Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein–methyltransferase superfamily
Open Access
- 1 September 2001
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 15 (17), 2250-2262
- https://doi.org/10.1101/gad.870101
Abstract
The retinoblastoma protein-interacting zinc finger gene RIZ(PRDM2) is a member, by sequence homology, of a nuclear protein–methyltransferase (MTase) superfamily involved in chromatin-mediated gene expression. The gene produces two protein products, RIZ1 that contains a conserved MTase domain and RIZ2 that lacks the domain. RIZ1 gene expression is frequently silenced in human cancers, and the gene is also a common target of frameshift mutation in microsatellite-unstable cancers. We now report studies of mice with a targeted mutation in the RIZ1 locus. The mutation inactivatesRIZ1 but not RIZ2. These RIZ1 mutant mice were viable and fertile but showed a high incidence of diffuse large B-cell lymphomas (DLBL) and a broad spectrum of unusual tumors. RIZ1deficiency also accelerated tumorigenesis in p53 heterozygous mutant mice. Finally, several missense mutations of RIZ1 were found in human tumor tissues and cell lines; one of these was particularly common in human DLBL tumors. These missense mutations, as well as the previously described frameshift mutation, all mapped to the MTase functional domains. All abolished the capacity of RIZ1 to enhance estrogen receptor activation of transcription. These data suggest a direct link between tumor formation and the MTase domain of RIZ1 and describe for the first time a tumor susceptibility gene among methyltransferases.Keywords
This publication has 53 references indexed in Scilit:
- Mapping of a minimal deleted region in human hepatocellular carcinoma to 1p36.13-p36.23 and mutational analysis of theRIZ (PRDM2) gene localized to the regionGenes, Chromosomes and Cancer, 2000
- A bird's eye view of global methylationNature Genetics, 2000
- Identification of a DNA Binding Protein Cooperating with Estrogen Receptor as RIZ (Retinoblastoma Interacting Zinc Finger Protein)Biochemical and Biophysical Research Communications, 1999
- Regulation of Transcription by a Protein MethyltransferaseScience, 1999
- Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formationThe EMBO Journal, 1998
- Codeletion ofCDKN2 andMTAP genes in a subset of non-Hodgkin's lymphoma may be associated with histologic transformation from low-grade to diffuse large-cell lymphomaGenes, Chromosomes and Cancer, 1998
- The Retinoblastoma Interacting Zinc Finger Gene RIZ Produces a PR Domain-lacking Product through an Internal PromoterPublished by Elsevier BV ,1997
- Report of the Second International Workshop on Human Chromosome 1 Mapping 1995Cytogenetic and Genome Research, 1996
- Identification and cloning of the G3B cDNA encoding a 3′ segment of a protein binding to GATA-3Gene, 1995
- Mutation and Cancer: Statistical Study of RetinoblastomaProceedings of the National Academy of Sciences of the United States of America, 1971