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Papers In Press, published online ahead of print November 21, 2005
Medicine, University of Hong Kong, Pokfulam
Corresponding Author: bcywong{at}hku.hk
Studies have implicated the role of heat-shock transcription factors 1 (HSF1) in repressing transcription of some non-heat shock genes. XIAP-associated factor 1 (XAF1) was an IAP interacting protein with effect of antagonizing the cytoprotective role of XIAP. XAF1 expression was lower in gastrointestinal cancers than in normal tissues with mechanism unclear. In the present study, we showed that gastrointestinal cancer tissues expressed higher level of HSF1 than matched normal tissues. The expression of XAF1 and HSF1 was negatively correlated in GI cancer cell lines. Stress stimuli, including heat, hypo-osmolarity and H2O2 significantly suppressed the expression of XAF1 while the alteration of HSF1 expression negatively correlated with XAF1 expression. We cloned varying length of 5’-flanking region of XAF1 gene into luciferase reporter vector and evaluated their promoter activities. A transcription silencer was found between -592nt and -1414nt region that were rich of nGAAn/nTTCn elements. A high affinity and functional HSF1 binding element within the -862/-821 nt region was determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Inactivation of this “heat-shock element” by either site-directed mutation or a HSF1 inhibitor, pifithrin-, restored the promoter activity of the silencer structure. Moreover, pretreatment with antioxidants suppressed HSF1 binding activity, increased the transcriptional activity and expression of XAF1. These findings suggested that endogenous stress pressure in cancer cells sustained the high level expression of HSF1 and subsequently suppressed XAF1 expression, implicating the synergized effect of two anti-apoptotic protein families, HSP and IAPs, in cytoprotection under stress circumstance.
J. Biol. Chem, 10.1074/jbc.M505890200
Submitted on May 31, 2005
Revised on October 26, 2005
Accepted on November 21, 2005
Heat shock factor 1 (HSF1) downregulates X-linked inhibitor of apoptosis protein-associated factor 1 (XAF 1) through transcriptional regulation
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