title: Down-regulation of cardiac lineage protein (CLP-1)  expression in CLP-1 +/- mice affords.
abstract: In order to understand the transcriptional mechanism that underlies cell protection to stress, we evaluated the role of CLP-1, a known inhibitor of the transcription elongation complex (pTEFb), in CLP-1 +/- mice hearts. Using the isolated heart model, we observed that the CLP-1 +/- hearts, when subjected to ischaemic stress and evaluated by haemodynamic measurements, exhibit significant cardioprotection. CLP-1 remains associated with the pTEFb complex in the heterozygous hearts, where as it is released in the wild-type hearts suggesting the involvement of pTEFb regulation in cell protection. There was a decrease in Cdk7 and Cdk9 kinase activity and consequently in phosphorylation of serine-5 and serine-2 of Pol II CTD in CLP-1 +/- hearts. However, the levels of mitochondrial proteins, PGC-1alpha and HIF-1alpha, which enhance mitochondrial activity and are implicated in cell survival, were increased in CLP-1 +/- hearts subjected to ischaemic stress compared to that in wild-type CLP-1 +/- hearts treated identically. There was also an increase in the expression of pyruvate dehydrogenase kinase (PDK-1), which facilitates cell adaptation to hypoxic stress. Taken together, our data suggest that regulation of the CLP-1 levels is critical to cellular adaptation of the survival program that protects cardiomyocytes against stress due collectively to a decrease in RNA Pol II phosphorylation but an increase in expression of target proteins that regulate mitochondrial function and metabolic adaptation to stress.
authors.affiliation: Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Mascareno
authors.affiliation: Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Irena
authors.initials: I
authors.lastname: Manukyan
authors.affiliation: Cardiovascular Research Center, University of Connecticut, School of Medicine, Farmington, CT, USA.
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Das
authors.affiliation: Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: M A Q
authors.initials: MAQ
authors.lastname: Siddiqui
mesh_terms: D000818:Animals; D015536:Down-Regulation; D051379:Mice; D017202:Myocardial Ischemia / Q000235:genetics / Q000503:physiopathology*; D010766:Phosphorylation; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: C118642:Hexim1 protein, mouse; D016601:RNA-Binding Proteins; D014157:Transcription Factors