Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily

George Steele-Perkins, Wei Fang, Xiao Hong Yang, Mireille Van Gele, Tobias Carling, Jian Gu, Inge M. Buyse, Jonathon A. Fletcher, Jinsong Liu, Roderick Bronson, Robert B. Chadwick, Albert De La Chapelle, Xiao Kun Zhang, Frank Speleman, Shi Huang

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

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 inactivates RIZ1 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. RIZ1 deficiency 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.

Original languageEnglish
Pages (from-to)2250-2262
Number of pages13
JournalGenes and Development
Volume15
Issue number17
DOIs
StatePublished - 1 Sep 2001
Externally publishedYes

Keywords

  • DLBL
  • Human cancer
  • MTase
  • Mutation
  • RIZ1
  • Tumor formation

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