Molecular and Cellular Biology, September 2000, p. 6612-6625, Vol. 20, No. 17
Section of Microbiology, University of
California at Davis, Davis, California 95616
Received 13 December 1999/Returned for modification 29 February
2000/Accepted 24 May 2000
The SMRT (silencing mediator of retinoic acid and thyroid hormone
receptor) corepressor participates in the repression of target gene
expression by a variety of transcription factors, including the nuclear
hormone receptors, promyelocytic leukemia zinc finger protein, and
B-cell leukemia protein 6. The ability of SMRT to associate with these
transcription factors and thereby to mediate repression is strongly
inhibited by activation of tyrosine kinase signaling pathways, such as
that represented by the epidermal growth factor receptor. We report
here that SMRT function is potently inhibited by a mitogen-activated
protein kinase (MAPK) kinase kinase (MAPKKK) cascade that operates
downstream of this growth factor receptor. Intriguingly, the SMRT
protein is a substrate for phosphorylation by protein kinases operating
at multiple levels in this MAPKKK pathway, including the MAPKs,
MAPK-extracellular signal-regulated kinase 1 (MEK-1), and MEK-1 kinase
(MEKK-1). Phosphorylation of SMRT by MEKK-1 and, to a lesser extent,
MEK-1 inhibits the ability of SMRT to physically tether to its
transcription factor partners. Notably, activation of MEKK-1 or MEK-1
signaling in transfected cells also leads to a redistribution of the
SMRT protein from a nuclear compartment to a more perinuclear or
cytoplasmic compartment. We suggest that SMRT-mediated repression is
regulated by the MAPKKK cascade and that changes both in the affinity
of SMRT for its transcription factors and in the subcellular
distribution of SMRT contribute to the loss of SMRT function that is
observed in response to kinase signal transduction.
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Copyright © 2000, American Society for Microbiology. All rights reserved.
The SMRT Corepressor Is Regulated by a MEK-1 Kinase Pathway:
Inhibition of Corepressor Function Is Associated with SMRT
Phosphorylation and Nuclear Export
*
Corresponding author. Mailing address: Section of
Microbiology, University of California at Davis, One Shields Ave.,
Davis, CA 95616. Phone: (530) 752-3013. Fax: (530) 752-9014. E-mail: mlprivalsky{at}ucdavis.edu.
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