Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway

被引：729

作者：

Nemoto, S ^{[1
]}

Finkel, T ^{[1
]}

机构：

[1] NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA

来源：

SCIENCE | 2002年 / 295卷 / 5564期

关键词：

D O I：

10.1126/science.1069004

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Genetic determinants of longevity include the forkhead-related transcription factor DAF-16 in the worm Caenorhabditis elegans and the p66shc locus in mice. We demonstrate that p66shc regulates intracellular oxidant levels in mammalian cells and that hydrogen peroxide can negatively regulate forkhead activity. In p66shc(-/-) cells, the activity of the mammalian forkhead homolog FKHRL1 is increased and redox-dependent forkhead inactivation is reduced. In addition, expression of FKHRL1 results in an increase in both hydrogen peroxide scavenging and oxidative stress resistance. These results demonstrate an important functional relation between three distinct elements linked to aging: forkhead proteins, p66shc, and intracellular oxidants.

引用

收藏

页码：2450 / 2452

页数：3

相关论文

共 25 条

[1] Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans [J].

Barsyte, D ;

Lovejoy, DA ;

Lithgow, GJ .

FASEB JOURNAL, 2001, 15 (03) :627-634

[2] Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1 [J].

Biggs, WH ;

Meisenhelder, J ;

Hunter, T ;

Cavenee, WK ;

Arden, KC .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (13) :7421-7426

[3] Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a) [J].

Brunet, A ;

Park, J ;

Tran, H ;

Hu, LS ;

Hemmings, BA ;

Greenberg, ME .

MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (03) :952-965

[4] Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor [J].

Brunet, A ;

Bonni, A ;

Zigmond, MJ ;

Lin, MZ ;

Juo, P ;

Hu, LS ;

Anderson, MJ ;

Arden, KC ;

Blenis, J ;

Greenberg, ME .

CELL, 1999, 96 (06) :857-868

[5] Oxidants, oxidative stress and the biology of ageing [J].

Finkel, T ;

Holbrook, NJ .

NATURE, 2000, 408 (6809) :239-247

[6] Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues [J].

Furuyama, T ;

Nakazawa, T ;

Nakano, I ;

Mori, N .

BIOCHEMICAL JOURNAL, 2000, 349 :629-634

[7]

HANG H, 2001, J BIOL CHEM, V276, P26357

[8]

Harman D, 1957, J GERONTOL, V2, P298

[9] daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans [J].

Henderson, ST ;

Johnson, TE .

CURRENT BIOLOGY, 2001, 11 (24) :1975-1980

[10] The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans [J].

Honda, Y ;

Honda, S .

FASEB JOURNAL, 1999, 13 (11) :1385-1393