PRDM2 (PR domain containing 2, with ZNF domain)

2008-03-01   Erika Di Zazzo , Bruno Moncharmont 

Dipartimento di Scienze per la Salute, Università degli studi del Molise, Via Francesco De Sanctis - edificio polifunzionale III, 86170 Campobasso, Italia

Identity

HGNC
LOCATION
1p36.21
LOCUSID
ALIAS
HUMHOXY1,KMT8,KMT8A,MTB-ZF,RIZ,RIZ1,RIZ2
FUSION GENES

DNA/RNA

Description

Spans 150 Kb; 5156 bp coding sequence; 13 exons.

Transcription

Two promoters localized, respectively, in exon 1 and exon 6 guide the synthesis of two transcripts: the first one encodes for the PR domain-containing product (RIZ1) and the other one for the PR domain-lacking form (RIZ2).

Proteins

Atlas Image

Description

RIZ1(280 kDa) and RIZ2(260 kDa) differ only for the presence in the larger form (RIZ1) of the PR domain. In the sequence of both proteins have been identified several domains:
  • PR domain (130 aa), endowed with histone-methyltransferase activity (Lys 9 of histone H3) and implicated in protein-protein interactions;
  • E1A like-domain (100 aa), contains the LXCXE sequence able to interact with the oncosupressor gene Rb;
  • two zinc-finger clusters;
  • proline-rich domain, containing a LXXLL motif mediating the interaction with estrogen receptor.
  • Expression

    RIZ1 and RIZ2 have an ubiquitous and approximately equimolar expression with higher expression levels in neuroendocrine tissues.

    Localisation

    nuclear

    Function

    RIZ Gene products are endowed with DNA-binding as well as transcription factor-binding activities, as evidenced by the independent isolation of RIZ as a retinoblastoma-binding protein (RIZ), a DNA-binding protein (MTB-Zf), or as a GATA3 transcription factor binding protein (G3B).
    MTB-Zf (essentially identical to RIZ2) binds to the MTE DNA element GTCATATGAC of human heme-oxygenase-1 gene and can weakly activate transcription.
    G3B (RIZ) interacts with the transcription factor GATA-3, regulating the expression of several genes critical for T-cell function and development.
    RIZ proteins bind the estrogen receptor in a hormone-dependent manner, acting as a co-activator.
    Estradiol binding to estrogen receptor complex converts RIZ activity from transcriptional repressor into co-activator.
    Specific siRNA silencing of RIZ1 form increases the MCF-7 breast cancer cells growth rate.
    RIZ proteins act as transcriptional repressors binding to GC-rich or Sp-1-binding elements.

    Mutations

    Germinal

    RIZ1 K.O. mice showed a high incidence of diffuse large B-cell lymphomas and a broad spectrum of unusual tumors.

    Somatic

    Deletion of the 1p36 region is frequent in several human cancers including neuroblastoma, breast cancer, intestinal tumors, and malignant melanoma.
    Frameshift mutations in the two poly adenine tracts, A(8) and A(9), generating truncated RIZ1/2 proteins lacking the COOH-terminal PR-binding motif, were found in MSI-high (MSI-H) primary cancers occurring in the pancreas, stomach, endometrium and colorectum.
    The single base substitution that changed A563 in the coding sequence (immediately C-terminal to the PR domain) to a G was found specially in diffuse large B-cell lymphomas (DLBL).
    Missense mutation of RIZ1 changing nucleotide G317 to A were discovered in Saos2 human osteosarcoma cells.
    RIZ harbors a naturally occurring CCT insertion/deletion polymorphism in exon 8 producing a proline insertion/deletion, modulating the impact of estradiol on bone mineral density (BMD).

