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J. Biol. Chem., Vol. 276, Issue 28, 25834-25840, July 13, 2001
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From the Ectopic production of the EVI1 transcriptional
repressor zinc finger protein is seen in 4-6% of human acute myeloid
leukemias. Overexpression also transforms Rat1 fibroblasts by an
unknown mechanism, which is likely to be related to its role in
leukemia and which depends upon its repressor activity. We show here
that mutant murine Evi-1 proteins, lacking either the N-terminal zinc finger DNA binding domain or both DNA binding zinc finger clusters, function as dominant negative mutants by reverting the transformed phenotype of Evi-1 transformed Rat1 fibroblasts. The dominant negative
activity of the non-DNA binding mutants suggests sequestration of
transformation-specific cofactors and that recruitment of these cellular factors might mediate Evi-1 transforming activity.
C-terminal binding
protein (CtBP) co-repressor family proteins bind PLDLS-like motifs. We show that the murine Evi-1 repressor domain has two such
sites, PFDLT (site a, amino acids 553-559) and PLDLS (site b, amino
acids 584-590), which independently can bind CtBP family co-repressor
proteins, with site b binding with higher affinity than site a.
Functional analysis of specific CtBP binding mutants show site b is
absolutely required to mediate both transformation of Rat1 fibroblasts
and transcriptional repressor activity. This is the first demonstration
that the biological activity of a mammalian cellular transcriptional
repressor protein is mediated by CtBPs. Furthermore, it suggests that
CtBP proteins are involved in the development of some acute leukemias
and that blocking their ability to specifically interact with EVI1
might provide a target for the development of pharmacological
therapeutic agents.
Evi-1 Transforming and Repressor Activities Are Mediated by CtBP
Co-repressor Proteins*
,
,,, and§§
Glasgow Caledonian University, School of
Biological & Biomedical Sciences, City Campus, Cowcaddens Rd., Glasgow,
G4 OBA, Scotland, the § Laboratoire de Biologie Cellulaire
et Hormonale, CHU Arnaud de Villeneuve, 371 av. du Doyen G. Giraud,
Montpellier 34295, Cedex 5, France, the ¶ Unité
Endocrinologie Moléculaire et Cellulaire des Cancers, INSERM U
540, Université de Montpellier I, 60 rue de Navacelles,
Montpellier 34090, France, the ** CRC Beatson Laboratories, Beatson
Institute for Cancer Research, Glasgow 961 1BD, Scotland, and
the Department of Biochemistry, G08,
University of Sydney, New South Wales 2006, Australia
*
This work was supported in part by the Cancer Research
Campaign (SP2343/0101) and by Tenovus-Scotland (S98/11).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a personal fellowship of the Kay Kendall Leukemia Fund.
§§
To whom correspondence should be addressed. Tel.: 1-141-331-3213;
Fax: 1-141-331-3208; E-mail: c.bartholomew@gcal.ac.uk.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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