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Keck Seminar: UNC-45 Chaperones in Heart Development and Cancer

November 30, 2012 by Henry Epstein, MD

Video is also posted on webcast.rice.edu.

Henry Epstein, MD | Professor and Chair, Neuroscience & Cell Biology, University of Texas Medical Branch at Galveston

UNC-45 is essential in multicellular organisms from Caenorhabditis elegans to mammals. In C. elegans, where there is only one protein isoform that can be uniquely expressed in muscle, rapid genetics has showed that the myosin binding UCS C-terminal region is more active than the full-length protein in rescuing unc-45 mutants. These results suggest that the protein partner Heat Shock Protein 90 that binds to the N-terminal TPR domain may serve as an inhibitor of UNC-45: myosin interaction in myosin assembly instead of being the primary chaperone.rn In mammals, there are two genes for UNC-45, UNC-45A expressed broadly in many cell types and functioning in cell division and motility, and UNC-45 B expressed in heart and skeletal myosin during development and post-natal life. The A gene is expressed as two protein isforms as the result of alternative RNA splicing, and they are coexpressed in all cells studied. We have also detected two protein isoforms for UNC-45B that arose by a similar mechanism. One isoform appears to be heart-specific and the other skeletal muscle-specific.rnrnKnockouts of UNC-45B block cardiac myosin expression and contraction and the formation of right heart structures. The effects on myosin are compatible with previously established observation. The effects on morphogenesis appear to be the result of second interaction of UNC-45B with the cardiogenic transcription factor GATA4.rnrnIn human breast cancer cells, UNC-45A mRNA and protein expression are significantly increased. Knockdowns of UNC-45A show that the enhanced cell proliferation and migration of the cancer cells are reduced. These experiments suggest that elevated UNC-45A levels are associated with the metastatic behavior of human breast cancer cells.



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