Lécuyer Eric, Larivière Simon, Sincennes Marie-Claude, Haman André, Lahlil Rachid, Todorova Margarita, Tremblay Mathieu, Wilkes Brian C, Hoang Trang
Institut de Recherche en Immunologie et Cancérologie and the Departments of, Université de Montréal, Montréal, Québec, H3C 2J7, Canada; Department of Molecular Biology, Université de Montréal, Montréal, Québec, H3C 2J7, Canada.
Institut de Recherche en Immunologie et Cancérologie and the Departments of, Université de Montréal, Montréal, Québec, H3C 2J7, Canada.
J Biol Chem. 2007 Nov 16;282(46):33649-33658. doi: 10.1074/jbc.M703939200. Epub 2007 Sep 17.
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.
基因表达程序由相互作用的转录因子网络建立。基本的螺旋-环-螺旋因子SCL和仅含LIM结构域的蛋白LMO2是造血过程中必不可少的转录因子复合物的组成成分。在此我们表明，LMO2和SCL是造血细胞中主要的相互作用伙伴，并且这种相互作用通过位于SCL的环和螺旋2中的保守界面发生。这种相互作用促使SCL复合物在DNA上组装，并是靶基因诱导以及刺激红系和巨核系分化所必需的。我们还证明，SCL决定造血细胞中LMO2的蛋白水平，并揭示与SCL的相互作用可防止LMO2被蛋白酶体降解。我们提出，SCL-LMO2相互作用将蛋白稳定与高阶蛋白复合物组装联系起来，从而提供了一种调节SCL复合物化学计量和时空活性的有力手段。这种相互作用可能是造血和白血病转录控制中的一个限速步骤，并且类似的机制可能在控制多种蛋白模块的组装中起作用。
