title: Coordinated regulation of differentiation and proliferation of embryonic cardiomyocytes by a jumonji (Jarid2)-cyclin D1 pathway.
abstract: 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.
authors: Mitsubishi Kagaku Institute of Life Sciences, Machida 194-8511, Japan.
authors: Kuniko
authors: K
authors: Nakajima
authors: Masayo
authors: M
authors: Inagawa
authors: Chiharu
authors: C
authors: Uchida
authors: Kumiko
authors: K
authors: Okada
authors: Shoji
authors: S
authors: Tane
authors: Mizuyo
authors: M
authors: Kojima
authors: Misae
authors: M
authors: Kubota
authors: Masatsugu
authors: M
authors: Noda
authors: Satoko
authors: S
authors: Ogawa
authors: Haruki
authors: H
authors: Shirato
authors: Michio
authors: M
authors: Sato
authors: Rika
authors: R
authors: Suzuki-Migishima
authors: Toshiaki
authors: T
authors: Hino
authors: Yukio
authors: Y
authors: Satoh
authors: Masatoshi
authors: M
authors: Kitagawa
authors: Takashi
authors: T
authors: Takeuchi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006321:Heart / Q000196:embryology* / Q000502:physiology; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D063151:Polycomb Repressive Complex 2; D015398:Signal Transduction; D013997:Time Factors
chemical_list: C530105:Ccnd1 protein, mouse; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; C093650:Jarid2 protein, mouse; D009419:Nerve Tissue Proteins; D019938:Cyclin D1; D063151:Polycomb Repressive Complex 2