Inhibition of germline proliferation during<i>C. elegans</i>dauer development requires PTEN, LKB1 and AMPK signalling

Narbonne, Patrick; Roy, Richard

doi:10.1242/dev.02232

Cited by 170 publications

(296 citation statements)

References 45 publications

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“…This is most notable during the L1 diapause stage and during an alternative postembryonic developmental stage called dauer, where it has been shown to affect germ-line stem cell quiescence, dauer maintenance, and survival (21)(22)(23). Mutations in the C. elegans tumor-suppressor ortholog PTEN/daf-18 cause similar defects in both dauer and L1 diapause-arrested larvae, although it most probably acts through a genetically independent pathway (15,24,25).…”

Section: Significancementioning

confidence: 99%

AMPK blocks starvation-inducible transgenerational defects in Caenorhabditis elegans

Demoinet

Roy

2017

Proc. Natl. Acad. Sci. U.S.A.

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Life history events, such as traumatic stress, illness, or starvation, can influence us through molecular changes that are recorded in a pattern of characteristic chromatin modifications. These modifications are often associated with adaptive adjustments in gene expression that can persist throughout the lifetime of the organism, or even span multiple generations. Although these adaptations may confer some selective advantage, if they are not appropriately regulated they can also be maladaptive in a context-dependent manner. We show here that during periods of acute starvation in Caenorhabditis elegans larvae, the master metabolic regulator AMP-activated protein kinase (AMPK) plays a critical role in blocking modifications to the chromatin landscape. This ensures that gene expression remains inactive in the germ-line precursors during adverse conditions. In its absence, critical chromatin modifications occur in the primordial germ cells (PGCs) of emergent starved L1 larvae that correlate with compromised reproductive fitness of the generation that experienced the stress, but also in the subsequent generations that never experienced the initial event. Our findings suggest that AMPK regulates the activity of the chromatin modifying COMPASS complex (complex proteins associated with Set1) to ensure that chromatin marks are not established until nutrient/energy contingencies are satisfied. Our study provides molecular insight that links metabolic adaptation to transgenerational epigenetic modification in response to acute periods of starvation.epigenetics | AMPK | histone methyltransferase | COMPASS | C. elegans

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Section: Significancementioning

confidence: 99%

AMPK blocks starvation-inducible transgenerational defects in Caenorhabditis elegans

Demoinet

Roy

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…AAK-2 is required for life-span extension in response to treatment with the plant product resveratrol, and to some but not all protocols of dietary restriction (Greer et al 2007;Greer and Brunet 2009). It is also required for the arrest of germ cell development that occurs on dietary restriction (Narbonne and Roy 2006), and for inhibition of triglyceride breakdown when worms enter the long-lived Dauer larval form (Narbonne and Roy 2009). Thus, C. elegans AMPK is involved in coupling the availability of nutrients to development and sexual maturation.…”

Section: Role Of Ampk Orthologs In Nonmammalian Eukaryotesmentioning

confidence: 99%

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

Hardie¹

2011

Cold Spring Harbor Symposia on Quantitative Biology

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Adenosine monophosphate -activated protein kinase (AMPK) is a cellular energy sensor activated by metabolic stresses that inhibit catabolic ATP production or accelerate ATP consumption. Once activated, AMPK switches on catabolic pathways, generating ATP, while inhibiting cell growth and proliferation, thus promoting energy homeostasis. AMPK is activated by the antidiabetic drug metformin, and by many natural products including "nutraceuticals" and compounds used in traditional medicines. Most of these xenobiotics activate AMPK by inhibiting mitochondrial ATP production. AMPK activation by metabolic stress requires the upstream kinase, LKB1, whose tumor suppressor effects may be largely mediated by AMPK. However, many tumor cells appear to have developed mechanisms to reduce AMPK activation and thus escape its growthrestraining effects. A similar phenomenon occurs during viral infection. If we can establish how down-regulation occurs in tumors and virus-infected cells, there may be therapeutic avenues to reverse these effects.

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“…Liver-specific Lkb1 deletion also causes metabolic defects and loss of activity of AMPK and increased mTOR signaling (Shaw et al, 2005). C. elegans LKB1/Par-4 and AMPK/aak-2 are required for lifespan extension under conditions of energy stress (Narbonne and Roy, 2006). More recently AMPK has been shown to be critical for cellular polarity and tight junction assembly (see below 'Polarity; AMPK-dependent mechanisms and links to energy stress').…”

Section: Biochemical Functions Of Lkb1mentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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Inhibition of germline proliferation duringC. elegansdauer development requires PTEN, LKB1 and AMPK signalling

Cited by 170 publications

References 45 publications

AMPK blocks starvation-inducible transgenerational defects in Caenorhabditis elegans

AMPK blocks starvation-inducible transgenerational defects in Caenorhabditis elegans

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

LKB1; linking cell structure and tumor suppression

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