Selective regulation of vitamin D receptor-responsive genes by TFIIH.
Mutations in the XPD subunit of the transcription/repair factor TFIIH cause the Xeroderma pigmentosum disorder. We show that in some XP-D deficient cells, transactivation by the vitamin D receptor (VDR) is selectively inhibited for a subset of responsive genes, such as CYP24, and that the XPD/R683W mutation prevents VDR recruitment on its promoter. Contrary to other nuclear receptors, VDR, which lacks a functional A/B domain, is not phosphorylated and consequently not regulated by the cdk7 kinase of TFIIH. In fact, we demonstrate that the VDR transactivation defect resides in Ets1, another activator that cannot be phosphorylated by TFIIH in XP-D cells. Indeed, the phosphorylated Ets1 seems to promote the binding of VDR to its responsive element and trigger the subsequent recruitment of coactivators and RNA pol II. We propose a model in which TFIIH regulates the activity of nuclear receptors by phosphorylating either their A/B domain or an additional regulatory DNA binding partner.
Drané
Pascal
P
Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404 Illkirch Cedex, France.
Compe
Emmanuel
E
Catez
Philippe
P
Chymkowitch
Pierre
P
Egly
Jean-Marc
JM
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019473:Transcription Factors, TFII / Q000378:metabolism*; D014807:Vitamin D / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase; D051759:Xeroderma Pigmentosum Group D Protein
D004268:DNA-Binding Proteins; C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D018167:Receptors, Calcitriol; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D014807:Vitamin D; D051758:Transcription Factor TFIIH; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human