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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Pathology B Study Section (PTHB)
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Marks, Cheryl L
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Sanford-Burnham Medical Research Institute
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Deng, Qingdong; Huang, Shi (2004) PRDM5 is silenced in human cancers and has growth suppressive activities. Oncogene 23:4903-10
Carling, Tobias; Kim, Keun-Cheol; Yang, Xiao-Hong et al. (2004) A histone methyltransferase is required for maximal response to female sex hormones. Mol Cell Biol 24:7032-42
Carling, Tobias; Du, Yong; Fang, Wei et al. (2003) Intragenic allelic loss and promoter hypermethylation of the RIZ1 tumor suppressor gene in parathyroid tumors and pheochromocytomas. Surgery 134:932-9; discussion 939-40
Fang, W; Piao, Z; Buyse, I M et al. (2001) Preferential loss of a polymorphic RIZ allele in human hepatocellular carcinoma. Br J Cancer 84:743-7
Steele-Perkins, G; Fang, W; Yang, X H et al. (2001) Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily. Genes Dev 15:2250-62
Jiang, G L; Huang, S (2001) Adenovirus expressing RIZ1 in tumor suppressor gene therapy of microsatellite-unstable colorectal cancers. Cancer Res 61:1796-8
Du, Y; Carling, T; Fang, W et al. (2001) Hypermethylation in human cancers of the RIZ1 tumor suppressor gene, a member of a histone/protein methyltransferase superfamily. Cancer Res 61:8094-9
Fang, W; Piao, Z; Simon, D et al. (2000) Mapping of a minimal deleted region in human hepatocellular carcinoma to 1p36.13-p36.23 and mutational analysis of the RIZ (PRDM2) gene localized to the region. Genes Chromosomes Cancer 28:269-75
Piao, Z; Fang, W; Malkhosyan, S et al. (2000) Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability. Cancer Res 60:4701-4
Yang, X H; Huang, S (1999) PFM1 (PRDM4), a new member of the PR-domain family, maps to a tumor suppressor locus on human chromosome 12q23-q24.1. Genomics 61:319-25

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