It is now well established that loss of tumor suppressor gene function commonly occurs in human cancer and plays a key role in tumor initiation as well as progression. A large body of evidence show that the retinoblastoma tumor suppressor gene (Rb) and components of the Rb suppressor pathway are important targets of alteration during tumor development. The RIZ gene was isolated based on its ability to bind to Rb protein. RIZ gene maps to chromosome band Ip36 which is commonly deleted in many types of human cancers including breast cancer, hepatoma, colon cancer, neuroblastoma, melanoma, and others. RIZ contains a PR domain related to the MDS1-EVI1 leukemia gene and the BLIMP1 transcription repressor. MDS1-EVI1 gene normally gives rise to a PR domain lacking product EVI1 through an internal promoter. EVI1 is an oncogene which is overexpressed in certain human and mouse myeloid leukemias. Similar to MDS1-EVI1, RIZ gene also normally produces two products RIZ1 and RIZ2. RIZ2 lacks the PR domain of RIZ1 and is generated through an internal promoter. Transcripts of RIZ1 and RIZ2 can be found in most normal tissues. However, RIZ1 transcript was undertectable in most of the hepatoma cell lines examined which RIZ2 trascripts were found in all cell lines. Oss of RIZ1 expression was also found in hepatoma tissues and in brest cancer cell lines. Reduced RIZ1 expression is found in a variety of human tumor cell lines and tissues. To address whether loss or reduction of RIZ1 expression may contribute to tumorigenesis, we generated a mouse strain homozygous for a targeted mutation in RIZ1. This strain expressed RIZ2 normally but has drastically reduced expression of the targeted RIZ1 allele. This mutant strain is viable and fertile but develops a broad and unusual spectrum of tumors. Taken together, these data provide conclusive evidence for RIZ1 as a tumor suppressor. The goal of this proposal is to understand the role of tumor suppressor genes in tumorigenesis. Specifically, the role of RIZ1 in tumrigenesis will be determined by accomplishing the following specific aims: 1) further analyze the spontaneous tumor incidence of mice homozygous and heterozygous for a targeted mutation in RIZ1. 2) address the mechanisms of tumor induction through cell biology and molecular biology studies. 3) develop in situ method for analysis of RIZ1 expression in tumors; study the mechanisms of loss of RIZ1 expression by characterizing the RIZ1 promoter.
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