AMP-activated protein kinase (AMPK) cross-talks with canonical Wnt signaling via phosphorylation of β-catenin at Ser 552

Zhao, Junxing; Yue, Wan‐Fu; Zhu, Mei; Nair, Sreejayan; Du, Min

doi:10.1016/j.bbrc.2010.03.161

Cited by 76 publications

(69 citation statements)

References 46 publications

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“…We postulate that AMPK regulates cell differentiation through cross-talk with the Wnt/␤-catenin signaling pathway. We previously observed that AMPK phosphorylates ␤-catenin, which enhances ␤-catenin stability (19). In this study we further observed that the mRNA expression of ␤-catenin was promoted by AMPK and suggested that histone deacetylase 5 (HDAC5) has an essential role in linking AMPK with ␤-catenin expression.…”

supporting

confidence: 51%

AMP-activated Protein Kinase Regulates β-Catenin Transcription via Histone Deacetylase 5

Zhao

Yue

Zhu

et al. 2011

Journal of Biological Chemistry

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AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism; it is inhibited under obese conditions and is activated by exercise and by many anti-diabetic drugs. Emerging evidence also suggests that AMPK regulates cell differentiation, but the underlying mechanisms are unclear. We hypothesized that AMPK regulates cell differentiation via altering ␤-catenin expression, which involves phosphorylation of class IIa histone deacetylase 5 (HDAC5). In both C3H10T1/2 cells and mouse embryonic fibroblasts (MEFs), AMPK activity was positively correlated with ␤-catenin content. Chemical inhibition of HDAC5 increased ␤-catenin mRNA expression. HDAC5 overexpression reduced and HDAC5 knockdown increased H3K9 acetylation and cellular ␤-catenin content. HDAC5 formed a complex with myocyte enhancer factor-2 to down-regulate ␤-catenin mRNA expression. AMPK phosphorylated HDAC5, which promoted HDAC5 exportation from the nucleus; mutation of two phosphorylation sites in HDAC5, Ser-259 and -498, abolished the regulatory role of AMPK on ␤-catenin expression. In conclusion, AMPK promotes ␤-catenin expression through phosphorylation of HDAC5, which reduces HDAC5 interaction with the ␤-catenin promoter via myocyte enhancer factor-2. Thus, the data indicate that AMPK regulates cell differentiation and development via cross-talk with the wingless and Int (Wnt)/ ␤-catenin signaling pathway. AMP-activated protein kinase (AMPK),2 a heterotrimeric enzyme composed of ␣, ␤, and ␥ subunits, is recognized as a critical regulator of energy metabolism (1-3). In addition to its capacity to acutely regulate the activity of metabolic enzymes through phosphorylation, AMPK also regulates gene expression (4 -9). Emerging evidence also suggests that AMPK regulates cell differentiation and tissue development (10 -12). Recently, it was shown that double knock-out of AMPK ␣1 and ␣2 subunits is lethal to mice at embryonic stage 10.5 (13), further confirming the important role of AMPK in early development. Mechanisms linking AMPK to cell differentiation and animal development, however, remain poorly defined.␤-Catenin is a key mediator of Wingless and Int (Wnt)/␤-catenin signaling pathway, which is required for early embryonic development (14, 15), cell proliferation, and differentiation (16 -18). We postulate that AMPK regulates cell differentiation through cross-talk with the Wnt/␤-catenin signaling pathway. We previously observed that AMPK phosphorylates ␤-catenin, which enhances ␤-catenin stability (19). In this study we further observed that the mRNA expression of ␤-catenin was promoted by AMPK and suggested that histone deacetylase 5 (HDAC5) has an essential role in linking AMPK with ␤-catenin expression.Epigenetic modifications including histone acetylation and methylation and DNA methylation regulate gene transcription (20,21). Histone acetylation is regulated by histone acetyltransferase and HDAC (22). HDAC5 belongs to the class IIa HDAC family and acts as a conserved transcriptional repressor. HDAC5 interacts with myocyte enhancer fact...

