Smad 4. In 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, HeLa cells treated with 5 ng/ml of TGF- for 24 h showed proliferation, whereas SiHa cells showed growth inhibition under the same conditions. TGF- treatment resulted in G₀/G₁ arrest with a reduction in S-phase only in SiHa cells. A chemical inhibitor of Smad activation (SB203580) blocked the growth inhibitory effect of TGF- in SiHa, whereas the proliferative response in HeLa was unaffected. TGF--induced translocation of phospho-Smad 2 was relatively less in HeLa than in SiHa cells. MAPK activation occurred within 5 min and persisted up to 15 min upon TGF- treatment in HeLa but was negligible in SiHa cells. TGF- activated JNK in HeLa, but SiHa cells showed a down-regulation of its activity. When an inhibitor of MAPK (U0126) was used, the TGF--mediated proliferative response in HeLa cells was completely abolished. SB203580 did not affect MAPK activation induced by TGF- in HeLa cells. We report for the first time an activation, presumably independent of Smad activation, of TGF--dependent MAPK within 5 min of treatment that resulted in cell cycle progression in a cervical adenocarcinoma cell line, HeLa.

Received for publication, April 26, 2004 , and in revised form, June 10, 2004.

^* This work was supported by a research grant from the Department of Science and Technology (to D. K.), by program support to the Rajiv Gandhi Center from the Department of Biotechnology, and by a senior research fellowship (to T. T. M.) from the Council of Scientific and Industrial Research, Government of India. 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.

To whom correspondence should be addressed. Tel.: 91-471-2347975; Fax: 91-471-2348096; E-mail: dkarunagaran{at}hotmail.com.

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