Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Base Sequence
-
Carrier Proteins*
-
Cell Cycle
-
Cell Cycle Proteins*
-
Cell Line
-
DNA, Complementary
-
DNA-Binding Proteins*
-
Down-Regulation / drug effects
-
E2F Transcription Factors
-
E2F2 Transcription Factor
-
E2F4 Transcription Factor
-
Histone Deacetylases / metabolism*
-
Humans
-
Keratinocytes / cytology
-
Keratinocytes / drug effects
-
Molecular Sequence Data
-
Nuclear Proteins / metabolism
-
Phosphoproteins / metabolism
-
Promoter Regions, Genetic
-
Protein Tyrosine Phosphatases / genetics*
-
Proteins*
-
Retinoblastoma Protein / metabolism
-
Retinoblastoma-Binding Protein 1
-
Retinoblastoma-Like Protein p107
-
Retinoblastoma-Like Protein p130
-
Transcription Factor DP1
-
Transcription Factors / metabolism*
-
Transforming Growth Factor beta / metabolism*
-
Transforming Growth Factor beta / pharmacology
-
cdc25 Phosphatases*
Substances
-
Carrier Proteins
-
Cell Cycle Proteins
-
DNA, Complementary
-
DNA-Binding Proteins
-
E2F Transcription Factors
-
E2F2 Transcription Factor
-
E2F4 Transcription Factor
-
E2F4 protein, human
-
Nuclear Proteins
-
Phosphoproteins
-
Proteins
-
RBL2 protein, human
-
Retinoblastoma Protein
-
Retinoblastoma-Binding Protein 1
-
Retinoblastoma-Like Protein p107
-
Retinoblastoma-Like Protein p130
-
Transcription Factor DP1
-
Transcription Factors
-
Transforming Growth Factor beta
-
CDC25A protein, human
-
Protein Tyrosine Phosphatases
-
cdc25 Phosphatases
-
Histone Deacetylases