Acetylated sp3 is a transcriptional activator.
Sp3 transcription factor can either activate or repress target gene expression. However, the molecular event that controls this dual function is unclear. We previously reported (Ammanamanchi, S., and Brattain, M. G. (2001) J. Biol. Chem. 276, 3348-3352) that unmodified Sp3 acts as a transcriptional repressor of transforming growth factor-beta receptors in MCF-7L breast cancer cells. We now report that histone deacetylase inhibitor trichostatin A (TSA) induces acetylation of Sp3, which acts as a transcriptional activator of transforming growth factor-beta receptor type II (RII) in MCF-7L cells. Mutation analysis indicated the TSA response is mediated through a GC box located on the RII promoter, which was previously identified as an Sp1/Sp3-binding site that was critical for RII promoter activity. Ectopic Sp3 expression in Sp3-deficient MCF-7E breast cancer cells repressed RII promoter activity in the absence of TSA. However, in the TSA-treated MCF-7E cells ectopic Sp3 activated RII promoter. Histone acetyltransferase p300 was shown to acetylate Sp3. Sp3-mediated RII promoter activity was stimulated by wild type p300 but not the histone acetyltransferase domain-deleted mutant p300 in MCF-7L cells, suggesting the positive effect of p300 acetylase activity on Sp3. Consequently, the results presented in this manuscript demonstrate that acetylation acts as a switch that controls the repressor and activator role of Sp3.
Ammanamanchi
Sudhakar
S
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Freeman
James W
JW
Brattain
Michael G
MG
D000107:Acetylation; D001943:Breast Neoplasms; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000378:metabolism / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007700:Kinetics; D005810:Multigene Family; D010190:Pancreatic Neoplasms; D011257:Pregnancy Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D011257:Pregnancy Proteins; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D015534:Trans-Activators; C012589:trichostatin A; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D006655:Histone Deacetylases