SMRT and N-CoR corepressors are regulated by distinct kinase signaling pathways
SMRT and N-CoR corepressors are regulated by distinct kinase signaling pathways
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DOI：
10.1074/jbc.m410128200
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发表时间：
2004-12-24
影响因子：
4.8
通讯作者：
Privalsky, ML
中科院分区：
文献类型：
--
作者：
Jonas, BA;Privalsky, ML
N-CoR和SMRT是协同抑制因子，与多种后生动物转录因子（包括核激素受体）合作并介导转录抑制。虽然由不同的遗传位点编码，但N-CoR和SMRT具有大量的序列相互关系，与组蛋白去乙酰化酶和辅助因子形成类似的组装，可以与重叠的转录因子伴侣相互作用，并在细胞中发挥重叠的功能。SMRT受MAPK信号通路的负调控，MAPK信号通路位于生长因子和应激信号通路的下游。我们在这里报道，尽管MEKK1的激活导致SMRT的磷酸化，其在体内和体外与转录因子伴侣分离，并从细胞核重新分布到细胞质室，但N-CoR对所有这些形式的调节都是难以抑制的。与MAPK级联相反，生长因子/细胞因子受体下游的其他信号转导通路似乎能够影响这两种辅助抑制因子。我们的研究结果表明，SMRT和N-CoR嵌入在不同的调控网络中，这两种协抑制因子对生长因子、细胞因子、分化和促生存信号的解释不同。
N-CoR and SMRT are corepressor paralogs that partner with and mediate transcriptional repression by a wide variety of metazoan transcription factors, including nuclear hormone receptors. Although encoded by distinct genetic loci, N-CoR and SMRT share substantial sequence interrelatedness, form analogous assemblies with histone deacetylases and auxiliary factors, can interact with overlapping sets of transcription factor partners, and exert overlapping functions in cells. SMRT is subject to negative regulation by MAPK signaling pathways operating downstream of growth factor and stress signaling pathways. We report here that whereas activation of MEKK1 leads to phosphorylation of SMRT, its dissociation from its transcription factor partners in vivo and in vitro, and its redistribution from the cell nucleus to a cytoplasmic compartment, N-CoR is refractory to all these forms of regulation. In contrast to this MAPK cascade, other signal transduction pathways operating downstream of growth factor/cytokine receptors appear able to affect both corepressor paralogs. Our results indicate that SMRT and N-CoR are embedded in distinct regulatory networks and that the two corepressors interpret growth factor, cytokine, differentiation, and prosurvival signals differently.