Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition

Resveratrol (RSV) is a natural polyphenol that has a beneficial effect on health, and resveratrol-induced autophagy has been suggested to be a key process in mediating many beneficial effects of resveratrol, such as reduction of inflammation and induction of cancer cell death. Although various resveratrol targets have been suggested, the molecule that mediates resveratrol-induced autophagy remains unknown. Here, we demonstrate that resveratrol induces autophagy by directly inhibiting the mTOR-ULK1 pathway. We found that inhibition of mTOR activity and presence of ULK1 are required for autophagy induction by resveratrol. In line with this mTOR dependency, we found that resveratrol suppresses the viability of MCF7 cells but not of SW620 cells, which are mTOR inhibitor sensitive and insensitive cancer cells, respectively. We also found that resveratrol-induced cancer cell suppression occurred ULK1 dependently. For the mechanism of action of resveratrol on mTOR inhibition, we demonstrate that resveratrol directly inhibits mTOR. We found that resveratrol inhibits mTOR by docking onto the ATP-binding pocket of mTOR (i.e., it competes with ATP). We propose mTOR as a novel direct target of resveratrol, and inhibition of mTOR is necessary for autophagy inductionopen

Deletion of PLC??1 in GABAergic neurons increases seizure susceptibility in aged mice

Synaptic inhibition plays a fundamental role in the information processing of neural circuits. It sculpts excitatory signals and prevents hyperexcitability of neurons. Owing to these essential functions, dysregulated synaptic inhibition causes a plethora of neurological disorders, including epilepsy, autism, and schizophrenia. Among these disorders, epilepsy is associated with abnormal hyperexcitability of neurons caused by the deficits of GABAergic neuron or decreased GABAergic inhibition at synapses. Although many antiepileptic drugs are intended to improve GABA-mediated inhibition, the molecular mechanisms of synaptic inhibition regulated by GABAergic neurons are not fully understood. Increasing evidence indicates that phospholipase C??1 (PLC??1) is involved in the generation of seizure, while the causal relationship between PLC??1 and seizure has not been firmly established yet. Here, we show that genetic deletion of PLC??1 in GABAergic neurons leads to handling-induced seizure in aged mice. In addition, aged Plcg1F/F; Dlx5/6-Cre mice exhibit other behavioral alterations, including hypoactivity, reduced anxiety, and fear memory deficit. Notably, inhibitory synaptic transmission as well as the number of inhibitory synapses are decreased in the subregions of hippocampus. These findings suggest that PLC??1 may be a key determinant of maintaining both inhibitory synapses and synaptic transmission, potentially contributing to the regulation of E/I balance in the hippocampus

Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11

PICT1 (also known as GLTSCR2) is considered a tumor suppressor because it stabilizes phosphatase and tensin homolog (PTEN), but individuals with oligodendrogliomas lacking chromosome 19q13, where PICT1 is located, have better prognoses than other oligodendroglioma patients. To clarify the function of PICT1, we generated Pict1-deficient mice and embryonic stem (ES) cells. Pict1 is a nucleolar protein essential for embryogenesis and ES cell survival. Even without DNA damage, Pict1 loss led to p53-dependent arrest of cell cycle phase G1 and apoptosis. Pict1-deficient cells accumulated p53, owing to impaired Mdm2 function. Pict1 binds Rpl11, and Rpl11 is released from nucleoli in the absence of Pict1. In Pict1-deficient cells, increased binding of Rpl11 to Mdm2 blocks Mdm2-mediated ubiquitination of p53. In human cancer, individuals whose tumors express less PICT1 have better prognoses. When PICT1 is depleted in tumor cells with intact P53 signaling, the cells grow more slowly and accumulate P53. Thus, PICT1 is a potent regulator of the MDM2-P53 pathway and promotes tumor progression by retaining RPL11 in the nucleolu

The thalamic mGluR1-PLC??4 pathway is critical in sleep architecture

The transition from wakefulness to a nonrapid eye movement (NREM) sleep state at the onset of sleep involves a transition from low-voltage, high-frequency irregular electroencephalography (EEG) waveforms to large-amplitude, low-frequency EEG waveforms accompanying synchronized oscillatory activity in the thalamocortical circuit. The thalamocortical circuit consists of reciprocal connections between the thalamus and cortex. The cortex sends strong excitatory feedback to the thalamus, however the function of which is unclear. In this study, we investigated the role of the thalamic metabotropic glutamate receptor 1 (mGluR1)-phospholipase C ??4 (PLC??4) pathway in sleep control in PLC??4-deficient (PLC??4-/-) mice. The thalamic mGluR1-PLC??4 pathway contains synapses that receive corticothalamic inputs. In PLC??4-/- mice, the transition from wakefulness to the NREM sleep state was stimulated, and the NREM sleep state was stabilized, which resulted in increased NREM sleep. The power density of delta (??) waves increased in parallel with the increased NREM sleep. These sleep phenotypes in PLC??4-/- mice were consistent in TC-restricted PLC??4 knockdown mice. Moreover, in vitro intrathalamic oscillations were greatly enhanced in the PLC??4-/- slices. The results of our study showed that thalamic mGluR1-PLC??4 pathway was critical in controlling sleep architecture.ope

