DOSAGE-DEPENDENT DOMINANCE OVER WILD-TYPE P53 OF A MUTANT P53 ISOLATED FROM NASOPHARYNGEAL CARCINOMA

被引:60
作者
SUN, Y [1 ]
DONG, ZG [1 ]
NAKAMURA, K [1 ]
COLBURN, NH [1 ]
机构
[1] NCI,FREDERICK CANC RES & DEV CTR,PROGRAM RESOURCES INC DYNCORP,BCDP,FREDERICK,MD 21702
关键词
P53; TUMOR SUPPRESSOR GENE; NASOPHARYNGEAL CARCINOMA; HETEROZYGOUS MUTATION; DOMINANT NEGATIVE;
D O I
10.1096/fasebj.7.10.8344492
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutational inactivation of p53, a tumor suppressor gene, is the most common genetic alteration found in human cancer. Most mutated p53s either lose tumor suppressor function or gain oncogenic activity. We recently reported the detection of a heterozygous point mutation of p53 at codon 280 in nasopharyngeal carcinoma (NPC) (1), a high-incidence malignancy in southern China and southeast Asia. Given its heterozygous state, in which both wild-type and mutated p53 gene were expressed, p53-thr280 should function dominantly in the presence of the wild-type form if it is to play a role in nasopharynx carcinogenesis. We tested this dominance hypothesis in the cells of two model systems: 1) human Saos-2 cells lacking endogenous p53, and 2) mouse JB6 tumor promotion-resistant cells (P-) expressing endogenous wild-type p53. The results showed dosage-dependent dominance of p53-thr280 in controlling WT p53-driven transcriptional activity; in governing cell growth; and in progressing P- phenotype to tumor promotion-sensitive (P+) phenotype. This dominant negative effect was seen at a 1:1 (WT:MU) ratio and was more striking at a ratio of 1:3. A model is proposed to explain the dominant negative effect of mutant p53. We conclude from this study that p53-thr280 is likely to be dominant in the heterozygous state found in NPC and that this dominant-negative mutated p53 may contribute to the genesis of NPC or of other carcinomas in which both mutant and wild-type p53 are expressed.
引用
收藏
页码:944 / 950
页数:7
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