脊椎动物心肌基因表达的分子调控

鉴定在心脏发育过程中指导心脏形成的分子途径,将对心脏是如何形成和这些途径的打断如何导致先天性以及后天性心脏病的发生提供一个基本的认识,尽管脊椎动物骨骼肌和心肌看起来很相似,然而,它们的细胞谱系的特化和模式化是由不同的基因推动的,已知有几个转录因子家族在心肌发育和模式建成中发挥重要作用,包括MADS同源盒蛋白MEF2和SRF,螺旋-环-螺旋HAND因子,锌指GATA-4/5/6因子和NK-2同源异型因子,这些转录因子能激活心脏目标基因,从而调控心肌基因的表达.     

PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation

The bHLH factors HAND1 and HAND2 are required for heart, vascular, neuronal, limb, and extraembryonic development. Unlike most bHLH proteins, HAND factors exhibit promiscuous dimerization properties. We report that phosphorylation/dephosphorylation via PKA, PKC, and a specific heterotrimeric protein phosphatase 2A (PP2A) modulates HAND function. The PP2A targeting-subunit B56delta specifically interacts with HAND1 and -2, but not other bHLH proteins. PKA and PKC phosphorylate HAND proteins in vivo, and only B56delta-containing PP2A complexes reduce levels of HAND1 phosphorylation. During RCHOI trophoblast stem cell differentiation, B56delta expression is downregulated and HAND1 phosphorylation increases. Mutations in phosphorylated residues result in altered HAND1 dimerization and biological function. Taken together, these results suggest that site-specific phosphorylation regulates HAND factor functional specificity.