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Molecular and Cellular Biology, November 2000, p. 8613-8622, Vol. 20, No. 22
Institut de Génétique et de
Biologie Moléculaire et Cellulaire, CNRS-INSERM,
Université Louis Pasteur, 67404 Illkirch-Strasbourg, France
Received 5 May 2000/Returned for modification 16 June 2000/Accepted 17 August 2000
Transcription factors of the CREB family control the expression of
a large number of genes in response to various signaling pathways.
Regulation mediated by members of the CREB family has been linked to
various physiological functions. Classically, activation by CREB is
known to occur upon phosphorylation at an essential regulatory
site (Ser133 in CREB) and the subsequent interaction with the
ubiquitous coactivator CREB-binding protein (CBP). However, the
mechanism by which selectivity is achieved in the identification of
target genes, as well as the routes adopted to ensure tissue-specific activation, remains unrecognized. We have recently described the first
tissue-specific coactivator of CREB family transcription factors, ACT
(activator of CREM in testis). ACT is a LIM-only protein which
associates with CREM in male germ cells and provides an activation
function which is independent of phosphorylation and CBP. Here we
characterize a family of LIM-only proteins which share common
structural organization with ACT. These are referred to as
four-and-a-half-LIM-domain (FHL) proteins and display
tissue-specific and developmentally regulated expression. FHL proteins
display different degrees of intrinsic activation potential. They
provide powerful activation function to both CREB and CREM when
coexpressed either in yeast or in mammalian cells, specific
combinations eliciting selective activation. Deletion analysis of the
ACT protein shows that the activation function depends on specific
arrangements of the LIM domains, which are essential for both
transactivation and interaction properties. This study uncovers the
existence of a family of tissue-specific coactivators that operate
through novel, CBP-independent routes to elicit transcriptional
activation by CREB and CREM. The future identification of additional
partners of FHL proteins is likely to reveal unappreciated aspects of
tissue-specific transcriptional regulation.
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
A Family of LIM-Only Transcriptional Coactivators:
Tissue-Specific Expression and Selective Activation of CREB and
CREM
*
Corresponding author. Mailing address: Institut de
Génétique et de Biologie Moléculaire et Cellulaire,
CNRS-INSERM, Université Louis Pasteur, B.P. 163, 67404 Illkirch-Strasbourg, France. Phone: 33 388 653410. Fax: 33 388 653246. E-mail: paolosc{at}igbmc.u-strasbg.fr.
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