    Implicated in

    Entity name
    Breast cancer
    Disease
    The RIZ gene might have a role in human breast cancer. In fact, RIZ1 expression is decreased or lost in human breast cancer, whereas RIZ2 expression is normal.
    Entity name
    Gastric cancer
    Disease
    RIZ1 might be a specific target of inactivation in human gastric cancer. Methylation of the RIZ1 promoter was detected in 37% of 30 cases and inactivation of the second allele occurred through frameshift mutation, loss of heterozygosity (LOH) or promoter methylation. Furthermore frameshift mutations in the two coding polyadenosine tracks of RIZ were found in 19 (48%) of 40 gastric carcinomas.
    Entity name
    Endometrial carcinoma
    Disease
    RIZ inactivation is highly selected during the clonal evolution of these tumors. Six (33%) of 18 endometrial carcinomas present frameshift mutation in the two coding polyadenosine tracts of RIZ.
    Entity name
    Colorectal carcinoma
    Disease
    RIZ might have a role in human colorectal tumorigenesis. The region 1p36 is frequently deleted in colorectal cancer; Furthermore, 37.5% of microsatellite-unstable colorectal tumors presents frameshift mutation, consisting of 1- or 2-bp deletions of a coding (A)8 or (A)9 tract, of the RIZ gene.
    Entity name
    Leukaemia
    Disease
    Suppression of RIZ1 expression or enhancement of RIZ2 expression may have an important role in leukaemogenesis. The expression of RIZ1 was significantly decreased in leukaemia cell lines (14 out of 17, 82%) and in patients with acute myeloblastic leukaemia (8 out of 14, 57%). In contrast, RIZ2 expression was increased in patients with acute lymphoblastic leukaemia (8 out of 11, 73%) compared with normal bone marrow cells.
    Entity name
    Ovarian carcinoma
    Disease
    Reduced expression of RIZ1 may play an important role in the pathogenesis and/or development of epithelial ovarian carcinoma, and is considered to be caused in part by aberrant DNA methylation. Decreased expression of RIZ1 was significantly correlated with histological subtypes (P < 0.0001), high tumor grade (P = 0.0153), advanced clinical stage (P = 0.0345), and high Ki67 index (P = 0.0117).
    Entity name
    Neuroblastoma
    Disease
    Advanced stages of neuroblastoma is genetically characterized by deletions or LOH for the short arm of chromosome 1 suggesting that in the deleted region there is a locus for putative suppressor gene.
    Entity name
    Hepatoma
    Disease
    Hepatomas present deletion of the chromosome 1 short arm suggesting that in this region is localized a gene whose functional loss may be involved in hepatocellular carcinogenesis.
    Entity name
    Prostate cancer
    Disease
    RIZ1 may be associated with prostate carcinogenesis. Transcriptional inactivation of RIZ1 gene by aberrant DNA methylation of promoter CpG island is detected in 20 (42.6%) of the 47 prostate cancer tissues.
    Entity name
    Thyroid carcinoma
    Disease
    RIZ1 have probably an important role in thyroid tumorigenesis. RIZ1 is lost in thyroid tumor cell line and is also significantly reduced in thyroid carcinomas when compared with normal thyroid tissues and benign tumors. The loss of RIZ1 is mediated by aberrant cytosine methylation of the RIZ1 promoter.
    Entity name
    Lung cancer
    Disease
    RIZ polymorphisms may be an important predictive markers for lung cancer susceptibility. In fact, the +92337G > A and +95701C > A polymorphisms are associated with reduced risk of lung adenocarcinomas.
    Entity name
    Ostheoporosis
    Disease
    The RIZ P704 insertion (+)/deletion (-) polymorphism modulates the impact of estradiol on bone mineral density (BMD). The RIZ P704 +/+ genotype is a risk factor for low BMD in elderly subjects with low estradiol levels, whereas the RIZ P704 +/+ genotype was associated with high BMD in premenopausal women.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    107066182000The retinoblastoma-interacting zinc-finger protein RIZ is a downstream effector of estrogen action.Abbondanza C et al
    179226842007Decreased expression of RIZ1 and its clinicopathological significance in epithelial ovarian carcinoma: correlation with epigenetic inactivation by aberrant DNA methylation.Akahira J et al
    84675111993Deletion of 1p36 as a primary chromosomal aberration in intestinal tumorigenesis.Bardi G et al
    92235171997In vitro analysis of the E1A-homologous sequences of RIZ.Buyse IM et al
    75386721995The retinoblastoma protein binds to RIZ, a zinc-finger protein that shares an epitope with the adenovirus E1A protein.Buyse IM et al
    117484552002The tumor suppressor gene RIZ in cancer gene therapy (review).Canote R et al
    152823042004A histone methyltransferase is required for maximal response to female sex hormones.Carling T et al
    106889042000Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis.Chadwick RB et al
    27343111989Loss of alleles from the distal short arm of chromosome 1 occurs late in melanoma tumor progression.Dracopoli NC et al
    117194342001Hypermethylation in human cancers of the RIZ1 tumor suppressor gene, a member of a histone/protein methyltransferase superfamily.Du Y et al
    108620322000Mapping 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.Fang W et al
    15511081992Loss of heterozygosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas.Fong CT et al
    163564932006Modulation of RIZ gene expression is associated to estradiol control of MCF-7 breast cancer cell proliferation.Gazzerro P et al
    25450981989Distal deletion of chromosome Ip in ductal carcinoma of the breast.Genuardi M et al
    173560552007The impact of estradiol on bone mineral density is modulated by the specific estrogen receptor-alpha cofactor retinoblastoma-interacting zinc finger protein-1 insertion/deletion polymorphism.Grundberg E et al
    170522632007DNA methylation of the RIZ1 gene is associated with nuclear accumulation of p53 in prostate cancer.Hasegawa Y et al
    97666441998RIZ1, but not the alternative RIZ2 product of the same gene, is underexpressed in breast cancer, and forced RIZ1 expression causes G2-M cell cycle arrest and/or apoptosis.He L et al
    103698081999The retinoblastoma protein-interacting zinc finger gene RIZ in 1p36-linked cancers.Huang S et al
    105084921999Decreased RIZ1 expression but not RIZ2 in hepatoma and suppression of hepatoma tumorigenicity by RIZ1.Jiang Gl et al
    171034612006RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma.Lal G et al
    90069461997The retinoblastoma interacting zinc finger gene RIZ produces a PR domain-lacking product through an internal promoter.Liu L et al
    105440421999Identification of a DNA binding protein cooperating with estrogen receptor as RIZ (retinoblastoma interacting zinc finger protein).Medici N et al
    86543901996cDNA cloning of a novel protein containing two zinc-finger domains that may function as a transcription factor for the human heme-oxygenase-1 gene.Muraosa Y et al
    77124841995Detection and cloning of a common region of loss of heterozygosity at chromosome 1p in breast cancer.Nagai H et al
    109872712000Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability.Piao Z et al
    111354392001RIZ, the retinoblastoma protein interacting zinc finger gene, is mutated in genetically unstable cancers of the pancreas, stomach, and colorectum.Sakurada K et al
    124725712002Altered expression of retinoblastoma protein-interacting zinc finger gene, RIZ, in human leukaemia.Sasaki O et al
    16469861991Abnormalities of chromosome 1 and loss of heterozygosity on 1p in primary hepatomas.Simon D et al
    75902931995Identification and cloning of the G3B cDNA encoding a 3' segment of a protein binding to GATA-3.Shapiro VS et al
    115441822001Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily.Steele-Perkins G et al
    145345442003Biallelic inactivation of the RIZ1 gene in human gastric cancer.Tokumaru Y et al
    93342091997Transcriptional repression mediated by the PR domain zinc finger gene RIZ.Xie M et al
    176936622007Genetic polymorphisms in the Rb-binding zinc finger gene RIZ and the risk of lung cancer.Yoon KA et al

