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Molecular and Cellular Biology, January 1999, p. 916-922, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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

Antonio Iavaronedagger and Joan Massagué*

Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York

Received 26 June 1998/Returned for modification 20 August 1998/Accepted 2 October 1998

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 .

* Corresponding author. Mailing address: Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, Box 116, 1275 York Ave., New York, NY 10021. Phone: (212) 639-8975. Fax: (212) 717-3298. E-mail: j-massague{at}ski.mskcc.org.

dagger Present address: Department of Neurology and Developmental and Molecular Biology, Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.

Molecular and Cellular Biology, January 1999, p. 916-922, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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