The Opposing Actions of Target of Rapamycin and AMP-Activated Protein Kinase in Cell Growth Control

Hindupur, Sravanth K.; González, Asier; Hall, Michael N.

doi:10.1101/cshperspect.a019141

Cited by 118 publications

(111 citation statements)

References 221 publications

(228 reference statements)

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“…AMPK activates autophagy (Hindupur, González & Hall, 2015) by directly or indirectly activating ULK1 (Egan et al., 2011; Kim, Kundu, Viollet & Guan, 2011). AMPK not only directly phosphorylates and activates ULK1 to induce autophagy, but also indirectly activates ULK1 by inhibiting mTORC1, which phosphorylates and inhibits ULK1 to disrupt the AMPK–ULK1 interaction (Inoki, Kim & Guan, 2012).…”

Section: Discussionmentioning

confidence: 99%

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Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

et al. 2018

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SummaryMicroglia‐mediated neuroinflammation plays a dual role in various brain diseases due to distinct microglial phenotypes, including deleterious M1 and neuroprotective M2. There is growing evidence that the peroxisome proliferator‐activated receptor γ (PPARγ) agonist rosiglitazone prevents lipopolysaccharide (LPS)‐induced microglial activation. Here, we observed that antagonizing PPARγ promoted LPS‐stimulated changes in polarization from the M1 to the M2 phenotype in primary microglia. PPARγ antagonist T0070907 increased the expression of M2 markers, including CD206, IL‐4, IGF‐1, TGF‐β1, TGF‐β2, TGF‐β3, G‐CSF, and GM‐CSF, and reduced the expression of M1 markers, such as CD86, Cox‐2, iNOS, IL‐1β, IL‐6, TNF‐α, IFN‐γ, and CCL2, thereby inhibiting NFκB–IKKβ activation. Moreover, antagonizing PPARγ promoted microglial autophagy, as indicated by the downregulation of P62 and the upregulation of Beclin1, Atg5, and LC3‐II/LC3‐I, thereby enhancing the formation of autophagosomes and their degradation by lysosomes in microglia. Furthermore, we found that an increase in LKB1–STRAD–MO25 complex formation enhances autophagy. The LKB1 inhibitor radicicol or knocking down LKB1 prevented autophagy improvement and the M1‐to‐M2 phenotype shift by T0070907. Simultaneously, we found that knocking down PPARγ in BV2 microglial cells also activated LKB1–AMPK signaling and inhibited NFκB–IKKβ activation, which are similar to the effects of antagonizing PPARγ. Taken together, our findings demonstrate that antagonizing PPARγ promotes the M1‐to‐M2 phenotypic shift in LPS‐induced microglia, which might be due to improved autophagy via the activation of the LKB1–AMPK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

“…AMPK activity is increased when its Thr172 residue in the activation loop is phosphorylated by upstream kinases (Hindupur et al., 2015). In mammals, there are three activating kinases for AMPK, namely LKB1, CaMKKβ, and TAK1.…”

Section: Discussionmentioning

confidence: 99%

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

et al. 2018

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Section: Glucose Metabolismmentioning

confidence: 99%

“…When cells experience a condition of energy stress (i.e., low levels of ATP availability), AMPK phosphorylates TSC2 (tuberous sclerosis complex 2), promoting the inhibitory activity of TSC1-TSC2 towards the mTOR (mammalian target of rapamycin) complex. By this mechanism, AMPK promotes the activation of alternative catabolic pathways to reestablish ATP levels, thus maintaining energy homeostasis [29][30][31].Recently, a connection between glucose and YAP/TAZ activity has been observed [32][33][34][35]. Inhibition of glucose uptake and of glycolysis, or a shift from aerobic glycolysis to oxidative phosphorylation, induced a corresponding inhibition of YAP/TAZ activity in human cultured cells.…”

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confidence: 96%

“…The TSC-mTOR pathway senses and integrates several metabolic parameters, including amino acids, energy status (through AMPK), and growth factor signaling (through PI3K), to control cell size and growth. In turn, by phosphorylating a set of effector proteins, mTOR upregulates several biosynthetic and energy-producing pathways, and prevents the initiation of autophagy, ultimately coordinating growth with nutrient availability [29,31].A recent report indicates that, in a mouse model for perivascular epithelioid tumors, mutation of the TSC tumor suppressor leads to massive upregulation of YAP (and TAZ) levels and activity [61]. YAP upregulation depends on mTOR and autophagy because mTOR inhibition downregulated YAP levels but was ineffective in the absence of the key autophagy mediator Atg7 ( Figure 2).…”

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confidence: 99%

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Control of YAP/TAZ Activity by Metabolic and Nutrient-Sensing Pathways

Santinon

Pocaterra

Dupont

2016

Trends in Cell Biology

145

124

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Forskolin Increases cAMP Levels and Enhances Recombinant Antibody Production in CHO Cell Cultures

Yoon

Kim

Lim³

et al. 2020

Biotechnology Journal

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Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger essential to many biological processes. Forskolin, a labdane diterpene, is widely used to increase cAMP levels in various cell types. When 5 µm of forskolin is added to recombinant Chinese hamster ovary (rCHO) cell cultures producing monoclonal antibody (mAb) (GSR cell line), it decreases specific growth rate (), but increases culture longevity and specific mAb productivity (q mAb). The beneficial effect of forskolin on culture longevity and q mAb outweighs its detrimental effect on , resulting in 1.5-fold increase in the maximum mAb concentration (MMC) without an adverse effect on mAb quality attributes such as aggregation, charge variation, and galactosylation. Forskolin induces cell cycle arrest at the G0/G1 phase via the LKB1/AMPK pathway and inhibits apoptosis via the CREB/Bcl-2 pathway. The beneficial effect of forskolin on mAb production is also demonstrated with another rCHO cell line (ABTAA). Addition of 5 µm forskolin to ABTAA cell cultures also results in 1.5-fold increase in the MMC. Taken together, the results obtained demonstrate that forskolin is an efficient chemical reagent to increase mAb production in rCHO cell cultures.

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The Opposing Actions of Target of Rapamycin and AMP-Activated Protein Kinase in Cell Growth Control

Cited by 118 publications

References 221 publications

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

Control of YAP/TAZ Activity by Metabolic and Nutrient-Sensing Pathways

Forskolin Increases cAMP Levels and Enhances Recombinant Antibody Production in CHO Cell Cultures

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