Disease relevance of PRDM2

• 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 [1].
• Modulation of RIZ gene expression is associated to estradiol control of MCF-7 breast cancer cell proliferation [2].
• Here, we have investigated the role of RIZ in hepatoma [3].
• Decreased RIZ1 expression was also found in other tumor types including neuroblastoma and lung cancer [4].
• Methylation of the RIZ1 promoter strongly correlated with lost or decreased RIZ1 mRNA expression in breast, liver, colon, and lung cancer cell lines as well as in liver cancer tissues [5].
• This study suggested that RIZ polymorphisms may be important predictive markers for lung cancer susceptibility [6].

High impact information on PRDM2

• RIZ1 gene expression is frequently silenced in human cancers, and the gene is also a common target of frameshift mutation in microsatellite-unstable cancers [1].
• 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 [1].
• In cultured cells, estradiol induced a redistribution of RIZ protein within the nucleus and in the cytoplasm [7].
• Four of eleven microsatellite-unstable colorectal cancer cell lines, three of which had frameshifts, showed reduced or absent mRNA expression of RIZ1 [8].
• In a cell line that is homozygous/hemizygous for the typical frameshift mutation, immunoblotting showed truncated RIZ protein, whereas adenovirus-mediated RIZ1 expression caused G(2)/M arrest and apoptosis [8].

Chemical compound and disease context of PRDM2

• AIM: To study the frameshift mutations of the retinoblastoma protein-interacting zinc finger gene RIZ in gastric cancer with microsatellite instability, and to identify two coding polyadenosine tracts of RIZ [9].
• AIM: Our previous studies showed increased sensitivity to 5-FU in colon cancer cell lines with microsatellite instability, and considered that mutations of TGFbeta-R II, IGF IIR, RIZ gene might enhance the potentials of cell growth and proliferation, which increased the sensitivity to 5-FU [10].

Biological context of PRDM2

• Silencing of RIZ1 expression stimulated cell proliferation, similar to the effect of estradiol on these cells, associated with a transient increase of c-myc expression [2].
• Experiments of chromatin immunoprecipitation indicated that RIZ2 protein expression was controlled by estrogen receptor and RIZ1 had a direct repressor function on c-myc gene expression [2].
• The PR-plus product RIZ1 is a candidate tumor suppressor because it can induce G(2)/M arrest and/or apoptosis and is commonly underexpressed in breast cancer [3].
• Adenovirus-mediated RIZ1 expression in hepatoma cell lines caused cell cycle arrest in G(2)/M and/or programmed cell death [3].
• The retinoblastoma protein-interacting zinc finger gene (RIZ) is a zinc-finger type DNA binding protein and is postulated as a member of the nuclear protein-methyltransferase superfamily [11].

Anatomical context of PRDM2

• In contrast, RIZ2 expression was increased in patients with acute lymphoblastic leukaemia (eight out of 11, 73%), compared with normal bone marrow cells [12].
• Screening a HeLa cell expression library with a probe designed with multiple repeats of this sequence resulted in the identification of a 1700-aa protein showing a complete homology with the product of the human retinoblastoma-interacting zinc-finger gene RIZ [13].
• Of 30 matched body fluid samples, methylated RIZ1 DNA was found in 11 (37%) NP swabs, 9 (30%) M & T rinsing fluid, 7 (23%) plasma, and 3 (10%) buffy coat samples [14].
• In this study, we examined mutations of two poly adenine tracts, A(8) and A(9), within the coding region of the RIZ gene, in MSI-high (MSI-H) primary cancers occurring in the pancreas, stomach, and colorectum [15].
• Forced expression of RIZ1 protein induced growth arrest and death of HL60 cells [16].

Associations of PRDM2 with chemical compounds

• RIZ1 is also a histone methyltransferase and methylates lysine 9 in histone H3 [17].
• Treatment with the methylation inhibitor 5-aza-2'-deoxycytidine activated RIZ1 mRNA expression in cancer cells [5].
• RIZ2 is generated by an internal promoter and lacks an NH2-terminal motif of RIZ1, the PR domain conserved in a subfamily of zinc finger genes that function as negative regulators of tumorigenesis [4].
• Also, S-adenosylhomocysteine or methyl donor deficiency inhibits RIZ1 and other H3 lysine 9 methylation activities [18].
• We performed in vitro studies comparing the abilities of RIZ1 P704 polymorphic variants (homozygous presence, P704+; absence, P704-; heterozygosity P704(+/-) of a proline at position 704) to coactivate the ERalpha and also examined the polymorphism associated to BMD of 343 Swedish women, aged 20-39 yr [19].

Physical interactions of PRDM2

• Estrogen receptor was co-immunoprecipitated from MCF-7 cell extract by antibodies to RIZ protein and vice versa, thus indicating an existing interaction between these two proteins [13].

Regulatory relationships of PRDM2

• Several RIZ1-regulated genes involved in insulin-like growth factor-1 (IGF-1) signaling were identified using cDNA microarrays [20].

Other interactions of PRDM2

• A domain is conserved between RIZ and the PRDI-BF1/Blimp-1 differentiation factor [21].
• A PRDM5 cDNA was isolated based on its homology to the PR domain of RIZ1 (PRDM2) [22].
• Reducing RIZ1 level correlated with decreased induction of pS2 gene by estrogen in MCF7 cells [23].
• However, a trend was observed: homozygotes for the rare alleles of the EHMT1, EHMT2 and PRDM2 had a mean value for both trimethylation of K9 and K27 of histone H3 remarkably different to the homozygotes for the common alleles [24].
• 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 [25].

Analytical, diagnostic and therapeutic context of PRDM2

• Both the full-length and the truncated RIZ1 polypeptide were located in the nucleus as shown by transfection and immunofluorescence analysis [26].
• By immunoprecipitation and immunoblot analysis we identified two different RIZ protein products of 280 and 250 kDa, designated RIZ1 and RIZ2, respectively [26].
• Moreover, using real-time quantitative methylation-specific PCR, methylation of the RIZ1 promoter was detected in 11 (37%) cases [27].
• Using fluorescence in situ hybridization, we determined that RIZ maps to 1p36 [28].
• Sequence analysis revealed frequent frameshift mutations of the RIZ gene [8].

References