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J. Biol. Chem., Vol. 278, Issue 28, 26216-26226, July 11, 2003

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Chromium(VI) Down-regulates Heavy Metal-induced Metallothionein Gene Transcription by Modifying Transactivation Potential of the Key Transcription Factor, Metal-responsive Transcription Factor 1^*

Sarmila Majumder , Kalpana Ghoshal    ¶, Dennis Summers, Shoumei Bai, Jharna Datta and Samson T. Jacob  ¶

From the Department of Molecular and Cellular Biochemistry, The Ohio State University, College of Medicine, The Ohio State University, Columbus, Ohio 43210

The robust induction of metallothionein-I and II (MT-I and MT-II) genes by several heavy metals such as zinc and cadmium requires the specific transcription factor metal-responsive transcription factor 1 (MTF1). Chromium (VI), a major environmental carcinogen, not only failed to activate these genes but also inhibited their induction by Zn²⁺ or Cd²⁺. The heavy metal-induced expression of another MTF1 target gene, zinc transporter 1 (ZnT-1), was also down-regulated by Cr⁶⁺. By contrast, the expression of two MTF1-independent Cd²⁺-inducible genes, heme oxygenase 1 (HO-1) and HSP-70, was not sensitive to Cr⁶⁺. Cr⁶⁺ did not also affect the expression of housekeeping genes such as GAPDH or -actin. Stable cell lines overexpressing variable levels of MTF1, the key transactivator of the MT genes, demonstrated differential resistance toward the inhibitory effect of Cr⁶⁺, indicating MTF1 as a target of chromium toxicity. The basal and inducible binding of MTF1 to metal response elements was not affected by treatment of cells with Cr⁶⁺. Transient transfection studies showed that the ability of MTF1 to transactivate the MT-I promoter was significantly compromised by Cr⁶⁺. The fusion protein consisting of a Gal-4 DNA binding domain and one or more of the three transactivation domains of MTF1, namely the acidic domain, proline-rich domain, and serine-threonine rich domain, activated the GAL-4-driven luciferase gene to different degrees, but all were sensitive to Cr⁶⁺. MTF1 null cells were prone to apoptosis after exposure to Zn²⁺ or Cd²⁺ that was augmented in presence Cr⁶⁺, whereas the onset of apoptosis was significantly delayed in cells overexpressing MTF1.

Received for publication, March 20, 2003 , and in revised form, April 23, 2003.

^* This research was supported in part by grants ES10874 from NIEHS, National Institutes of Health and CA81024 from NCI, National Institutes of Health (S. T. J.). 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.

These authors contributed equally to this work.

^¶ To whom correspondence should be addressed: Dept. of Molecular and Cellular Biochemistry, The Ohio State University, College of Medicine, 333 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210. Tel.: 614-688-5494; Fax: 614-688-5600; E-mail: ghoshal.1{at}osu.edu.^¶ To whom correspondence should be addressed: Dept. of Molecular and Cellular Biochemistry, The Ohio State University, College of Medicine, 333 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210. Tel.: 614-688-5494; Fax: 614-688-5600; E-mail: jacob.42{at}osu.edu.

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