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

Abstract

cdc25A is a tyrosine phosphatase that activates G₁cyclin-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 β (TGF-β) or removal of serum factors. Here we show that the TGF-β-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-β 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-β.

ACKNOWLEDGMENTS

We thank Charles Zhang for expert technical assistance and Stacy Blain for critically reading the manuscript.

A.I. was the recipient of a fellowship from the Clinical Scholars Training Program of the Memorial Sloan-Kettering Cancer Center. J.M. is an Investigator of the Howard Hughes Medical Institute.