Heat and heavy metal stress synergize to mediate transcriptional hyperactivation by metal-responsive transcription factor MTF-1.
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.
Saydam
Nurten
N
Institute of Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Steiner
Florian
F
Georgiev
Oleg
O
Schaffner
Walter
W
D002460:Cell Line; D004268:DNA-Binding Proteins; D006358:Hot Temperature; D006801:Humans; D019216:Metals, Heavy / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D000097809:Transcription Factor MTF-1
D004268:DNA-Binding Proteins; D019216:Metals, Heavy; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1