It is becoming increasingly apparent that carcinogenesis is the result of the deregulation of the intricate control mechanisms involved in cell growth and differentiation. Mutations in the p53 gene are the single most common genetic alteration in human tumors. Recently, a cellular protein encoded by the murine double minute (mdm-2) gene was discovered to interact with the p53 tumor suppressor protein in ways which implicate Mdm-2 as a cellular regulator of wild-type p53. Overexpression of mdm-2 has been identified in a number of human and murine tumors. Nearly all these tumors proliferate in the presence of a growth-suppressing, wild- type p53 protein. Thus it has been hypothesized that, in vivo, high levels of Mdm-2 protein can overcome the tumor suppressive activities of wild- type p53. We and other laboratories have observed that the mdm-2 gene produces multiple mRNAs encoding proteins with sizes ranging from 90-54 kDa.
The first aim of this proposal will be to assay the effects of the various Mdm-2 proteins produced from a murine plasmacytoma cell line harboring a novel mdm-2 translocation. We propose to clone the various mdm-2 cDNAs, assaying each for its effects both on cellular differentiation and transformation.
The second aim will test the hypothesis that one or more of the Mdm-2 proteins function as DNA binding transcription factor either alone or in concert with p53. For example, in MOPC21 murine plasmacytomas, Mdm-2 may inactivate the expressed wild-type p53 protein by creating a heterologous Mdm-2:p53 complex that binds to a different DNA binding site, thereby activating a new class of response genes. Finally we propose to test whether Mdm-2 proteins can interact with cellular proteins other than p53. To address this question we will use the yeast two-hybrid system to search for other Mdm-2 protein:protein interactions. Using molecular biology approaches, the overall goal of this proposal is to determine how aberrant mdm-2 gene expression and protein function relates to lymphoid cancers and to identify what contributions the Mdm-2 protein makes in normal cell growth and development.
| Tuttle, Rebecca; Miller, Kelly R; Maiorano, J Nicholas et al. (2012) Novel senescence associated gene, YPEL3, is repressed by estrogen in ER+ mammary tumor cells and required for tamoxifen-induced cellular senescence. Int J Cancer 130:2291-9 |
| Kelley, Kevin D; Miller, Kelly R; Todd, Amber et al. (2010) YPEL3, a p53-regulated gene that induces cellular senescence. Cancer Res 70:3566-75 |
