Functional studies in Rb regulation of skeletal myogenic program

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Title: Functional studies in Rb regulation of skeletal myogenic program
Authors: Huh, Michael S
Date: 2007
Abstract: The molecular orchestration of skeletal muscle differentiation is a concerted process involving muscle specific transcription factors and components of the cell cycle machinery. The functional capacity of the master myogenic transcription factors MyoD and Myf5 are directly coupled to cell cycle regulatory molecules. MyoD activation powerfully induces differentiation and cell cycle withdrawal in G1. Transit through the G1 restriction point is regulated by the retinoblastoma (Rb) protein. Therefore, skeletal muscle differentiation was assessed in the absence of Rb by histology, immunohistochemistry, and molecular techniques. Rb null myoblasts displayed profound deficiencies in their ability to exit the cell cycle, inhibit apoptosis, and fuse into terminally differentiated myotubes. Global expression analysis revealed a much higher number of deregulated genes in fully differentiated Rb- myotubes than in proliferating Rb- myoblasts. Specifically, the loss of Rb in myotubes resulted in upregulation of cell cycle genes and the downregulation of muscle structural genes and glycolytic enzymes. Finally, ChIP-RDA genomic location analysis identified E2F7 and Myf5 as direct targets of Rb complexes. These data present a transcriptional model in which Rb potentiates the activity of MyoD by repressing Myf5, thereby promoting the progression of skeletal muscle differentiation.
URL: http://hdl.handle.net/10393/29658
http://dx.doi.org/10.20381/ruor-13079
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
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