The physiological roles of primary phospholipase C

none4siThe roles of phosphoinositide-specific phospholipase C (PLC) have been extensively investigated in diverse cell lines and pathological conditions. Among the PLC isozmes, primary PLCs, PLC-β and PLC-γ, are directly activated by receptor activation, unlike other secondary PLCs (PLC-ɛ, PLC-δ1, and PLC-η1). PLC-β isozymes are activated by G protein couple receptor and PLC-γ isozymes are activated by receptor tyrosine kinase (RTK). Primary PLCs are differentially expressed in different tissues, suggesting their specific roles in diverse tissues and regulate a variety of physiological and pathophysiological functions. Thus, dysregulation of phospholipases contributes to a number of human diseases and primary PLCs have been identified as therapeutic targets for prevention and treatment of diseases. Here we review the roles of primary PLCs in physiology and their impact in pathology.noneYang YR; Follo MY; Cocco L; Suh PG.Yang YR; Follo MY; Cocco L; Suh PG

The physiological roles of primary phospholipase C

The roles of phosphoinositide-specific phospholipase C (PLC) have been extensively investigated in diverse cell lines and pathological conditions. Among the PLC isozmes, primary PLCs, PLC-?? and PLC-??, are directly activated by receptor activation, unlike other secondary PLCs (PLC-e{open}, PLC-??1, and PLC-??1). PLC-?? isozymes are activated by G protein couple receptor and PLC-?? isozymes are activated by receptor tyrosine kinase (RTK). Primary PLCs are differentially expressed in different tissues, suggesting their specific roles in diverse tissues and regulate a variety of physiological and pathophysiological functions. Thus, dysregulation of phospholipases contributes to a number of human diseases and primary PLCs have been identified as therapeutic targets for prevention and treatment of diseases. Here we review the roles of primary PLCs in physiology and their impact in pathology.close

O-GlcNAc cycling enzymes control vascular development of the placenta by modulating the levels of HIF-1??

Introduction: Placental vasculogenesis is essential for fetal growth and development, and is affected profoundly by oxygen tension (hypoxia). Hypoxia-inducible factor-1 alpha: (HIF-1 alpha), which is stabilized at the protein level in response to hypoxia, is essential for vascular morphogenesis in the placenta. Many studies suggested that responses to hypoxia is influenced by O-GlcNAcylation. O-GlcNAcylation is regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) that catalyze the addition and removal of O-GlcNAc respectively. Methods: We generated OGA deficient mice and evaluated OGA(-/-) placentas. The analysis of OGA(-/-) placentas was focused on morphological change and placental vasculogenesis. HIF-1 alpha: protein stability or transcriptional activity under dysregulation of O-GlcNAcylation were evaluated by Western blot, RT-qPCR and luciferase reporter gene assays in MEFs or MS1 cell line. Results: Deletion of OGA results in defective placental vasculogenesis. OGA(-/-) placentas showed an abnormal placental shape and reduced vasculature in the labyrinth, which caused a developmental delay in the embryos. OGA deletion, which elevates O-GlcNAcylation and downregulates O-GlcNAc transferase (OGT), suppressed HIF-1 alpha stabilization and the transcription of its target genes. In contrast, the overexpression of O-GlcNAc cycling enzymes enhanced the expression and transcriptional activity of HIF-1 alpha. Discussion: These results suggest that OGA plays a critical role in placental vasculogenesis by modulating HIP-1 alpha stabilization. Control of O-GlcNAcylation is essential for placental development. (C) 2015 Elsevier Ltd. All rights reserved.close0

Phospholipase C-gamma 1 involved in brain disorders

Phosphoinositide-specific phospholipase C-??1 (PLC-??1) is an important signaling regulator involved in various cellular processes. In brain, PLC-??1 is highly expressed and participates in neuronal cell functions mediated by neurotrophins. Consistent with essential roles of PLC-??1, it is involved in development of brain and synaptic transmission. Significantly, abnormal expression and activation of PLC-??1 appears in various brain disorders such as epilepsy, depression, Huntington's disease and Alzheimer's disease. Thus, PLC-??1 has been implicated in brain functions as well as related brain disorders. In this review, we discuss the roles of PLC-??1 in neuronal functions and its pathological relevance to diverse brain diseases.close

Phospholipase C gamma 1 represses colorectal cancer growth by inhibiting the Wnt/beta-catenin signaling axis

As essential phospholipid signaling regulators, phospholipase C (PLC)s are activated by various extra cellular ligands and mediate intracellular signal transduction. PLC gamma 1 is involved in regulating various cancer cell functions. However, the precise in vivo link between PLC gamma 1 and cancer behavior remains undefined. To investigate the role of PLC gamma 1 in colorectal carcinogenesis, we generated an intestinal tissue-specific Plcg1 knock out (KO) in adenomatous polyposis coli (Apc)(Min/+) mice. Plcg1 deficiency in Apc(Min/+) mice showed earlier death, with a higher colorectal tumor incidence in both number and size than in wild-type mice. Mechanistically, inhibition of PLC gamma 1 increased the levels of its substrate phosphoinositol 4,5-bisphosphate (PIP2) at the plasma membrane and promoted the activation of Wnt receptor low-density lipoprotein receptor-related protein 6 (LRP6) by glycogen synthase kinase 3 beta (GSK3 beta) to enhance beta-catenin signaling. Enhanced cell proliferation and Wnt/beta-catenin signaling were observed in colon tumors from Plcg1 KO mice. Furthermore, low PLC gamma 1 expression was associated with a poor prognosis of colon cancer patients. Collectively, we demonstrated the role of PLC gamma 1 in vivo as a tumor suppressor relationship between the regulation of the PIP2 level and Wnt/beta-catenin-dependent intestinal tumor formation. (C) 2021 Elsevier Inc. All rights reserved