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Date of Award

9-2004

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. Michael A. Rudnicki

Abstract

Embryonic studies clearly demonstrate that MyoD and Myf5 are required for specification of the myogenic lineage. Moreover, MyoD plays an essential role in initiating expression of myogenin and inducing differentiation. However, the factors and mechanisms which temporally regulate expression of myogenic genes are not fully understood. Furthermore, the controversy of whether cell cycle withdrawal precedes induction of MyoD transcriptional activity, or MyoD activity induces cell cycle withdrawal, still exist. In this thesis, I demonstrate that although MyoD transcriptional activity is regulated by cell cycle regulators, such as pRb, cdk4 and cyclin D 1, these molecules are functioning in a cell cycle-independent manner. In addition, MyoD regulates cell cycle progression, and more specifically S-phase entry, by regulating the stability of cyclin E. Moreover, MyoD regulates expression of cyclin Dl indirectly by modulating activation of NF-lCB. Importantly, I demonstrate how the E-protein, HEB, regulates myogenic gene expression in an isoform-specific, MRF-specific, and promoterspecific manner. In the absence of HEB, MyoD is unable to effectively induce expression of myogenin, and differentiation is inhibited. Therefore, ubiquitously expressed factors, such as pRb and HEB, are able to regulate the restricted pattern of gene expression in myogenic differentiation.

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