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• W2023680135 endingPage "5431" @default.
• W2023680135 startingPage "5420" @default.
• W2023680135 abstract "The Fas/FasL signaling pathway has previously been demonstrated to be critical for triggering germ cell apoptosis in response to mono-(2-ethylhexyl)phthalate (MEHP)-induced Sertoli cell injury. Although Sertoli cells ubiquitously express the FasL protein, MEHP-induced germ cell apoptosis appears to tightly correlate with increased levels of Sertoli cell FasL. Here we characterize the transcriptional regulation of the murine FasL gene in Sertoli cells after MEHP exposure. A serial deletion strategy for 1.5 kb of the 5'-upstream activating sequence of the FasL promoter was used to determine transcriptional activity in response to MEHP. Luciferase activity of the FasL promoter in the rat Sertoli cell line ASC-17D revealed that two regions, -500 to -324 and -1250 to -1000, were necessary to drive the inducible transcription of FasL. Sequence analysis of these two regions revealed two cis-regulatory elements, NF-kappaB and Sp-1. By site-directed mutagenesis, electrophoretic mobility shift and chromatin immunoprecipitation assays, it was confirmed that MEHP-induced FasL expression is enhanced through the transcriptional regulation of both NF-kappaB and Sp-1. Experiments performed both in vitro and in vivo revealed that MEHP exposure results in an increased production of sTNF-alpha and that sTNF-alpha-mediated NF-kappaB activation causes robust increases in FasL levels in both the ASC-17D Sertoli cell line and in primary rat Sertoli cell/germ cell co-cultures. In the seminiferous epithelium, Sertoli cells express TNFR1, whereas germ cells produce TNF-alpha. Therefore, sTNF-alpha released by germ cells after MEHP-induced Sertoli cell injury acts upon Sertoli cell TNFR1 and activates NF-kappaB and Sp-1 that consequently causes a robust induction of FasL expression. These novel findings point to a potential feed-forward signaling mechanism by which germ cells prompt Sertoli cells to trigger their apoptotic elimination." @default.
• W2023680135 created "2016-06-24" @default.
• W2023680135 creator A5005788391 @default.
• W2023680135 creator A5008061497 @default.
• W2023680135 creator A5038443300 @default.
• W2023680135 creator A5061082492 @default.
• W2023680135 date "2007-02-01" @default.
• W2023680135 modified "2023-10-16" @default.
• W2023680135 title "Transcriptional Regulation of FasL Expression and Participation of sTNF-α in Response to Sertoli Cell Injury" @default.
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• W2023680135 doi "https://doi.org/10.1074/jbc.m609068200" @default.
• W2023680135 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17192273" @default.
• W2023680135 hasPublicationYear "2007" @default.
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