Increased apoptosis induction by 121F mutant p53

被引:102
作者
Saller, E
Tom, E
Brunori, M
Otter, M
Estreicher, A
Mack, DH
Iggo, R [1 ]
机构
[1] Swiss Inst Expt Canc Res, CH-1066 Epalinges, Switzerland
[2] Eos Biotechnol, S San Francisco, CA 94080 USA
关键词
apoptosis; MDM2; p53; PIR121; Rad;
D O I
10.1093/emboj/18.16.4424
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
p53 mutants in tumours have a reduced affinity for DNA and a reduced ability to induce apoptosis, We describe a mutant with the opposite phenotype, an increased affinity for some p53-binding sites and an increased ability to induce apoptosis, The apoptotic function requires transcription activation by p53, The mutant has an altered sequence specilicity and selectively fails to activate MDM2 transcription. Loss of MDM2 feedback results in overexpression of the mutant, but the mutant kills better than wild-type p53 even in MDM2-null cells. Thus the apoptotic phenotype is due to a combination of decreased MDM2 feedback control and increased or unbalanced expression of other apoptosis-inducing p53 target genes. To identify these genes, DNA chips were screened using RNA from cells expressing the apoptosis-inducing mutant, 121F, and a sequence-specificity mutant with the reciprocal phenotype, 277R. Two potential new mediators of p53-dependent apoptosis were identified, Rad and PIR121, which are induced better by 121F than wild-type p53 and not induced by 277R, The 121F mutant kills untransformed MDM2-null but not wild-type mouse embryo fibroblasts and kills tumour cells irrespective of p53 status. It may thus expand the range of tumours which can be treated by p53 gene therapy.
引用
收藏
页码:4424 / 4437
页数:14
相关论文
共 89 条
[61]  
PONTEN J, 1968, ACTA PATHOL MIC SC, V74, P465
[62]   Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype [J].
Rampino, N ;
Yamamoto, H ;
Ionov, Y ;
Li, Y ;
Sawai, H ;
Reed, JC ;
Perucho, M .
SCIENCE, 1997, 275 (5302) :967-969
[63]   The p53 targets mdm2 and Fas are not required as mediators of apoptosis in vivo [J].
Reinke, V ;
Lozano, G .
ONCOGENE, 1997, 15 (13) :1527-1534
[64]   Identification of a novel class of genomic DNA-binding sites suggests a mechanism for selectivity in target gene activation by the tumor suppressor protein p53 [J].
Resnick-Silverman, L ;
St Clair, S ;
Maurer, M ;
Zhao, K ;
Manfredi, JJ .
GENES & DEVELOPMENT, 1998, 12 (14) :2102-2107
[65]   RAD - A MEMBER OF THE RAS FAMILY OVEREXPRESSED IN MUSCLE OF TYPE-II DIABETIC HUMANS [J].
REYNET, C ;
KAHN, CR .
SCIENCE, 1993, 262 (5138) :1441-1444
[66]  
Roemer K, 1996, ONCOGENE, V12, P2069
[67]   Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein [J].
Roth, J ;
Dobbelstein, M ;
Freedman, DA ;
Shenk, T ;
Levine, AJ .
EMBO JOURNAL, 1998, 17 (02) :554-564
[68]   Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant [J].
Rowan, S ;
Ludwig, RL ;
Haupt, Y ;
Bates, S ;
Lu, X ;
Oren, M ;
Vousden, KH .
EMBO JOURNAL, 1996, 15 (04) :827-838
[69]  
Sambrook J., 2002, MOL CLONING LAB MANU
[70]  
SCHATZBERG AF, 1992, J CLIN PSYCHIAT, V53, P20