Redox Control and Interplay Between p53 Isoforms: Roles in the Regulation of Basal p53 Levels, Cell Fate, and Senescence

被引:40
作者
Hafsi, Hind [1 ]
Hainaut, Pierre [1 ]
机构
[1] Int Agcy Res Canc, F-69372 Lyon 08, France
关键词
SEQUENCE-SPECIFIC DNA; TUMOR-SUPPRESSOR P53; RESPONSE ELEMENTS; OXIDATIVE STRESS; BINDING ACTIVITY; UP-REGULATION; METAL-IONS; IN-VITRO; GENE; MODULATION;
D O I
10.1089/ars.2010.3771
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
The p53 tumor suppressor protein has achieved stardom in molecular oncology owing to frequent inactivation in a large range of cancers. Known as a factor activated by multiple forms of stress and causing a broad suppressive response to DNA damage, its regulation and functions in basal (non-stress) conditions has received relatively little attention. We summarize recent findings highlighting roles of p53 in physiological processes such as stem cell maintenance, development, aging and senescence, and regulation of basal oxidative cell metabolism. We suggest that these properties are regulated through two integrated biochemical systems: the redox-sensing capacity of the p53 protein (due to its structural features and its regulation by redox factors such as thioredoxin, metallothioneins, or the redox-repair enzyme APE1/ref-1), and the expression of p53 as multiple isoforms with antagonist effects. We propose that interactions between p53 and its isoforms Delta 40p53 or Delta 133p53 play critical roles in intracellular signaling by reactive oxygen species. We also discuss evidence that p53 controls energy production by repressing glycolysis and enhancing mitochondrial oxidative metabolism. Together, these mechanisms suggest that p53 acts not only as a "guardian of the genome'' against DNA damage but also as a finely-tuned regulator of redox-dependent physiological processes. Antioxid. Redox Signal. 15, 1655-1667.
引用
收藏
页码:1655 / 1667
页数:13
相关论文
共 83 条
[11]   CRYSTAL-STRUCTURE OF A P53 TUMOR-SUPPRESSOR DNA COMPLEX - UNDERSTANDING TUMORIGENIC MUTATIONS [J].
CHO, YJ ;
GORINA, S ;
JEFFREY, PD ;
PAVLETICH, NP .
SCIENCE, 1994, 265 (5170) :346-355
[12]   ΔN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53 [J].
Courtois, S ;
Verhaegh, G ;
North, S ;
Luciani, MG ;
Lassus, P ;
Hibner, U ;
Oren, M ;
Hainaut, P .
ONCOGENE, 2002, 21 (44) :6722-6728
[13]   p53 protein variants: structural and functional similarities with p63 and p73 isoforms [J].
Courtois, S ;
de Fromentel, CC ;
Hainaut, P .
ONCOGENE, 2004, 23 (03) :631-638
[14]  
Fei PW, 2002, CANCER RES, V62, P7316
[15]  
Flaman JM, 1996, ONCOGENE, V12, P813
[16]   A p53-Dependent Response Limits Epidermal Stem Cell Functionality and Organismal Size in Mice with Short Telomeres [J].
Flores, Ignacio ;
Blasco, Maria A. .
PLOS ONE, 2009, 4 (03)
[17]   Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53 [J].
Forrester, K ;
Ambs, S ;
Lupold, SE ;
Kapust, RB ;
Spillare, EA ;
Weinberg, WC ;
FelleyBosco, E ;
Wang, XW ;
Geller, DA ;
Tzeng, E ;
Billiar, TR ;
Harris, CC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (06) :2442-2447
[18]   p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence [J].
Fujita, Kaori ;
Mondal, Abdul M. ;
Horikawa, Izumi ;
Nguyen, Giang H. ;
Kumamoto, Kensuke ;
Sohn, Jane J. ;
Bowman, Elise D. ;
Mathe, Ewy A. ;
Schetter, Aaron J. ;
Pine, Sharon R. ;
Ji, Helen ;
Vojtesek, Borivoj ;
Bourdon, Jean-Christophe ;
Lane, David P. ;
Harris, Curtis C. .
NATURE CELL BIOLOGY, 2009, 11 (09) :1135-U208
[19]   Regulation of human p53 activity and cell localization by alternative splicing [J].
Ghosh, A ;
Stewart, D ;
Matlashewski, G .
MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (18) :7987-7997
[20]  
Gloire G, 2009, ANTIOXID REDOX SIGN, V11, P2209, DOI [10.1089/ars.2009.2463, 10.1089/ARS.2009.2463]