Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stem cell-based therapy is being considered as an alternative treatment for cardiomyopathy. Hence understanding the basic molecular mechanisms of cardiomyocyte differentiation is important. Besides BMP or Wnt family proteins, TGF-beta family members are thought to play a role in cardiac development and differentiation. Although TGF-beta has been reported to induce cardiac differentiation in embryonic stem cells, the differential role of TGF-beta isoforms has not been elucidated. In this study, employing the DMSO-induced cardiomyocyte differentiation system using P19CL6 mouse embryonic teratocarcinoma stem cells, we investigated the TGF-beta-induced signaling pathway in cardiomyocyte differentiation. TGF-beta1, but not the other two isoforms of TGF-beta, was induced at the mRNA and protein level at an early stage of differentiation, and Smad2 phosphorylation increased in parallel with TGF-beta1 induction. Inhibition of TGF-beta1 activity with TGF-beta 1-specific neutralizing antibody reduced cell cycle arrest as well as expression of the CDK inhibitor p21WAF1. The antibody also inhibited induction of the cardiac transcription factor Nkx2.5. Taken together, these results suggest that TGF-beta1 is involved in cardiomyocyte differentiation by regulating cell cycle progression and cardiac gene expression in an autocrine or paracrine manner.
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PMID:Involvement of TGF-beta1 signaling in cardiomyocyte differentiation from P19CL6 cells. 1818 60

Activation of Ras signaling in cardiomyocytes has been linked to pathogenic myocardial hypertrophy progression and subsequent heart failure. Whether cardiomyopathy can regress once initiated needs to be established more fully. A 'tet-off' system was used to regulate expression of H-Ras-G12V in myocardium to examine whether Ras-induced pathogenic myocardial hypertrophy could resolve after removal of Ras signaling in vivo. Ras activation at weaning for 2 wk caused hypertrophy, whereas activation for 4 to 8 wk led to cardiomyopathy and heart failure. Discontinuing H-Ras-G12V transgene expression after cardiomyopathy onset led to improved survival and cardiomyopathy lesion scores, with reduced heart:body weight ratios, demonstrating the reversibility of early pathogenic hypertrophy. Activation of Ras and downstream ERK 1/2 was associated with elevated expression of proliferating cell nuclear antigen and cyclins B1 and D1, indicating cell-cycle activation and reentry. Coordinate elevation of broad-spectrum cyclin-dependent kinase inhibitors (p21, p27, and p57) and Tyr15 phosphorylation of cdc2 signified the activation of cell-cycle checkpoints; absence of cell-cycle completion and cardiomyocyte replication were documented by using immunohistochemistry for mitosis and cytokinesis markers. After resolution of cardiomyopathy, cell-cycle activators and inhibitors examined returned to basal levels, a change that we interpreted as exit from the cell cycle. Cardiac cell-cycle regulation plays a role in recovery from pathogenic hypertrophy. The model we present provides a means to further explore the underlying mechanisms governing cell-cycle capacity in cardiomyocytes, as well as progression and regression of pathogenic cardiomyocyte hypertrophy.
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PMID:Capacity for resolution of Ras-MAPK-initiated early pathogenic myocardial hypertrophy modeled in mice. 2153 21