The cell cycle is composed of a series of steps which can be negatively or positively regulated by various factors. Chief among the negative regulators is the p53 protein. Alteration or inactivation of p53 by mutation, or by its interactions with oncogene products of DNA tumour viruses, can lead to cancer. These mutations seem to be the most common genetic change in human cancers.
The p53 tumor suppressor gene is inactivated in human tumors by several distinct mechanisms. The best characterized inactivation mechanisms are: (i) gene mutation; (ii) p53 protein association with viral proteins; (iii) p53 protein association with the MDM2 cellular oncoprotein. The MDM2 gene has been shown to be abnormally up-regulated in human tumors and tumor cell lines by gene amplification, increased transcript levels and enhanced translation. This communication presents a brief review of the spectrum of MDM2 abnormalities in human tumors and compares the tissue distribution of MDM2 amplification and p53 mutation frequencies. In this study, 3889 samples from tumors or xenografts from 28 tumor types were examined for MDM2 amplification from previously published sources. The overall frequency of MDM2 amplification in these human tumors was 7%. Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%). Tumors which showed a higher incidence of MDM2 amplification than p53 mutation were soft tissue tumors, testicular germ cell cancers and neuro-blastomas. Data from studies where both MDM2 amplification and p53 mutations were analyzed within the same samples showed that mutations in these two genes do not generally occur within the same tumor. In these studies, 29 out of a total of 33 MDM2 amplification-positive tumors had wild-type p53. We hypothesize that heretofore uncharacterized carcinogens favor MDM2 amplification over p53 mutations in certain tumor types. A database listing the MDM2 gene amplifications is available on the World Wide Web at http://www. infosci.coh.org/mdm2 . Charts of MDM2 amplification frequencies and comparisons with p53 genetic alterations are also available at this Web site.
ABSTRACTp53 activates transcription of genes with a p53 response element, and it can repress genes lacking the element. Here we demonstrate that wild-type but not mutant p53 Inhibits transcription in a HeLa nuclear extract from minimal promoters. Wild-type but not mutant p53 binds to human TATA-binding protein (TBP). p53 does not bind to yeast TBP, and it cannot Inhibit tscription in a HeLa extract where yeast TBP subsitutes for hun TBP. These results suggest a model in which p53 binds to TBP and interferes with transcriptional initiation.The p53 gene product functions as a transcription factor. It can activate transcription when bound to a promoter through a heterologous DNA-binding domain (1,2). Wild-type p53 (p53wt) binds to DNA sequences termed p53 response elements (3, 4), and when these binding sites are adjacent to a minimal promoter, they stimulate expression in a p53-dependent fashion (5-8). p53wt also negatively regulates a variety of genes that lack a p53 response element, including the c-fos, c-jun, retinoblastoma, interleukin 6, and proliferating cell nuclear antigen genes as well as the p53 gene itself (9)(10)(11)(12). Expression of a class I major histocompatibility complex gene (9) and the Ha-rasl gene (13,14), however, are reportedly neither activated nor repressed by p53wt. Thus, it appears that p53wt may exert positive or negative effects on the expression of some but not all genes, and this may form the mechanistic basis for its ability to regulate cell proliferation.Here we show that p53wt, but not mutant p53 (p53mt), inhibits transcription in nuclear extracts from minimal promoters. Furthermore, p53wt can bind directly to the human TATA-binding protein (TBP). These results suggest that p53 functions as part of the transcriptional machinery, regulating transcription. MATERIALS AND METHODSPlasmids, Chioramphenicol Acetyltranserase (CAT) Assays, and Protein Purifiation. p11-4 encodes a murine pS3wt (m-p53wt) cDNA and pSVKH215 contains a m-p53mt cDNA with a four-amino acid insert at residue 215; both are controlled by the simian virus 40 early promoter (15). pc53-CIN encodes a human p53wt (h-pS3wt) gene containing introns 2-4, under control of the cytomegalovirus immediate-early promoter, and pc53-Cx22AN is identical to pc53-CIN except that its coding region contains an Arg-175 to His substitution (16). pTICAT (17), p50-2 (8), and pMLTATA (18) have been described. h-p53wt and His-175 h-p53mt cDNAs were subcloned into pETild DNA (19) to create pET-p53wt and pET-p53mt. Plasmids 12028The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
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