Normal cellular proliferation is initiated by growth factors that bind to their specific receptors and ultimately results in the sequential expression of genes important in regulating cell growth. Although a number of cell cycle regulatory genes have been identified, further elucidation of this genetic program will enhance our understanding of normal and neoplastic cell growth. Immediate-early genes are expressed within minutes of growth factor stimulation and include the c-myc proto-oncogene; delayed-early genes are activated hours after growth factor stimulation, but before DNA synthesis, and include the HMG-I/Y gene. To better understand the mechanisms by which delayed-early genes are activated in the G1/S transition of the cell cycle, we have been studying the regulation of the HMG-I/Y gene. Their laboratory has recently shown that HMG-I/Y is a gene target of c-Myc. Their preliminary results also indicate that the HMG-I isoform alone causes neoplastic transformation in an experimental cell line. Because expression of both c-myc and HMG-I/Y are correlated with cellular proliferation and neoplastic transformation, we hypothesize that HMG-I/Y is an important c-Myc target gene required by c-Myc for the regulation of normal and neoplastic cell growth. In addition, HMG-I/Y expression is increased in cancerous cell lines not characterized by elevated c-myc expression. They, therefore, propose that HMG-I may also lead to neoplastic transformation, independent of c-Myc. Thus, the major focus of this research proposal will be to define the role of HMG-I/Y in neoplastic transformation.
The specific aims and basic experimental approaches outlined in this proposal include: 1) Evaluate the role of HMG-I/Y in transformed cell lines characterized by increased c-myc and/or HMG-I/Y expression. Antisense and potential dominant-negative HMG-I/Y vectors will be transfected into appropriate cell lines and subjected to soft agar transformation assays to address this aim. 2) Determine if HMG-I/Y plays a role in apoptosis induced by c-Myc. Antisense and potential dominant-negative HMG-I/Y vectors will also be used. In addition, we will determine if ectopic expression of HMG-I/Y leads to apoptosis. 3) Investigate the mechanisms by which HMG-I leads to neoplastic transformation. By mutagenesis analysis, we will identify the domains of the HMG-I protein required for cell transformation in soft agar assays. Target genes regulated by HMG-I/Y will be determined using representational difference analysis from an inducible HMG-I/Y cell line. 4) Explore the role of Mad, Mxi, and AP-2 in the regulation of HMG-I/Y. Additional co-transfection experiments and mutagenesis analysis using the HMG-I/Y promoter constructs will be performed. Insight gained from these studies should advance our understanding of malignancies associated with increased c-myc and or HMG-I/Y expression and may lead to new treatment strategies.
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