These cells, now called myocytes, line up moreover and fuse with neigh boring cells to produce a single membrane structure housing potentially hundreds of nuclei. The process of myogenesis is dependent upon the expression of the Myogenic Regulatory Fators that include Myf5, MyoD, myogenin and MRF4. Both MyoD and Myf5 are expressed in proliferative myoblasts and Myf5 is downregulated as cells progress through myogenesis. Once the cells exit the cell cycle, myogenin and MRF4 are expressed. MRF4 can also act upstream of Myf5 and MyoD. Although there appears to be a certain degree of re dundancy between the MRFs, data from knockout stud ies suggest unique roles for these transcription factors. The majority of myoblasts follow this rather predictable pattern of myogenesis and, in mature muscle, most of the nuclei are terminally differentiated.

However, the process of myogenesis is also characterized by a small percentage of cells that escape differentiation, maintain Pax7 expression, downregulate MyoD, and return to quiescence. These Pax7 MyoD cells are thought to maintain Inhibitors,Modulators,Libraries a small pool of muscle stem cells, from which future proliferative myoblasts may be derived. Cells that escape differentiation and that fail to return to quiescence undergo apoptosis. Indeed, apoptosis is normally regarded as a natural part of differentiation, and identifying factors involved in cell cycle control and survival undoubtedly play an important role in our gen eral understanding of myogenesis and in the etiology of many muscle degenerative diseases.

Inhibitors,Modulators,Libraries Previously, our lab characterized a protein termed Numb Interacting Protein, an interactor of the cell fate determinant, Numb, in Drosophila Melanogastor. Mammals have two isoforms of NIP, but the role of mammalian NIP genes in Numb function has not been demonstrated. Subsequently, Inhibitors,Modulators,Libraries others identified NIP1 and NIP2 as genes arranged in head to head orientation with dual oxidases. Specifically, the protein products of these genes, renamed DUOXA1 and DUOXA2 respect ively, were shown to be important for the maturation of DUOX1 and DUOX2 and, ultimately, the production of H2O2 and thyroid hormone. Dual oxidases belong to the nicotinamide adenine dinucleotide phosphate oxidase family of enzymes responsible for the generation of reactive oxygen species in a variety of cell types. The family is made up of Nox1 through Nox5 and DUOX1 and DUOX2.

While some family members require additional subunits for proper function, DUOX1 Inhibitors,Modulators,Libraries and DUOX2 have no such requirement. Inhibitors,Modulators,Libraries Instead, these two Ca2 dependent Nox members rely on DUOXA1 and DUOXA2 for their maturation andor translocation to the plasma membrane for their activation. Research has demonstrated that DUOXA1 research use and DUOXA2 form heterodimeric complexes with their respective dual oxidases and, in their absence, DUOX enzymes remain internalized in the endoplasmic reticulum and H2O2 is not produced.