Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis

The distal portion of chromosome Ip is one of the most commonly affected re gions in human cancer. In this study of hereditary and sporadic colorectal cancer, a region of frequent deletion was identified at 32.2 centimorgans f rom 1ptel. Deletion breakpoints clustered in the vicinity of or inside the gene RIZ, which encodes a retinoblastoma protein-interacting zinc finger pr otein. 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 tumor s, being present in 9 of 24 (37.5%) primary tumors and in 6 of 11 (54.5%) c ell lines; in 2 cell lines the mutation was homozygous/hemizygous. The muta tions apparently were selected clonally in tumorigenesis, because similar p oly(A) tracts in other genes were not affected. Two alternative products of the gene exist, RIZ1, which contains a PR ((P) under bar RDI-BF1-(R) under bar IZ1) domain implicated in tumor suppressor function, and RIZ2, which i s lacking this motif. Furthermore, the C-terminal region, which contains th e poly(A) tracts, includes a PR-binding motif, possibly mediating interacti ons with other proteins or with RIZ itself (oligomerization). Four of eleve n microsatellite-unstable colorectal cancer cell lines, three of which had frameshifts, showed reduced or absent mRNA expression of RIZ1. In a cell li ne that is homozygous/hemizygous for the typical frameshift mutation, immun oblotting showed truncated RIZ protein, whereas adenovirus-mediated RIZ1 ex pression caused G(2)/M arrest and apoptosis. We propose that RIZ is a targe t of the observed Ip alterations, with impairment of the PR domain-mediated function through either frameshift mutation or genomic deletion.