Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis

作者：Robert B. Chadwick, G L Jiang, Garth A. Bennington, Bo Yuan, Cheryl K.H. Johnson, Michael W. Stevens, Theodore H. Niemann, Païvi Peltomäki, Shi Huang, Albert de la Chapelle · 发表于：Proceedings of the National Academy of Sciences · 年份：2000 · DOI：10.1073/pnas.040579497 · 被引用次数：176 · 研究领域：Genetic factors in colorectal cancer、Cancer-related Molecular Pathways、Hedgehog Signaling Pathway Studies

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...