Effects of Caenorhabditis elegans sgk‐1 mutations on lifespan, stress resistance, and DAF‐16/FoxO regulation. Issue 5 (19th July 2013)

• Record Type: Journal Article
• Authors: Chen, Albert Tzong‐Yang; Guo, Chunfang; Dumas, Kathleen J.; Ashrafi, Kaveh; Hu, Patrick J.
• Is Part Of: Aging cell. Volume 12:Issue 5(2013:Oct.)
• Page Start: 932
• Page End: 940
• Publication Date: 2013-07-19
• Subjects: Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.12120
• Languages: English
• ISSNs: 1474-9718

Abstract

<abstract abstract-type="main" id="acel12120-abs-0001"> <title>Summary</title> <p>The AGC family serine–threonine kinases Akt and Sgk are similar in primary amino acid sequence and <italic>in vitro</italic> substrate specificity, and both kinases are thought to directly phosphorylate and inhibit FoxO transcription factors. In the nematode <italic>Caenorhabditis elegans</italic>, it is well established that AKT‐1 controls dauer arrest and lifespan by regulating the subcellular localization of the FoxO transcription factor DAF‐16. SGK‐1 is thought to act similarly to AKT‐1 in lifespan control by phosphorylating and inhibiting the nuclear translocation of DAF‐16/FoxO. Using <italic>sgk‐1</italic> null and gain‐of‐function mutants, we now provide multiple lines of evidence indicating that AKT‐1 and SGK‐1 influence <italic>C. elegans</italic> lifespan, stress resistance, and DAF‐16/FoxO activity in fundamentally different ways. Whereas AKT‐1 shortens lifespan, SGK‐1 promotes longevity in a DAF‐16‐/FoxO‐dependent manner. In contrast to AKT‐1, which reduces resistance to multiple stresses, SGK‐1 promotes resistance to oxidative stress and ultraviolet radiation but inhibits thermotolerance. Analysis of several DAF‐16/FoxO target genes that are repressed by AKT‐1 reveals that SGK‐1 represses a subset of these genes while having little influence on the expression of others. Accordingly, unlike AKT‐1, which promotes the cytoplasmic sequestration of DAF‐16/FoxO, SGK‐1 does not influence DAF‐16/FoxO subcellular localization. Thus, in spite of their similar <italic>in vitro</italic> substrate specificities, Akt and Sgk influence longevity, stress resistance, and FoxO activity through distinct mechanisms <italic>in vivo</italic>. Our findings highlight the need for a re‐evaluation of current paradigms of FoxO regulation by Sgk.</p> </abstract>