TAF1 histone acetyltransferase activity in Sp1 activation of the cyclin D1 promoter.
A missense mutation within the histone acetyltransferase (HAT) domain of the TATA binding protein-associated factor TAF1 induces ts13 cells to undergo a late G(1) arrest and decreases cyclin D1 transcription. We have found that TAF1 mutants (Delta844-850 and Delta848-850, from which amino acids 844 through 850 and 848 through 850 have been deleted, respectively) deficient in HAT activity are unable to complement the ts13 defect in cell proliferation and cyclin D1 transcription. Chromatin immunoprecipitation assays revealed that histone H3 acetylation was reduced at the cyclin D1 promoter but not the c-fos promoter upon inactivation of TAF1 in ts13 cells. The hypoacetylation of H3 at the cyclin D1 promoter was reversed by treatment with trichostatin A (TSA), a histone deacetylase inhibitor, or by expression of TAF1 proteins that retain HAT activity. Transcription of a chimeric promoter containing the Sp1 sites of cyclin D1 and c-fos core remained TAF1 dependent in ts13 cells. Treatment with TSA restored full activity to the cyclin D1-c-fos chimera at 39.5 degrees C. In vivo genomic footprinting experiments indicate that protein-DNA interactions at the Sp1 sites of the cyclin D1 promoter were compromised at 39.5 degrees C in ts13 cells. These data have led us to hypothesize that TAF1-dependent histone acetylation facilitates transcription factor binding to the Sp1 sites, thereby activating cyclin D1 transcription and ultimately G(1)-to-S-phase progression.
Hilton
Traci L
TL
University of Washington, School of Medicine, Department of Pharmacology, 1959 NE Pacific Street, Health Sciences Center, Box 357280, Seattle, WA 98195-7280, USA.
Li
Yun
Y
Dunphy
Elizabeth L
EL
Wang
Edith H
EH
D000107:Acetylation / Q000187:drug effects; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics*; D005816:Genetic Complementation Test; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017434:Protein Structure, Tertiary; D020218:Response Elements / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D035381:TATA-Binding Protein Associated Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D035362:Transcription Factor TFIID / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*
D006657:Histones; D016329:Sp1 Transcription Factor; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D019938:Cyclin D1; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C069001:TATA-binding protein associated factor 250 kDa