E2F and Histone Deacetylase Mediate Transforming Growth Factor β Repression of cdc25A during Keratinocyte Cell Cycle Arrest

  • Iavarone A
  • Massagué J
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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.

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Iavarone, A., & Massagué, J. (1999). E2F and Histone Deacetylase Mediate Transforming Growth Factor β Repression of cdc25A during Keratinocyte Cell Cycle Arrest. Molecular and Cellular Biology, 19(1), 916–922. https://doi.org/10.1128/mcb.19.1.916

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