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J. Biol. Chem., Vol. 282, Issue 46, 33649-33658, November 16, 2007

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Protein Stability and Transcription Factor Complex Assembly Determined by the SCL-LMO2 Interaction^*

Eric Lécuyer¹², Simon Larivière, Marie-Claude Sincennes¹, André Haman, Rachid Lahlil, Margarita Todorova, Mathieu Tremblay¹, Brian C. Wilkes^¶, and Trang Hoang^||**34

From the Institut de Recherche en Immunologie et Cancérologie and the Departments of Molecular Biology, ^||Pharmacology, and ^**Biochemistry, Université de Montréal, Montréal, Québec H3C 2J7, Canada and the ^¶Institut de Recherche Clinique de Montréal, Montréal, Québec H2W 1R7, Canada

Gene expression programs are established by networks of interacting transcription factors. The basic helix-loop-helix factor SCL and the LIM-only protein LMO2 are components of transcription factor complexes that are essential for hematopoiesis. Here we show that LMO2 and SCL are predominant interaction partners in hematopoietic cells and that this interaction occurs through a conserved interface residing in the loop and helix 2 of SCL. This interaction nucleates the assembly of SCL complexes on DNA and is required for target gene induction and for the stimulation of erythroid and megakaryocytic differentiation. We also demonstrate that SCL determines LMO2 protein levels in hematopoietic cells and reveal that interaction with SCL prevents LMO2 degradation by the proteasome. We propose that the SCL-LMO2 interaction couples protein stabilization with higher order protein complex assembly, thus providing a powerful means of modulating the stoichiometry and spatiotemporal activity of SCL complexes. This interaction likely provides a rate-limiting step in the transcriptional control of hematopoiesis and leukemia, and similar mechanisms may operate to control the assembly of diverse protein modules.

Received for publication, May 14, 2007 , and in revised form, August 20, 2007.

^* This work was funded by grants from the Canadian Institutes of Health Research and the National Cancer Institute of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3 and Table S1.

¹ Recipients of Canadian Institutes of Health Research studentships.

² Present address: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1 Canada.

³ Recipient of the Canada Research Chair in Cell Differentiation and the Genetics of Acute Leukemias.

⁴ To whom correspondence should be addressed: Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, P. O. Box 6128, Downtown Branch, Montréal, Québec H3C 2J7, Canada. Tel.: 514-343-6970; Fax: 514-987-5757; E-mail: Trang.hoang{at}umontreal.ca.

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