    Other Information

    Locus ID:

    NCBI: 7799
    MIM: 601196
    HGNC: 9347
    Ensembl: ENSG00000116731

    Variants:

    dbSNP: 7799
    ClinVar: 7799
    TCGA: ENSG00000116731
    COSMIC: PRDM2

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000116731ENST00000235372Q13029
    ENSG00000116731ENST00000311066Q13029
    ENSG00000116731ENST00000343137Q13029
    ENSG00000116731ENST00000376048Q13029
    ENSG00000116731ENST00000407521D6RJM6
    ENSG00000116731ENST00000413440Q13029
    ENSG00000116731ENST00000484063D6RAA0
    ENSG00000116731ENST00000487453S4R3F7
    ENSG00000116731ENST00000491134H0Y9J3
    ENSG00000116731ENST00000503842D6RED5
    ENSG00000116731ENST00000505823D6RED5

    Expression (GTEx)

    0
    5
    10
    15
    20
    25
    30
    35
    40

    Pathways

    PathwaySourceExternal ID
    Lysine degradationKEGGko00310
    Lysine degradationKEGGhsa00310

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    146336782003Inactivation of a histone methyltransferase by mutations in human cancers.50
    210416082011Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up.48
    117194342001Hypermethylation in human cancers of the RIZ1 tumor suppressor gene, a member of a histone/protein methyltransferase superfamily.38
    198436712009Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylation in colorectal cancer.38
    165012482006Genetic variants in epigenetic genes and breast cancer risk.28
    191245062009Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer.22
    206750092010Epigenetic inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involves both DNA methylation and histone modifications.17
    249669402014Methylation of PRDM2, PRDM5 and PRDM16 genes in lung cancer cells.16
    171034612006RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma.14
    179632972007Silencing SMYD3 in hepatoma demethylates RIZI promoter induces apoptosis and inhibits cell proliferation and migration.14

    Citation

    Erika Di Zazzo ; Bruno Moncharmont

    PRDM2 (PR domain containing 2, with ZNF domain)

    Atlas Genet Cytogenet Oncol Haematol. 2008-03-01

    Online version: http://atlasgeneticsoncology.org/gene/41834/prdm2-(pr-domain-containing-2-with-znf-domain)