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J. Biol. Chem., Vol. 282, Issue 12, 8715-8723, March 23, 2007

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Cadmium-responsive Element of the Human Heme Oxygenase-1 Gene Mediates Heat Shock Factor 1-dependent Transcriptional Activation^*

From the Mechanism of Health Effect Research Group, National Institute of Occupational Safety and Health, Kawasaki 214-8585, Japan

Transcription of a number of mammalian genes is activated by heavy metals, but mechanisms of signaling and transcriptional regulation are not well understood. From a comparison of heavy metal responses of several human genes, it was noted that the heme oxygenase-1 (HO-1) gene is quite similar in the spectrum of metal response and induction kinetics to the heat shock protein 70 (HSP70) gene, suggesting a common regulatory mechanism shared by these genes. The cadmium-responsive element (CdRE) known to be responsible for the metal regulation of ho-1 formed complexes with proteins from heavy metal-treated HeLa cells in an electrophoretic mobility shift assay (EMSA). These complexes were indistinguishable in mobility from those formed by the heat shock factor 1 (HSF1) and the heat shock element involved in hsp70 regulation, suggesting the involvement of HSF1 also in the CdRE complexes. Competitive EMSA and supershift analysis with an anti-HSF1 antibody revealed that HSF1 was in fact a component of the CdRE complexes. A fine analysis on the affinity of HSF1 to a series of mutant CdRE sequences showed that HSF1 recognizes a sequence motif TnCTAGA. Transient transfection analysis with overexpressed recombinant HSF1 demonstrated that CdRE has HSF1-dependent enhancer-like activity that requires direct binding of HSF1. In the absence of overexpressed HSF1, however, CdRE by itself was insufficient to mediate heavy metal-induced transcription, suggesting requirement of additional regulatory sequences. The finding that HSF1 is directly involved in the regulation of ho-1 with an anti-oxidative role revealed a new aspect of the biological defense mechanism.

Received for publication, October 5, 2006 , and in revised form, January 22, 2007.

^* 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.

² Present address: Dept. of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York University, New York, NY 10029.

¹ To whom correspondence should be addressed: Mechanism of Health Effect Research Group, National Institute of Occupational Safety and Health, 6-21-1, Nagao, Tama-ku, Kawasaki 214-8585, Japan. Tel.: 81-44-865-6111; Fax: 81-44-865-6124; E-mail: koizumi{at}h.jniosh.go.jp.

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