This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A common denominator of most human cancers is activation of the MYC family of transcription factors. c-Myc functions are generally required for cell growth and cell cycle traverse and its expression is sufficient to drive quiescent cells into S phase. Furthermore, activation of c-Myc blocks terminal differentiation and can induce angiogenesis. Thus, defining the pathways of Myc-mediated cell cycle progression and angiogenesis might help to identify novel therapeutic targets. While it has been intensively studied, the precise role that c-Myc plays in these processes remains largely unresolved. Our studies using in vitro systems, as well as knockout and transgenic mice have demonstrated that c-Myc is required to regulate vasculogenesis, angiogenesis and tumorigenesis. In addition, our recent studies have demonstrated that c-Myc is important for the regulation of angiogenic factors that are important for the progression of intestinal cancer in the ApcMin mouse model. Taken together, these data support the hypothesis that colorectal tumorigenesis is governed by Myc's ability to regulate cell proliferation and to function as a master regulator of factors responsible for cell proliferation, growth and angiogenesis. The experiments laid out in this research proposal address these central issues, with a main focus on Myc's role in intestinal tumorigenesis and angiogenesis. The following Specific Aims are proposed:
Specific Aim #1. Identify the angiogenic factors regulated by Myc during intestinal tumorigenesis. A. Examine the expression of angiogenic factors in ApcMin/+ c-myc+/+ mice versus ApcMin/+ c-myc+/- mice. B. Determine the mechanism(s) by which c-Myc regulates expression of several factors that are important for tumor angiogenesis (HuR, VEGF, Ang-2, ephrin-A2, EphA2 and EphB2). C. Define the physiological consequences of c-Myc's regulation of these factors.
Specific Aim #2. Determine the role of Myc in the colonic epithelium during tumorigenesis. A. Assess the effect of c-Myc loss during neoplastic disease. B. Assess the effect of N-Myc loss during neoplastic disease.
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