HDAC5-mTORC1 Interaction in Differential Regulation of Ghrelin and Nucleobindin 2 (NUCB2)/Nesfatin-1

Ma, Liangxiao; Tang, Hong; Yin, Yue; Yu, Ruili; Zhao, Jing; Yin, Li; Mulholland, Michael W.; Zhang, Weizhen

doi:10.1210/me.2015-1184

Cited by 15 publications

(16 citation statements)

References 38 publications

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“…The exact mechanism by which HDAC5 AA activates the mTOR pathway in RGC remains to be elucidated. There is evidence in a hypothalamic cell line that HDAC5 interacts and deacetylates Raptor, thereby activating mTOR (Ma et al, 2015). A similar mechanism might be taking place in RGCs.…”

Section: Discussionmentioning

confidence: 95%

“…In RGC, these manipulations not only promote optic nerve regeneration but also RGC survival, by blocking the injury-induced dephosphorylation of the S6 ribosomal protein (S6) after optic nerve crush (Park et al, 2008). Since it has recently shown that, in a hypothalamic cell line, cytoplasmic HDAC5 can indirectly regulate mTOR activation (Ma et al, 2015), we tested if HDAC5 AA activates the mTOR pathway to promote RGC survival and regeneration. We observed a 10% increase in the number of surviving RGCs (labeled with the nuclear marker Brn3a) after injury in retinas overexpressing HDAC5 AA compared to the other treatments (One-way ANOVA F(2, 12)= 13.38, p=0.00089 with Tukey's post hoc test; p=0.004 vs GFP and p=0.001 vs HDAC5 DAD but not difference (p=0.75) between HDAC5 DAD and GFP) ( Figure 3D and E).…”

Section: Hdac5 Aa Activates Mtor and Increases Optic Nerve Regeneratimentioning

confidence: 99%

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HDAC5 promotes optic nerve regeneration by activating the mTOR pathway

Pita-Thomas

Mahar

Joshi

et al. 2019

Experimental Neurology

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Neurons in the central nervous system (CNS) regenerate poorly compared to their counterparts in the peripheral nervous system. We previously showed that, in peripheral sensory neurons, nuclear HDAC5 inhibits the expression of regenerative associated genes. After nerve injury, HDAC5 is exported to the cytoplasm to promote axon regeneration. Here we investigated the role of HDAC5 in retinal ganglion cells (RGC), a CNS neuron which fails to survive and regenerate axons after injury. In contrast to PNS neurons, we found that HDAC5 is mostly cytoplasmic in naïve RGCs and its localization is not affected by optic nerve injury, suggesting that HDAC5 does not directly suppress regenerative associated genes in these cells. Manipulation of the PKCμ pathway, the canonical pathway that regulates HDAC5 localization in PNS neurons by phosphorylating serine 259 and 498, and other pathways that regulate nuclear/cytoplasmic transport did not affect HDAC5 cytoplasmic localization in RGC. Also, an HDAC5 mutant whose serine 259 and 488 were replaced by alanine (HDAC5 AA) to prevent phosphorylation and nuclear export showed a predominantly cytoplasmic localization, suggesting that HDAC5 resides mostly in the cytoplasm in RGCs. Interestingly, expression of HDAC5 AA , but not HDAC5 wild type, in RGCs in vivo

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Section: Discussionmentioning

confidence: 95%

Section: Hdac5 Aa Activates Mtor and Increases Optic Nerve Regeneratimentioning

confidence: 99%

HDAC5 promotes optic nerve regeneration by activating the mTOR pathway

Pita-Thomas

Mahar

Joshi

et al. 2019

Experimental Neurology

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“…Because ghrelin is known for its orexigenic and lipogenic effects, and is regulated by mTOR and its downstream molecular, ribosomal protein S6 kinase beta‐1 (S6K1) (Supporting Fig. ), we hypothesized that mTOR signaling in X/A‐like cell affects organism‐level metabolism by manipulating ghrelin production.…”

Section: Resultsmentioning

confidence: 99%

“…Production of ghrelin from gastric X/A‐like cells is tightly linked with organism energy supply . Studies using the pharmacological approach suggest that gastric mTOR may serve as a critical molecule mediating the effect of energy supply on the production of ghrelin .…”

