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

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.

Epigenetics and cancer

“…The RIZ gene produces two proteins, RIZ1 and RIZ2, because of the use of alternative promoters. Interestingly, only RIZ1 harbors a SET domain and appears to be the main target of inactivation in tumors (Huang 2002), and mice lacking Riz1 function only are prone to tumor formation (Steele-Perkins et al 2001). In accordance with a tumor-suppressive function of RIZ1, ectopic expression in cancer cell lines results in cell cycle arrest and/or apoptosis (He et al 1998;Jiang et al 1999).…”

“…RIZ1, originally isolated from its interaction with the RB tumor suppressor protein (Buyse et al 1995), was the first SET domain protein demonstrated to be a tumor suppressor (Steele-Perkins et al 2001). The RIZ1 SET domain was recently shown to be a histone H3 Lys 9-specific methyltransferase (Kim et al 2003).…”

PRDM5 is silenced in human cancers and has growth suppressive activities

“…Both PRDM2 and PRDM1 have growth arrest and proapoptotic activities He et al, 1998). Deficiency in the PR-domain of PRDM2 causes tumor susceptibility in mice and mutations in this domain are present in human cancers (Steele-Perkins et al, 2001;. The MDS1-EVI1 (PRDM3) gene is commonly mutated in myeloid leukemia and also contains a PR domain (Fears et al, 1996).…”

A potential role for PRDM12 in the pathogenesis of chronic myeloid leukaemia with derivative chromosome 9 deletion

“…Several groups, including our laboratory, have investigated this marker on CLL B cells and found that greater than 30% CD38 expression within a CLL leukemic population correlates to an overall shorter time to progression and, in general, a poor clinical outcome. [1][2][3][4][5] However, another study suggests that scoring CLL B-cell CD38 expression using both percent-positive and mean fluorescence intensity (MFI) is a more accurate prognostic tool for B-CLL patients. 6 Recently, Ghia et al 7 found that even a small distinct population of CD38 pos cells, displayed as a small peak in a bimodal CD38-staining profile, was associated with progressive disease.…”

“…5 Indeed, haploinsuffuciency has been proposed as a model to explain the more aggressive phenotype of homozygous knockouts of RIZ, the most widely studied PRDM family member. 3 In addition, structural rearrangement, mutation and/or aberrant expression of RIZ, MDS-EVI1 and MEL1 have been reported in myeloid malignancies. 4,7,9 PRDM family members share the feature of expressing two protein products that differ in the presence or absence of the PR domain.…”