Development of novel therapy for heart failure using Cdk9 as a target molecule

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Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor gamma coactivator 1alphaPeroxisome proliferator-activated receptor gamma coactivator (PGC)-1 is a critical transcriptional regulator of energy metabolism. Here we found that PGC-1alpha is a short lived and aggregation-prone protein. PGC-1alpha localized throughout the nucleoplasm and was rapidly destroyed via the ubiquitin-proteasome pathway. Upon proteasome inhibition, PGC-1alpha formed insoluble polyubiquitinated aggregates. Ubiquitination of PGC-1alpha depended on the integrity of the C terminus-containing arginine-serine-rich domains and an RNA recognition motif. Interestingly, ectopically expressed C-terminal fragment of PGC-1alpha was autonomously ubiquitinated and aggregated with promyelocytic leukemia protein. Cooperation of the N-terminal region containing two PEST-like motifs was required for prevention of aggregation and targeti … More ng of the polyubiquitinated PGC-1alpha for degradation. This region thereby negatively controlled the aggregation properties of the C-terminal region to regulate protein turnover and intranuclear compartmentalization of PGC-1alpha Exogenous expression of the PGC-1alpha C-terminal fragment interfered with degradation of full-length PGC-1alpha and enhanced its coactivation properties. We concluded that PGC-1alpha function is critically regulated at multiple steps via intramolecular cooperation among several distinct structural domains of the protein.HEXIM-1 alleviated hypoxia-induced right ventricular hypertrophyHEXIM-1 is an endogenous inhibitor of Cdk9. To examine the effect of Cdk9 inhibition on the development of cardiac hypertrophy, we developed loss of function model of Cdk9 activity by transgenic over-expression of HEXIM-1. Cardiac-specific HEXIM-1 TG mice and wild-type littermates were subjected to hypoxia (11% O_2). Right ventricular hypertrophy produced by hypoxia was milder in HEXIM-1 TG mice compared to wild-type littermates. Less