Activation of adenomatous polyposis coli (APC) gene expression by the DNA-alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine requires p53

被引:58
作者
Narayan, S
Jaiswal, AS
机构
[1] Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77555 USA
[2] Univ Texas, Med Branch, Sealy Ctr Oncol & Hematol, Galveston, TX 77555 USA
关键词
D O I
10.1074/jbc.272.49.30619
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
Development of colon cancer is a multistep process frequently involving mutations in both the APC and p53 tumor suppressor genes. In this study we treated the HCT-116 colon cancer cell line with alkylating agents including N-methyl-N'-nitro-N-nitrosoguanidine (MNNG),which is known to cause colon cancer in animals, and examined the expression of both APC and p53 genes. Exposure of cells with MNNG caused an 8-12-fold increase in the level of APC mRNA and protein. APC induction was shown to result from increased nuclear transcription of the APC gene and correlated with a concomitant increase in the p53 protein level after MNNG treatment. A necessary role for p53 in APC gene regulation is supported by the failure of MNNG to induce APC expression in cell lines either expressing very low levels of p53 (HeLa cells) or no p53 (K562 erythroleukemia cells). The overexpression of wild-type p53 gene into HCT-116 cells mimicked the effect of MNNG-induced expression of APC mRNA. A direct causal role for p53 in APC gene regulation was further evaluated by transfecting the wild-type p53 gene into K562 cells and observing a B-fold increase in the APC gene expression. These results support a model featuring a direct link between p53 and APC in response to alkylation-induced DNA damage and suggest a novel role for p53 in a stress-response pathway involving APC.
引用
收藏
页码:30619 / 30622
页数:4
相关论文
共 34 条
[1]   THE TUMOR-SUPPRESSOR GENE-PRODUCT APC BLOCKS CELL-CYCLE PROGRESSION FROM G(0)/G(1) TO S-PHASE [J].
BAEG, GH ;
MATSUMINE, A ;
KURODA, T ;
BHATTACHARJEE, RN ;
MIYASHIRO, I ;
TOYOSHIMA, K ;
AKIYAMA, T .
EMBO JOURNAL, 1995, 14 (22) :5618-5625
[2]   NH2-terminal deletion of beta-catenin results in stable colocalization of mutant beta-catenin with adenomatous polyposis coli protein and altered MDCK cell adhesion [J].
Barth, AIM ;
Pollack, AL ;
Altschuler, Y ;
Mostov, KE ;
Nelson, WJ .
JOURNAL OF CELL BIOLOGY, 1997, 136 (03) :693-706
[3]  
Cheng KC, 1997, CURR TOP MICROBIOL, V221, P5
[4]   WAF1, A POTENTIAL MEDIATOR OF P53 TUMOR SUPPRESSION [J].
ELDEIRY, WS ;
TOKINO, T ;
VELCULESCU, VE ;
LEVY, DB ;
PARSONS, R ;
TRENT, JM ;
LIN, D ;
MERCER, WE ;
KINZLER, KW ;
VOGELSTEIN, B .
CELL, 1993, 75 (04) :817-825
[5]   DIETARY FACTORS AND RISK OF COLON-CANCER [J].
GIOVANNUCCI, E ;
WILLETT, WC ;
STUBBS, A .
ANNALS OF MEDICINE, 1994, 26 (06) :443-452
[6]  
GRODEN J, 1995, CANCER RES, V55, P1531
[7]   THE MOLECULAR-BASIS OF TURCOTS-SYNDROME [J].
HAMILTON, SR ;
LIU, B ;
PARSONS, RE ;
PAPADOPOULOS, N ;
JEN, J ;
POWELL, SM ;
KRUSH, AJ ;
BERK, T ;
COHEN, Z ;
TETU, B ;
BURGER, PC ;
WOOD, PA ;
TAQI, F ;
BOOKER, SV ;
PETERSEN, GM ;
OFFERHAUS, GJA ;
TERSMETTE, AC ;
GIARDIELLO, FM ;
VOGELSTEIN, B ;
KINZLER, KW .
NEW ENGLAND JOURNAL OF MEDICINE, 1995, 332 (13) :839-847
[8]   EXPRESSION OF THE APC GENE AFTER TRANSFECTION INTO A COLONIC-CANCER CELL-LINE [J].
HARGEST, R ;
WILLIAMSON, R .
GUT, 1995, 37 (06) :826-829
[9]  
HARPER JW, 1993, CELL, V75, P805
[10]  
Ichii Shigetoshi, 1992, Human Molecular Genetics, V1, P387, DOI 10.1093/hmg/1.6.387