NO POINT MUTATION OF HA-RAS OR P53 GENES EXPRESSED IN PRENEOPLASTIC-TO-NEOPLASTIC PROGRESSION AS MODELED IN MOUSE JB6 CELL VARIANTS

被引:52
作者
SUN, Y [1 ]
NAKAMURA, K [1 ]
HEGAMYER, G [1 ]
DONG, ZG [1 ]
COLBURN, N [1 ]
机构
[1] NCI,FREDERICK CANC RES & DEV CTR,PROGRAM RESOURCES INC DYN CORP,BCDP,FREDERICK,MD 21701
关键词
TUMOR PROMOTION PROGRESSION; POINT MUTATION; P53; EXPRESSION; MESSENGER RNA TRANSCRIPTS; TPA REGULATION;
D O I
10.1002/mc.2940080111
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
Alterations of the p53 gene have been found in many human and animal tumors, and ras mutations have been seen somewhat less frequently. Loss of p53 tumor suppressor activity has been implicated in multistage tumor promotion/progression after initiation by Ha-ras or Ki-ras activation. Whether p53 or ras alterations occur during promotion of neoplastic transformation in JB6 cells has not been reported. Using a series of mouse JB6 variants representing different stages of progression toward the tumor-cell phenotype, we investigated whether mutational activation of Ha-ras and mutational inactivation and altered expression of the p53 gene occurred during progression. We report here that neither point mutations of the Ha-ras or p53 genes nor p53 structural alterations were involved in this process. Although there was no significant difference in steady-state levels of p53 mRNA, an elevated level of immunoprecipitable p53 protein was observed in a subset of transformed cells. We also report the detection of a second 2.2-kb p53-hybridizing transcript. This transcript was not translated into p53 protein and may be a nuclear precursor of the mature message. Both p53-hybridizing transcripts were downregulated by prolonged 12-0-tetradecanoylphorbol-13-acetate (TPA) treatment (24 h) regardless of the stage of progression. We conclude from this study that in JB6 variants (1) mutational activation of Ha-ras and inactivation of p53 are unlikely to be involved in preneoplastic progression; (2) increased amounts of p53 protein may be involved in a subset of transformed cells, possibly reflecting a longer half-life, as demonstrated in other systems; and (3) late downregulation of p53 mRNA but not protein expression may be a secondary response in the TPA-mediated signal transduction pathway. (C) 1993 Wiley-Liss, Inc.*
引用
收藏
页码:49 / 57
页数:9
相关论文
共 46 条
[1]   DIFFERENTIAL C-JUN EXPRESSION IN RESPONSE TO TUMOR PROMOTERS IN JB6 CELLS SENSITIVE OR RESISTANT TO NEOPLASTIC TRANSFORMATION [J].
BENARI, ET ;
BERNSTEIN, LR ;
COLBURN, NH .
MOLECULAR CARCINOGENESIS, 1992, 5 (01) :62-74
[2]   APL/JUN FUNCTION IS DIFFERENTIALLY INDUCED IN PROMOTION-SENSITIVE AND RESISTANT JB6 CELLS [J].
BERNSTEIN, LR ;
COLBURN, NH .
SCIENCE, 1989, 244 (4904) :566-569
[3]   12-O-TETRADECANOYLPHORBOL-13-ACETATE INDUCED LEVELS OF AP-1 PROTEINS - A 46-KDA PROTEIN IMMUNOPRECIPITATED BY ANTI-FRA-1 AND INDUCED IN PROMOTION-RESISTANT BUT NOT PROMOTION-SENSITIVE JB6 CELLS [J].
BERNSTEIN, LR ;
BRAVO, R ;
COLBURN, NH .
MOLECULAR CARCINOGENESIS, 1992, 6 (03) :221-229
[4]   ANALYSIS OF THE GENE CODING FOR THE MURINE CELLULAR TUMOR-ANTIGEN P53 [J].
BIENZ, B ;
ZAKUTHOURI, R ;
GIVOL, D ;
OREN, M .
EMBO JOURNAL, 1984, 3 (09) :2179-2183
[5]   ISOLATION AND CHARACTERIZATION OF THE 5' FLANKING REGION OF THE MOUSE C-HARVEY-RAS GENE [J].
BROWN, K ;
BAILLEUL, B ;
RAMSDEN, M ;
FEE, F ;
KRUMLAUF, R ;
BALMAIN, A .
MOLECULAR CARCINOGENESIS, 1988, 1 (03) :161-170
[6]   CARCINOGEN-INDUCED MUTATIONS IN THE MOUSE C-HA-RAS GENE PROVIDE EVIDENCE OF MULTIPLE PATHWAYS FOR TUMOR PROGRESSION [J].
BROWN, K ;
BUCHMANN, A ;
BALMAIN, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (02) :538-542
[7]  
BURNS PA, 1991, ONCOGENE, V6, P2363
[8]   MUTATIONS IN HUMAN-BREAST CANCER - AN OVERVIEW [J].
CALLAHAN, R ;
CAMPBELL, G .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1989, 81 (23) :1780-1786
[9]   GENETIC MECHANISMS OF TUMOR SUPPRESSION BY THE HUMAN P53 GENE [J].
CHEN, PL ;
CHEN, YM ;
BOOKSTEIN, R ;
LEE, WH .
SCIENCE, 1990, 250 (4987) :1576-1580
[10]  
COLBURN NH, 1978, CANCER RES, V38, P624