E2F and histone deacetylase mediate transforming growth factor beta repression of cdc25A during keratinocyte cell cycle arrest.
cdc25A is a tyrosine phosphatase that activates G1 cyclin-dependent kinases (Cdk's). In human keratinocytes, cdc25A expression is down-regulated after the initial drop in Cdk activity caused by cell exposure to the antimitogenic cytokine transforming growth factor beta (TGF-beta) or removal of serum factors. Here we show that the TGF-beta-inhibitory-response element ... in the cdc25A promoter maps to an E2F site at nucleotides -62 to -55 from the transcription start site. This site is not required for basal transcription in keratinocytes. We provide evidence that the cell cycle arrest program activated by TGF-beta in human keratinocytes includes the generation of E2F4-p130 complexes that in association with histone deacetylase HDAC1 inhibit the activity of the cdc25A promoter from this repressor E2F site. This mechanism is part of a program that places keratinocytes in the quiescent state following the initial drop in Cdk activity caused by cell exposure to TGF-beta.
Mesh Terms:
Base Sequence, Carrier Proteins, Cell Cycle, Cell Cycle Proteins, Cell Line, DNA, Complementary, DNA-Binding Proteins, Down-Regulation, E2F Transcription Factors, E2F2 Transcription Factor, E2F4 Transcription Factor, Histone Deacetylases, Humans, Keratinocytes, Molecular Sequence Data, Nuclear Proteins, Phosphoproteins, Promoter Regions, Genetic, Protein Tyrosine Phosphatases, Proteins, Retinoblastoma Protein, Retinoblastoma-Binding Protein 1, Retinoblastoma-Like Protein p107, Retinoblastoma-Like Protein p130, Transcription Factor DP1, Transcription Factors, Transforming Growth Factor beta, cdc25 Phosphatases
Base Sequence, Carrier Proteins, Cell Cycle, Cell Cycle Proteins, Cell Line, DNA, Complementary, DNA-Binding Proteins, Down-Regulation, E2F Transcription Factors, E2F2 Transcription Factor, E2F4 Transcription Factor, Histone Deacetylases, Humans, Keratinocytes, Molecular Sequence Data, Nuclear Proteins, Phosphoproteins, Promoter Regions, Genetic, Protein Tyrosine Phosphatases, Proteins, Retinoblastoma Protein, Retinoblastoma-Binding Protein 1, Retinoblastoma-Like Protein p107, Retinoblastoma-Like Protein p130, Transcription Factor DP1, Transcription Factors, Transforming Growth Factor beta, cdc25 Phosphatases
Mol. Cell. Biol.
Date: Jan. 01, 1999
PubMed ID: 9858615
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