HSF1 down-regulates XAF1 through transcriptional regulation
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HSF1 down-regulates XAF1 through transcriptional regulation

发表时间：2006-12-17 09:35

编辑于 09:35h 学术成果, 研究论文

StudieshaveindicatedtheroleofHSF1(heat-shocktranscription factor 1) in repressing the transcription of some nonheat shock genes.XAF1(XIAP-associatedfactor1)wasaninhibitorofapopto- sis-interacting protein with the effect of antagonizing the cytopro- tective role of XIAP. XAF1 expression was lower in gastrointestinal cancers than in normal tissues with the mechanism unclear. Here weshowedthatgastrointestinalcancertissuesexpressedhigherlev- els of HSF1 than matched normal tissues. The expression of XAF1 and HSF1 was negatively correlated in gastrointestinal cancer cell lines. Stress stimuli, including heat, hypo-osmolarity, and H 2 O 2 , significantly suppressed the expression of XAF1, whereas the alter- ation of HSF1 expression negatively correlated with XAF1 expres- sion. We cloned varying lengths of the 5?-flanking region of the XAF1 gene into luciferase reporter vectors, and we evaluated their promoteractivities.Atranscriptionsilencerwasfoundbetweenthe ?592- and ?1414-nucleotide region that was rich in nGAAn/nT- TCn elements (where n indicates G, A, T, or C). A high affinity and functional HSF1-binding element within the ?862/?821-nucleo- tide region was determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Inactivation of this “heat-shock element” by either site-directed mutation or an HSF1 inhibitor, pifithrin- ? , restored the promoter activity of the silencer structure. Moreover, pretreatment with antioxidants suppressed HSF1bindingactivityandincreasedthetranscriptionalactivityand 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 inhibitors of apoptosis, in cytoprotection under stress circumstances.

第一署名医院：南方医科大学南方医院

HSF1 down-regulates XAF1 through transcriptional regulation （查看pdf）