Functional divergence of dafachronic acid pathways in the control of C. elegans development and lifespan

被引：29

作者：

Dumas, Kathleen J. ^{[1
]}

Guo, Chunfang ^{[1
]}

Wang, Xi ^{[1
]}

Burkhart, Kirk B. ^{[3
]}

Adams, Elizabeth J. ^{[1
]}

Alam, Elena ^{[1
]}

Hu, Patrick J. ^{[1
,2
,4
]}

机构：

[1] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Internal Med, Sch Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA

[3] Univ Wisconsin, Dept Genet, Madison, WI 53706 USA

[4] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA

来源：

DEVELOPMENTAL BIOLOGY | 2010年 / 340卷 / 02期

关键词：

C; elegans; Dauer; Lifespan; Aging; Insulin signaling; Steroid hormones; Nuclear receptors; Dafachronic acids; Akt; FoxO; CONTROLLING DAUER FORMATION; GUANYLYL CYCLASE DAF-11; AGE-1; PI3; KINASE; CAENORHABDITIS-ELEGANS; LARVAL DEVELOPMENT; TRANSCRIPTION FACTOR; SIGNALING PATHWAY; NUCLEAR RECEPTOR; HUMAN LONGEVITY; INSULIN;

D O I：

10.1016/j.ydbio.2010.02.022

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Steroid hormone and insulin/insulin-like growth factor signaling (IIS) pathways control development and lifespan in the nematode Caenorhabditis elegans by regulating the activity of the nuclear receptor DAF-12 and the FoxO transcription factor DAF-16, respectively. The DAF-12 ligands Delta(4)- and Delta(7)-dafachronic acid (DA) promote bypass of the dauer diapause and proper gonadal migration during larval development; in adults, DAs influence lifespan. Whether Delta(4)- and Delta(7)-DA have unique biological functions is not known. We identified the 3-beta-hydroxysteroid dehydrogenase (3 beta HSD) family member HSD-1, which participates in Delta(4)-DA biosynthesis, as an inhibitor of DAF-16/FoxO activity. Whereas IIS promotes the cytoplasmic sequestration of DAF-16/FoxO, HSD-1 inhibits nuclear DAF-16/FoxO activity without affecting DAF-16/FoxO subcellular localization. Thus, HSD-1 and IIS inhibit DAF-16/FoxO activity via distinct and complementary mechanisms. In adults, HSD-1 was required for full lifespan extension in IIS mutants, indicating that HSD-1 interactions with IIS are context-dependent. In contrast to the Delta(7)-DA biosynthetic enzyme DAF-36, HSD-1 is dispensable for proper gonadal migration and lifespan extension induced by germline ablation. These findings provide insights into the molecular interface between DA and IIS pathways and suggest that Delta(4)- and Delta(7)-DA pathways have unique as well as overlapping biological functions in the control of development and lifespan. (C) 2010 Elsevier Inc. All rights reserved.

引用

页码：605 / 612

页数：8

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