c-Myc expression is commonly activated in leukemia and promotes transformation by acting as a master transcriptional regulator of genes necessary for cell cycle progression. The investigators were the first group to recognize that c-Myc was also an important regulator of apoptosis. The investigators have established that c-Myc-induced pathways which regulate myeloid cell cycle progression and apoptosis are separable and their long term goal is to define the mechanisms by which c-Myc regulates these pathways (Aim 1). c-Myc activities are assumed to be antagonized by the functions of a family of transcriptional regulators, the Mads factors, which compete with c-Myc for binding to Max, a shared dimerization partner required for DNA binding. The investigators have identified a novel Mads family member and concomitant expression of Mads factors in myeloid cells suggests their functions are not redundant. The conventional model suggest that Mads factors suppress c-Myc and that Max is required for both c-Myc and Mads functions. This proposal will test both tenets of this hypothesis and will also determine whether these factors have unique effects upon hematopoietic cell fate (Aims 1 and 2). As indicators of their ability to modulate c-Myc functions, the investigators will determine effects of Max and Mads factors upon c-Myc induced cell cycle progression apoptosis (Aim 1) and transcriptional activation (Aim 2). The investigators have demonstrated that ornithine decarboxylase (ODC), the rate limiting enzyme of polyamine biosynthesis, is a direct c-Myc transcription target and is a mediator of c-Myc-induced apoptosis and cell cycle progression. The investigators will determine the mechanism by which c-Myc regulates ODC and whether regulation of ODC by c-Myc and growth factors is modulated by Max and Mads factors (Aim 2). The investigators' findings have demonstrated that other effectors of c-Myc-induced apoptosis exist and the investigators have evidence that another target activated by c-Myc is a member of the CED-3 cysteine protease family, which are executioners of apoptosis throughout phylogeny.
Aim 3 will address the role of this protease as a mediator of c-Myc functions and its regulation by the Myc-Max-Mad network. Thus, these studies will determine both the biological effects and biochemical functions of the Myc-Max-Mad network in the control of hematopoiesis.
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