Does control of mutant p53 by Mdm2 complicate cancer therapy?

被引：23

作者：

Prives, Carol ^{[1
]}

White, Eileen ^{[2
]}

机构：

[1] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA

[2] Rutgers State Univ, Ctr Adv Biotechnol & Med, Canc Inst New Jersey, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA

来源：

GENES & DEVELOPMENT | 2008年 / 22卷 / 10期

关键词：

metastasis; mouse model; gain of function; p53; stability;

D O I：

10.1101/gad.1680508

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Missense mutant forms of p53 are expressed at high levels in some human cancers and may contribute to oncogenesis. In this issue of Genes & Development, Terzian and colleagues (pp. 1337-1344) describe a mutant p53 knock-in mouse in which normal tissues and some tumors have low levels of mutant p53 protein unless Mdm2 or p16(INK4A) are absent. Once stabilized, mutant p53 promotes metastasis. Therefore, therapies that release p53 from Mdm2 might have unwanted consequences when cells have sustained a mutation in p53.

引用

页码：1259 / 1264

页数：6

共 59 条

[1] Post-translational modifications and activation of p53 by genotoxic stresses [J].

Appella, E ;

Anderson, CW .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 2001, 268 (10) :2764-2772

[2] MDM2 EXPRESSION IS INDUCED BY WILD TYPE-P53 ACTIVITY [J].

BARAK, Y ;

JUVEN, T ;

HAFFNER, R ;

OREN, M .

EMBO JOURNAL, 1993, 12 (02) :461-468

[3] DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis [J].

Bartkova, J ;

Horejsi, Z ;

Koed, K ;

Krämer, A ;

Tort, F ;

Zieger, K ;

Guldberg, P ;

Sehested, M ;

Nesland, JM ;

Lukas, C ;

Orntoft, T ;

Lukas, J ;

Bartek, J .

NATURE, 2005, 434 (7035) :864-870

[4] A post-ubiquitination role for MDM2 and hHR23A in the p53 degradation pathway [J].

Brignone, C ;

Bradley, KE ;

Kisselev, AF ;

Grossman, SR .

ONCOGENE, 2004, 23 (23) :4121-4129

[5] ARF-BP1/mule is a critical mediator of the ARF tumor suppressor [J].

Chen, DL ;

Kon, N ;

Li, MY ;

Zhang, WZ ;

Qin, J ;

Gu, W .

CELL, 2005, 121 (07) :1071-1083

[6] GAIN OF FUNCTION MUTATIONS IN P53 [J].

DITTMER, D ;

PATI, S ;

ZAMBETTI, G ;

CHU, S ;

TERESKY, AK ;

MOORE, M ;

FINLAY, C ;

LEVINE, AJ .

NATURE GENETICS, 1993, 4 (01) :42-46

[7] The ubiquitin ligase COP1 is a critical negative regulator of p53 [J].

Dornan, D ;

Wertz, I ;

Shimizu, H ;

Arnott, D ;

Frantz, GD ;

Dowd, P ;

O' Rourke, K ;

Koeppen, H ;

Dixit, VM .

NATURE, 2004, 429 (6987) :86-92

[8] The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation [J].

Esser, C ;

Scheffner, M ;

Höhfeld, J .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (29) :27443-27448

[9] Small-molecule inhibitors of the p53 suppressor HDM2: have protein-protein interactions come of age as drug targets? [J].

Fischer, PM ;

Lane, DP .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2004, 25 (07) :343-346

[10] The complexity of p53 modulation: emerging patterns from divergent signals [J].

Giaccia, AJ ;

Kastan, MB .

GENES & DEVELOPMENT, 1998, 12 (19) :2973-2983

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