title: Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis.
abstract: The distal portion of chromosome 1p is one of the most commonly affected regions in human cancer. In this study of hereditary and sporadic colorectal cancer, a region of frequent deletion was identified at 32.2 centimorgans from 1ptel. Deletion breakpoints clustered in the vicinity of or inside the gene RIZ, which encodes a retinoblastoma protein-interacting zinc finger protein. Sequence analysis revealed frequent frameshift mutations of the RIZ gene. The mutations consisted of 1- or 2-bp deletions of a coding (A)(8) or (A)(9) tract and were confined to microsatellite-unstable colorectal tumors, being present in 9 of 24 (37.5%) primary tumors and in 6 of 11 (54.5%) cell lines; in 2 cell lines the mutation was homozygous/hemizygous. The mutations apparently were selected clonally in tumorigenesis, because similar poly(A) tracts in other genes were not affected. Two alternative products of the gene exist, RIZ1, which contains a PR (PRDI-BF1-RIZ1) domain implicated in tumor suppressor function, and RIZ2, which is lacking this motif. Furthermore, the C-terminal region, which contains the poly(A) tracts, includes a PR-binding motif, possibly mediating interactions with other proteins or with RIZ itself (oligomerization). Four of eleven microsatellite-unstable colorectal cancer cell lines, three of which had frameshifts, showed reduced or absent mRNA expression of RIZ1. 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. We propose that RIZ is a target of the observed 1p alterations, with impairment of the PR domain-mediated function through either frameshift mutation or genomic deletion.
authors.affiliation: Division of Human Cancer Genetics and Department of Pathology, Ohio State University, Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Chadwick
authors.forename: G L
authors.initials: GL
authors.lastname: Jiang
authors.forename: G A
authors.initials: GA
authors.lastname: Bennington
authors.forename: B
authors.initials: B
authors.lastname: Yuan
authors.forename: C K
authors.initials: CK
authors.lastname: Johnson
authors.forename: M W
authors.initials: MW
authors.lastname: Stevens
authors.forename: T H
authors.initials: TH
authors.lastname: Niemann
authors.forename: P
authors.initials: P
authors.lastname: Peltomaki
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.forename: A
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D017209:Apoptosis; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D016368:Frameshift Mutation; D016195:G2 Phase; D016147:Genes, Tumor Suppressor; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D019656:Loss of Heterozygosity; D008938:Mitosis; D009687:Nuclear Proteins / Q000235:genetics*; D011061:Poly A / Q000235:genetics; D020033:Protein Isoforms; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D011061:Poly A; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human