Mitsubishi Kagaku Institute of Life Sciences, Machida 194-8511, Japan.
Development. 2011 May;138(9):1771-82. doi: 10.1242/dev.059295. Epub 2011 Mar 29.
In general, cell proliferation and differentiation show an inverse relationship, and are regulated in a coordinated manner during development. Embryonic cardiomyocytes must support embryonic life by functional differentiation such as beating, and proliferate actively to increase the size of the heart. Therefore, progression of both proliferation and differentiation is indispensable. It remains unknown whether proliferation and differentiation are related in these embryonic cardiomyocytes. We focused on abnormal phenotypes, such as hyperproliferation, inhibition of differentiation and enhanced expression of cyclin D1 in cardiomyocytes of mice with mutant jumonji (Jmj, Jarid2), which encodes the repressor of cyclin D1. Analysis of Jmj/cyclin D1 double mutant mice showed that Jmj was required for normal differentiation and normal expression of GATA4 protein through cyclin D1. Analysis of transgenic mice revealed that enhanced expression of cyclin D1 decreased GATA4 protein expression and inhibited the differentiation of cardiomyocytes in a CDK4/6-dependent manner, and that exogenous expression of GATA4 rescued the abnormal differentiation. Finally, CDK4 phosphorylated GATA4 directly, which promoted the degradation of GATA4 in cultured cells. These results suggest that CDK4 activated by cyclin D1 inhibits differentiation of cardiomyocytes by degradation of GATA4, and that initiation of Jmj expression unleashes the inhibition by repression of cyclin D1 expression and allows progression of differentiation, as well as repression of proliferation. Thus, a Jmj-cyclin D1 pathway coordinately regulates proliferation and differentiation of cardiomyocytes.
一般来说，细胞增殖和分化呈负相关，并在发育过程中协调调节。胚胎心肌细胞必须通过功能分化（如跳动）来支持胚胎生命，并积极增殖以增加心脏的大小。因此，增殖和分化的进展都是必不可少的。这些胚胎心肌细胞中的增殖和分化是否相关尚不清楚。我们专注于异常表型，如过度增殖、分化抑制和 cyclin D1 表达增强，在突变 jumonji（Jmj，Jarid2）的小鼠心肌细胞中观察到这种现象，该突变编码 cyclin D1 的抑制剂。对 Jmj/cyclin D1 双突变小鼠的分析表明，Jmj 通过 cyclin D1 对正常分化和 GATA4 蛋白的正常表达是必需的。对转基因小鼠的分析表明，cyclin D1 的过表达降低了 GATA4 蛋白的表达，并以 CDK4/6 依赖的方式抑制了心肌细胞的分化，而外源性表达 GATA4 可挽救异常分化。最后，CDK4 直接磷酸化 GATA4，促进了培养细胞中 GATA4 的降解。这些结果表明，cyclin D1 激活的 CDK4 通过 GATA4 的降解抑制心肌细胞的分化，而 Jmj 表达的启动通过抑制 cyclin D1 表达的抑制释放了这种抑制，从而允许分化的进展以及增殖的抑制。因此，Jmj-cyclin D1 途径协调调节心肌细胞的增殖和分化。