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confidence: 51%

AMP-activated Protein Kinase Regulates β-Catenin Transcription via Histone Deacetylase 5

Zhao

Yue

Zhu

et al. 2011

Journal of Biological Chemistry

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“…AMPK has also been shown to modulate the Wingless Int-1 (Wnt) signaling pathway (23)(24)(25), which is implicated in the pathogenesis of OA (26). Wnt stimulation in cartilage promotes the accumulation and nuclear translocation of β-catenin, an effector of Wnt signaling, where it activates the expression of catabolic target genes such as metalloproteinases (26).…”

Section: Resultsmentioning

confidence: 99%

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Yan

Duan

Pan

et al. 2016

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

113

121

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Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration. Using a murine model of controlled knee joint impact injury that allows the examination of cartilage responses to injury at specific time points, we show that intraarticular delivery of a peptidic nanoparticle complexed to NF-κB siRNA significantly reduces early chondrocyte apoptosis and reactive synovitis. Our data suggest that NF-κB siRNA nanotherapy maintains cartilage homeostasis by enhancing AMPK signaling while suppressing mTORC1 and Wnt/β-catenin activity. These findings delineate an extensive crosstalk between NF-κB and signaling pathways that govern cartilage responses postinjury and suggest that delivery of NF-κB siRNA nanotherapy to attenuate early inflammation may limit the chronic consequences of joint injury. Therapeutic benefits of siRNA nanotherapy may also apply to primary OA in which NF-κB activation mediates chondrocyte catabolic responses. Additionally, a critical barrier to the successful development of OA treatment includes ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Here, we show that the peptide–siRNA nanocomplexes are nonimmunogenic, are freely and deeply penetrant to human OA cartilage, and persist in chondrocyte lacunae for at least 2 wk. The peptide–siRNA platform thus provides a clinically relevant and promising approach to overcoming the obstacles of drug delivery to the highly inaccessible chondrocytes.

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“…These results identify GATA3 as a novel downstream target of Wnt/␤-catenin and suggest that there is cross-talk between AMPK and the Wnt/␤-catenin signaling pathway in preadipocytes. In fact, previous studies have shown that AMPK regulates cell differentiation and development by promoting ␤-catenin expression, stabilizing ␤-catenin, and enhancing ␤-catenin/TCF-mediated transcription (34,35). Additionally, AICAR and activated AMPK inhibit adipocyte differentiation by down-regulating the expression of adipogenic factors in vitro and reducing adipose tissue content in diet-induced obesity (DIO) mice (37,46,52).…”

Section: Discussionmentioning

confidence: 99%

“…As a co-repressor, CtBP has been reported to inhibit Wnt signaling targets by binding directly to TCFs or by preventing the interaction between ␤-catenin and TCFs (30 -33), leading to the inhibition of Wnt target genes. As an energy sensor, the AMP-activated protein kinase (AMPK) signaling pathway also activates the Wnt/␤-catenin signaling that regulates cell differentiation and development (34,35). In addition, 5-amino-imidazolecarboxamide ribonucleoside (AICAR), an activator of AMPK, has been used as an experimental tool to activate AMPK in vitro and in vivo.…”

mentioning

confidence: 99%

Wnt/β-Catenin Mediates AICAR Effect to Increase GATA3 Expression and Inhibit Adipogenesis

Wang¹,

Di²

2015

Journal of Biological Chemistry

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Background: Adipogenesis can be modulated by various signaling pathways and transcription factors. Results: AICAR-activated AMPK inactivates GSK3␤, which stimulates Wnt/␤-catenin signaling and relieves CtBP repression, thus increasing GATA3 and inhibiting adipogenesis. Conclusion: AMPK controls the Wnt/␤-catenin/GATA3 axis via inactivating GSK3␤ to coordinately modulate adipogenesis. Significance: These findings provide new insight into the molecular mechanism and signal transduction of adipogenesis.

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AMP-activated protein kinase (AMPK) cross-talks with canonical Wnt signaling via phosphorylation of β-catenin at Ser 552

Cited by 76 publications

References 46 publications

AMP-activated Protein Kinase Regulates β-Catenin Transcription via Histone Deacetylase 5

AMP-activated Protein Kinase Regulates β-Catenin Transcription via Histone Deacetylase 5

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Wnt/β-Catenin Mediates AICAR Effect to Increase GATA3 Expression and Inhibit Adipogenesis

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