Phosphorylation of RNA polymerase II in cardiac hypertrophy: cell enlargement signals converge on cyclin T/Cdk9.
Cardiac myocyte enlargement is the eponymous characteristic of cardiac hypertrophy, regardless of the instigating signal. Such triggers include biomechanical stress (e.g., work load, compensation for ischemic damage), sarcomeric protein mutations, cytoskeletal protein mutations, abnormal energetics, G protein-coupled receptors for ligands (including angiotensin II and endothelin-1), or their signal transducers within cells. In turn, increased myocyte size reflects increased RNA and protein content per cell as responses to these stimuli. In eukaryotic cells, the large subunit of RNA polymerase II (RNAPII) becomes extensively phosphorylated in its serine-rich C-terminal domain (CTD) during the transition from transcript initiation to transcript elongation - that is, "escape" of RNAPII from the promoter-proximal region into the open reading frame. Although this process is believed to be crucial to productive synthesis of mRNA and is known to be governed by two atypical cyclin-dependent kinases, Cdk7 and Cdk9, surprisingly little is understood of how regulatory pathways within cells intersect these RNAPII-directed protein kinases. Investigations of the CTD kinase module in cardiac hypertrophy provide a tentative initial map of a molecular circuit controlling cell size through regulated phosphorylation of RNAPII.
Kulkarni
Prathit A
PA
Center for Cardiovascular Development and Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Sano
Motoaki
M
Schneider
Michael D
MD
D000818:Animals; D001696:Biomechanical Phenomena; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D048429:Cell Size; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D012319:RNA Polymerase II / Q000378:metabolism*; D015398:Signal Transduction; D000095043:Cyclin-Dependent Kinase-Activating Kinase
C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human