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confidence: 99%

mTOR Signaling in X/A‐Like Cells Contributes to Lipid Homeostasis in Mice

Yin

et al. 2018

Hepatology

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Gastric mechanistic target of rapamycin (mTOR) signaling is inversely associated with the expression and secretion of ghrelin, a 28-aa peptide hormone produced by gastric X/A-like cells. Ghrelin contributes to obesity and hepatic steatosis. We sought to control global lipid metabolism through manipulating gastric mTOR signaling in X/A-like cells METHODS: We established a ghrl-cre transgene in which the cre enzyme is expressed in X/A-like cells under the control of the ghrelin-promoter. mTOR and TSC1 mice were separately bred with ghrl-cre mice to generate mTOR-ghrl-cre (mG) or TSC1-ghrl-cre (TG) mice, within which mTOR signaling was suppressed or activated respectively. Lipid metabolism in liver and adipose depots was analyzed RESULTS: Under the control of the ghrelin-promoter, cre enzyme is exclusively expressed in stomach X/A-like cells in adult animals. Knockout of mTOR in X/A-like cells increased circulating acyl-ghrelin and promoted hepatic lipogenesis with effects on adipose depots. Activation of mTOR signaling by deletion of its upstream inhibitor, tuberous sclerosis 1 (TSC1), decreased ghrelin expression and secretion, altering lipid metabolism as evidenced by resistance to high fat diet-induced obesity and hepatic steatosis. Both ghrelin administration and rapamycin, an inhibitor of mTOR, altered the phenotypes of TG mice CONCLUSION: Gastric mTOR signaling in X/A-like cells contributes to organism lipid homeostasis by regulating hepatic and adipose lipid metabolism. Gastric mTOR signaling may provide an alternative strategy for intervention in lipid disorders. This article is protected by copyright. All rights reserved.

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“…HDAC5 has been shown to co-precipitates with regulatory-associated protein of mTOR (Raptor); HDAC5 inhibition promotes Raptor acetylation, subsequently inhibiting mTORC1 signaling 57 . Conversely, P13K/Akt/mTOR regulates HDAC3 phosphorylation, promoting its activity 58 .…”

Section: Discussionmentioning

confidence: 99%

Co-inhibition of mTORC1, HDAC and ESR1α retards the growth of triple-negative breast cancer and suppresses cancer stem cells

et al. 2018

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Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer. It causes the majority of breast cancer-related deaths, which has been largely associated with the plasticity of tumor cells and persistence of cancer stem cells (CSCs). Conventional chemotherapeutics enrich CSCs and lead to drug resistance and disease relapse. Development of a strategy capable of inhibiting both bulk and CSC populations is an unmet medical need. Inhibitors against estrogen receptor 1, HDACs, or mTOR have been studied in the treatment of TNBC; however, the results are inconsistent. In this work, we found that patient TNBC samples expressed high levels of mTORC1 and HDAC genes in comparison to luminal breast cancer samples. Furthermore, co-inhibition of mTORC1 and HDAC with rapamycin and valproic acid, but neither alone, reproducibly promoted ESR1 expression in TNBC cells. In combination with tamoxifen (inhibiting ESR1), both S6RP phosphorylation and rapamycin-induced 4E-BP1 upregulation in TNBC bulk cells was inhibited. We further showed that fractionated CSCs expressed higher levels of mTORC1 and HDAC than non-CSCs. As a result, co-inhibition of mTORC1, HDAC, and ESR1 was capable of reducing both bulk and CSC subpopulations as well as the conversion of fractionated non-CSC to CSCs in TNBC cells. These observations were partially recapitulated with the cultured tumor fragments from TNBC patients. Furthermore, co-administration of rapamycin, valproic acid, and tamoxifen retarded tumor growth and reduced CD44high/+/CD24low/− CSCs in a human TNBC xenograft model and hampered tumorigenesis after secondary transplantation. Since the drugs tested are commonly used in clinic, this study provides a new therapeutic strategy and a strong rationale for clinical evaluation of these combinations for the treatment of patients with TNBC.

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HDAC5-mTORC1 Interaction in Differential Regulation of Ghrelin and Nucleobindin 2 (NUCB2)/Nesfatin-1

Cited by 15 publications

References 38 publications

HDAC5 promotes optic nerve regeneration by activating the mTOR pathway

HDAC5 promotes optic nerve regeneration by activating the mTOR pathway

mTOR Signaling in X/A‐Like Cells Contributes to Lipid Homeostasis in Mice

Co-inhibition of mTORC1, HDAC and ESR1α retards the growth of triple-negative breast cancer and suppresses cancer stem cells

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