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.
| Resar, Linda M S (2010) The high mobility group A1 gene: transforming inflammatory signals into cancer? Cancer Res 70:436-9 |
| Hristov, Alexandra C; Cope, Leslie; Reyes, Marcelo Delos et al. (2009) HMGA2 protein expression correlates with lymph node metastasis and increased tumor grade in pancreatic ductal adenocarcinoma. Mod Pathol 22:43-9 |
| Hillion, Joelle; Wood, Lisa J; Mukherjee, Mita et al. (2009) Upregulation of MMP-2 by HMGA1 promotes transformation in undifferentiated, large-cell lung cancer. Mol Cancer Res 7:1803-12 |
| Di Cello, Francescopaolo; Hillion, Joelle; Hristov, Alexandra et al. (2008) HMGA2 participates in transformation in human lung cancer. Mol Cancer Res 6:743-50 |
| Dolde, Christine E; Mukherjee, Mita; Cho, Chung et al. (2002) HMG-I/Y in human breast cancer cell lines. Breast Cancer Res Treat 71:181-91 |
| Pedulla, M L; Treff, N R; Resar, L M et al. (2001) Sequence and analysis of the murine Hmgiy (Hmga1) gene locus. Gene 271:51-8 |
| Wood, L J; Mukherjee, M; Dolde, C E et al. (2000) HMG-I/Y, a new c-Myc target gene and potential oncogene. Mol Cell Biol 20:5490-502 |
| Wood, L J; Maher, J F; Bunton, T E et al. (2000) The oncogenic properties of the HMG-I gene family. Cancer Res 60:4256-61 |
