Role of Sirtuins in Stem Cell Differentiation

Rodríguez, Ramón María Alvargonzález; Fernández, Agustín F.; Fraga, Mario F.

doi:10.1177/1947601913479798

Cited by 35 publications

(29 citation statements)

References 104 publications

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“…Significant alterations of the cellular redox status have been demonstrated during both self-renewal and cell differentiation33. To study whether HX modifies levels of the intracellular nucleotide NAD, we performed nicotinamide assay and demonstrated higher levels of NAD in white matter cells after HX (Fig.…”

Section: Resultsmentioning

confidence: 99%

Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury

et al. 2016

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Regenerative processes in brain pathologies require the production of distinct neural cell populations from endogenous progenitor cells. We have previously demonstrated that oligodendrocyte progenitor cell (OPC) proliferation is crucial for oligodendrocyte (OL) regeneration in a mouse model of neonatal hypoxia (HX) that reproduces diffuse white matter injury (DWMI) of premature infants. Here we identify the histone deacetylase Sirt1 as a Cdk2 regulator in OPC proliferation and response to HX. HX enhances Sirt1 and Sirt1/Cdk2 complex formation through HIF1α activation. Sirt1 deacetylates retinoblastoma (Rb) in the Rb/E2F1 complex, leading to dissociation of E2F1 and enhanced OPC proliferation. Sirt1 knockdown in culture and its targeted ablation in vivo suppresses basal and HX-induced OPC proliferation. Inhibition of Sirt1 also promotes OPC differentiation after HX. Our results indicate that Sirt1 is an essential regulator of OPC proliferation and OL regeneration after neonatal brain injury. Therefore, enhancing Sirt1 activity may promote OL recovery after DWMI.

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Section: Resultsmentioning

confidence: 99%

Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury

et al. 2016

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“…SIRT1 is plays an important role in cell survival, signal transduction, and apoptosis, by deacetylation of specific cell signaling molecules (p53, FOXO3, FOXO4, NF-kB, and HIFs) [36,37]. However, a few studies have suggested that SIRT1 may act as a tumor activator in various human cancers, including breast cancer, prostate cancer, or ovarian cancer [38,39].…”

Section: Discussionmentioning

confidence: 99%

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

Tae¹,

Son²,

Lee³

et al. 2020

Int. J. Biol. Sci.

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Ovarian cancer is a common gynecological cancer that is found worldwide. Class III histone deacetylase (HDAC) inhibitors, a new class of anticancer agents, induce autophagy in various human cancer cells. The aim of the present study was to investigate the antitumor activity of MHY2245, a new synthetic SIRT inhibitor, on human ovarian cancer cells. We found that MHY2245 exhibited potent cytotoxicity to SKOV3 cells in a time-and concentration-dependent manner. The cytotoxicity of MHY2245 (IC 50 =0.32 µM) was higher than that of doxorubicin (DOX, IC 50 =1.38µM) against SKOV3 cells. MHY2245 significantly inhibited SIRT1 enzyme activity, reduced the expression of SIRT1, increased cell cycle arrest at G 2 /M phase, and induced apoptotic cell death in SKOV3 cells via expression of cytochrome c, cleaved-PARP, cleaved caspase-3, and Bax. This might be associated with blocking of the pyruvate kinase M2 (PKM2)/mTOR pathway. MHY2245 also inhibited tumor growth and reduced tumor size when SKOV3 cells were transplanted into nude mice. Our results indicate that MHY2245 exerts antitumor activity against ovarian cancer cells by blocking the PKM2/mTOR pathway. We suggest that MHY2245 is a promising anticancer agent that disrupts ovarian cancer cell metabolism.

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“…Protein acetylation is emerging as an evolutionarily conserved regulatory mechanism involved in coordinating a variety of metabolic pathways in response to different conditions, including glycolysis, fatty acid synthesis, gluconeogenesis, cell cycle, DNA repair, cell survival and differentiation, mitochondrial biogenesis, and autophagy . This is achieved by epigenetic modulation of histone and nonhistone proteins in the nucleus, to regulate gene expression, and by modulation of specific protein substrates within the mitochondria and the cytoplasm .…”

Section: Discussionmentioning

confidence: 99%

Rapid modulation of the silent information regulator 1 by melatonin after hypoxia‐ischemia in the neonatal rat brain

Carloni

Riparini

Buonocore

et al. 2017

Journal of Pineal Research

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Increasing evidence indicates that melatonin possesses protective effects toward different kinds of damage in various organs, including the brain. In a neonatal model of hypoxia-ischemia (HI), melatonin was neuroprotective and preserved the expression of the silent information regulator 1 (SIRT1) 24 hours after the insult. This study aimed to gain more insight into the role of SIRT1 in the protective effect of melatonin after HI by studying the early (1 hour) modulation of SIRT1 and its downstream targets, and the consequences on necrosis, apoptosis, autophagy, and glial cell activation. We found that melatonin administered 5 minutes after the ischemic insult significantly reduced necrotic cell death assessed 1 hour after its administration. In parallel, we found a reduced activation of the early phases of intrinsic apoptosis, detected by reduced BAX translocation to the mitochondria and preservation of the mitochondrial expression of cytochrome C, indicating a reduced outer mitochondrial membrane permeabilization in the melatonin-treated ischemic animals. These effects were concomitant to increased expression and activity of SIRT1, reduced expression and acetylation of p53, and increased autophagy activation. Melatonin also reduced HI-induced glial cells activation. SIRT1 was expressed in neurons after HI and melatonin but not in reactive glial cells expressing GFAP. Colocalization between SIRT1 and GFAP was found in some cells in control conditions. In summary, our results provide more insight into the connection between SIRT1 and melatonin in neuroprotection. The possibility that melatonin-induced SIRT1 activity might contribute to differentiate neuronal progenitor cells during the neurodegenerative process needs to be further investigated.

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Role of Sirtuins in Stem Cell Differentiation

Cited by 35 publications

References 104 publications

Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury

Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

Rapid modulation of the silent information regulator 1 by melatonin after hypoxia‐ischemia in the neonatal rat brain

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