Clp-1-Mediated Transcriptional Control Of Hypertrophic Gene Programs Underlying Cardiac Hypertrophy

Cardiac hypertrophy is the heart's response to increased work, pressure, or volume overload. It begins with a compensatory phase that allows the heart to meet imposed demand through rapid expression of stress response genes. A decompensatory phase follows marked by additional adaptive stress response gene expression that with prolonged stress progressively turns maladaptive, leading the heart into failure. The transition from compensatory to decompensatory hypertrophy is likely to reflect changes in the transcription factors and regulatory molecules that control these programs in response to changes in stress stimuli and the status of cardiomyocytes throughout the hypertrophic process. Our laboratory has been studying the role of one such transcriptional regulatory molecule, CLP-1 (cardiac lineage protein-1), in the cellular response to hypertrophic stimuli. CLP-1, the mouse homolog of the human HEXIM I gene, is an inhibitor of P-TEFb (transcription elongation factor b), a component of the transcriptional apparatus that controls RNA polymerase II activity and gene transcription. Knockout of the CLP-1 gene results in a severe form of hypertrophy in fetal mice suggesting that in the absence of the CLP-1 inhibitor, uninhibited P-TEFb activity may lead to unregulated expression of stress response genes and decompensatory hypertrophy. Because of its critical role in regulating the stress gene response to hypertrophic stimuli, we review our laboratory's work on CLP-1, its control of P-TEFb under various hypertrophic conditions, and how it may play an important role in a novel gene control mechanism, called promoter proximal pausing, that ensures the rapid expression of stress response genes in response to hypertrophic stimuli.