Differential regulation of Hand1 homodimer and Hand1-E12 heterodimer activity by the cofactor FHL2
Differential regulation of Hand1 homodimer and Hand1-E12 heterodimer activity by the cofactor FHL2
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DOI：
10.1128/mcb.24.22.9835-9847.2004
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发表时间：
2004-11-01
影响因子：
5.3
通讯作者：
Riley, PR
中科院分区：
文献类型：
--
作者：
Hill, AA;Riley, PR
基本螺旋-环-螺旋 (bHLH) 因子 Hand1 在心脏形态发生中发挥着重要作用，但其确切功能仍不清楚。涉及 Hand1 的蛋白质-蛋白质相互作用提供了一种确定如何调节发育中心脏中 Hand1 诱导的基因表达的方法。已知 Hand1 在体外可与几乎普遍存在的 E 因子和其他谱系限制的 B 类 bHLH 蛋白形成异二聚体，或与自身形成同二聚体。迄今为止，尚未报道涉及非 bHLH 蛋白的 Hand1 蛋白相互作用。异二聚体与同二聚体的选择是由 Hand1 的磷酸化状态介导的；然而，人们对这些二聚体的体内功能知之甚少，更重要的是，对它们的调节方式知之甚少。为了了解二聚化后如何调节心脏中的 Hand1 活性，我们研究了 Hand1 蛋白与非 bHLH 因子的三级相互作用。我们描述了 Hand1 与 LIM 结构域蛋白 FHL2 的新型相互作用，FHL2 是一种在发育中的心血管系统中表达的已知转录共激活因子和辅抑制因子。 FHL2 通过 bHLH 结构域与 Hand1 相互作用，能够抑制 Hand1/E12 异二聚体诱导的转录，但对 Hand1/Hand1 同二聚体活性没有影响。 FHL2 的这种作用不是在二聚化水平上介导的，也不是通过 Hand1/E12 DNA 结合的作用介导的。总之，我们的数据描述了通过辅因子 FHL2 关联对 Hand1 异二聚体与同二聚体的新型差异调节，并提供了对发育中心脏中 Hand1 活性三级控制潜力的见解。
The basic helix-loop-helix (bHLH) factor Hand1 plays an essential role in cardiac morphogenesis, and yet its precise function remains unknown. Protein-protein interactions involving Hand1 provide a means of determining how Hand1-induced gene expression in the developing heart might be regulated. Hand1 is known to form either heterodimers with near-ubiquitous E-factors and other lineage-restricted class B bHLH proteins or homodimers with itself in vitro. To date, there have been no reported Hand1 protein interactions involving non-bHLH proteins. Heterodimer-versus-homodimer choice is mediated by the phosphorylation status of Hand1; however, little is known about the in vivo function of these dimers or, importantly, how they are regulated. In an effort to understand how Hand1 activity in the heart might be regulated postdimerization, we have investigated tertiary Hand1-protein interactions with non-bHLH factors. We describe a novel interaction of Hand1 with the LIM domain protein FHL2, a known transcriptional coactivator and corepressor expressed in the developing cardiovascular system. FHL2 interacts with Hand1 via the bHLH domain and is able to repress Hand1/E12 heterodimer-induced transcription but has no effect on Hand1/Hand1 homodimer activity. This effect of FHL2 is not mediated either at the level of dimerization or via an effect of Hand1/E12 DNA binding. In summary, our data describe a novel differential regulation of Hand1 heterodimers versus homodimers by association of the cofactor FHL2 and provide insight into the potential for a tertiary level of control of Hand1 activity in the developing heart.