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J. Biol. Chem., Vol. 278, Issue 34, 31879-31883, August 22, 2003

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Heat and Heavy Metal Stress Synergize to Mediate Transcriptional Hyperactivation by Metal-responsive Transcription Factor MTF-1^*

Nurten Saydam, Florian Steiner, Oleg Georgiev and Walter Schaffner 

From the Institute of Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland

Mammalian cells react to heavy metal stress by transcribing a number of genes that contain metal-response elements (MREs) in their promoter/enhancer region; this activation is mediated by metal-responsive transcription factor-1 (MTF-1). Well-known target genes of MTF-1 are those encoding metallothioneins, small, cysteine-rich proteins with a high affinity for heavy metals. The response to heat shock, another cell stress, is mediated by heat shock transcription factor 1 (HSF1), which activates a battery of heat shock genes. Little is known about the cross-talk between the different anti-stress systems of the cell. Here we report a synergistic activation of metal-responsive promoters by heavy metal load (zinc or cadmium) and heat shock. An obvious explanation, cooperativity between MTF-1 and HSF1, seems unlikely: transfected HSF1 boosts the activity of an Hsp70 promoter but hardly affects an MRE-containing promoter upon exposure to metal and heat shock. A clue to the mechanism is given by our finding that heat shock leads to intracellular accumulation of heavy metals. We propose that the known anti-apoptotic effect of heat shock proteins allows for cell survival despite heavy metal accumulation and, consequently, results in a hyperactivation of the metal response pathway.

Received for publication, February 28, 2003 , and in revised form, June 9, 2003.

^* This work was supported by the Swiss National Science Foundation and the Kanton Zürich. 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.: 41-1-635-3150/51; Fax: 41-1-635-6811; E-mail: wschaffn{at}molbio.unizh.ch.

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