Phospholipases are widely occurring and can be found in several different organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase C (PLC) is a class of phospholipases that ...cleaves phospholipids on the diacylglycerol (DAG) side of the phosphodiester bond producing DAGs and phosphomonoesters. Among PLCs, phosphoinositide-specific PLC (PI-PLC) constitutes an important step in the inositide signaling pathways. The structures of PI-PLC isozymes show conserved domains as well as regulatory specific domains. This is important, as most PI-PLCs share a common mechanism, but each of them has a peculiar role and can have a specific cell distribution that is linked to a specific function. More importantly, the regulation of PLC isozymes is fundamental in health and disease, as there are several PLC-dependent molecular mechanisms that are associated with the activation or inhibition of important physiopathological processes. Moreover, PI-PLC alternative splicing variants can play important roles in complex signaling networks, not only in cancer but also in other diseases. That is why PI-PLC isozymes are now considered as important molecules that are essential for better understanding the molecular mechanisms underlying both physiology and pathogenesis, and are also potential molecular targets useful for the development of innovative therapeutic strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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 induction.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
O-GlcNAcylation is a posttranslational modification that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to serine or threonine residues of many proteins. This protein modification interacts with key ...cellular pathways involved in transcription, translation, and proteostasis. Although ubiquitous throughout the body, O-GlcNAc is particularly abundant in the brain, and various proteins commonly found at synapses are O-GlcNAcylated. Recent studies have demonstrated that the modulation of O-GlcNAc in the brain alters synaptic and neuronal functions. Furthermore, altered brain O-GlcNAcylation is associated with either the etiology or pathology of numerous neurodegenerative diseases, while the manipulation of O-GlcNAc exerts neuroprotective effects against these diseases. Although the detailed molecular mechanisms underlying the functional roles of O-GlcNAcylation in the brain remain unclear, O-GlcNAcylation is critical for regulating diverse neural functions, and its levels change during normal and pathological aging. In this review, we will highlight the functional importance of O-GlcNAcylation in the brain and neurodegenerative diseases.
O‐GlcNAcylation of intracellular proteins (O‐GlcNAc) is a post‐translational modification that often competes with phosphorylation in diverse cellular signaling pathways. Recent studies on human ...malignant tumors have demonstrated that O‐GlcNAc is implicated in cellular features relevant to metastasis. Here, we report that lysophosphatidic acid (LPA)‐induced ovarian cancer cell (OVCAR‐3) migration is regulated by O‐GlcNAc. We found that O‐GlcNAc modification of ERM family proteins, a membrane‐cytoskeletal crosslinker, was inversely correlated with its phosphorylation status. Moreover, the LPA‐induced formation of membrane protrusion structures, as well as the migration of OVCAR‐3 cells, was reduced by the accumulation of O‐GlcNAc. Collectively, these findings suggest that O‐GlcNAc is an essential signaling element controlling ERM family proteins involved in OVCAR‐3 cell migration.
In this study, novel molecular mechanisms regulating ERM proteins, which play an important role in cell migration, were revealed. In addition to the regulation of activity by phosphorylation, o‐GlcNAc modification plays an important role in regulating the activity of ERM proteins involved in cell skeletal rearrangements and migration.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Coordinated expression of guidance molecules and their signal transduction are critical for correct brain wiring. Previous studies have shown that phospholipase C gamma1 (PLCγ1), a signal transducer ...of receptor tyrosine kinases, plays a specific role in the regulation of neuronal cell morphology and motility in vitro. However, several questions remain regarding the extracellular stimulus that triggers PLCγ1 signaling and the exact role PLCγ1 plays in nervous system development. Here, we demonstrate that PLCγ1 mediates axonal guidance through a netrin‐1/deleted in colorectal cancer (DCC) complex. Netrin‐1/DCC activates PLCγ1 through Src kinase to induce actin cytoskeleton rearrangement. Neuronal progenitor‐specific knockout of Plcg1 in mice causes axon guidance defects in the dorsal part of the mesencephalon during embryogenesis. Adult Plcg1‐deficient mice exhibit structural alterations in the corpus callosum, substantia innominata, and olfactory tubercle. These results suggest that PLCγ1 plays an important role in the correct development of white matter structure by mediating netrin‐1/DCC signaling.
Synopsis
Netrin‐1 activates PLCγ1 via Src kinase, which is crucial for axon guidance and corpus callosum and mDA system development.
PLCγ1 promotes axon extension and guidance by mediating netrin‐1/DCC signaling.
Netrin‐1 activates the lipase activity of PLCγ1 through phosphorylation of the Y783‐residue by Src kinase.
Disruption of PLCγ1 signaling adversely affects corpus callosum structural and mDA system development.
Netrin‐1 activates PLCγ1 via Src kinase, which is crucial for axon guidance and corpus callosum and mDA system development.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Dysregulation of O‐GlcNAc modification catalyzed by O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA) contributes to the etiology of chronic diseases of aging, including cancer, cardiovascular ...disease, type 2 diabetes, and Alzheimer’s disease. Here we found that natural aging in wild‐type mice was marked by a decrease in OGA and OGT protein levels and an increase in O‐GlcNAcylation in various tissues. Genetic disruption of OGA resulted in constitutively elevated O‐GlcNAcylation in embryos and led to neonatal lethality with developmental delay. Importantly, we observed that serum‐stimulated cell cycle entry induced increased O‐GlcNAcylation and decreased its level after release from G2/M arrest, indicating that O‐GlcNAc cycling by OGT and OGA is required for precise cell cycle control. Constitutively, elevated O‐GlcNAcylation by OGA disruption impaired cell proliferation and resulted in mitotic defects with downregulation of mitotic regulators. OGA loss led to mitotic defects including cytokinesis failure and binucleation, increased lagging chromosomes, and micronuclei formation. These findings suggest an important role for O‐GlcNAc cycling by OGA in embryonic development and the regulation of the maintenance of genomic stability linked to the aging process.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Epilepsy is characterized by recurrent seizures due to abnormal hyperexcitation of neurons. Recent studies have suggested that the imbalance of excitation and inhibition (E/I) in the central nervous ...system is closely implicated in the etiology of epilepsy. In the brain, GABA is a major inhibitory neurotransmitter and plays a pivotal role in maintaining E/I balance. As such, altered GABAergic inhibition can lead to severe E/I imbalance, consequently resulting in excessive and hypersynchronous neuronal activity as in epilepsy. Phospholipase C (PLC) is a key enzyme in the intracellular signaling pathway and regulates various neuronal functions including neuronal development, synaptic transmission, and plasticity in the brain. Accumulating evidence suggests that neuronal PLC is critically involved in multiple aspects of GABAergic functions. Therefore, a better understanding of mechanisms by which neuronal PLC regulates GABAergic inhibition is necessary for revealing an unrecognized linkage between PLC and epilepsy and developing more effective treatments for epilepsy. Here we review the function of PLC in GABAergic inhibition in the brain and discuss a pathophysiological relationship between PLC and epilepsy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Human bone marrow-derived mesenchymal stem cells (hBMSCs) present promising opportunities for therapeutic medicine. Carbon derivatives showed only marginal enhancement in stem cell differentiation ...toward bone formation. Here we report that red-light absorbing carbon nitride (C3N4) sheets lead to remarkable proliferation and osteogenic differentiation by runt-related transcription factor 2 (Runx2) activation, a key transcription factor associated with osteoblast differentiation. Accordingly, highly effective hBMSCs-driven mice bone regeneration under red light is achieved (91% recovery after 4 weeks compared to 36% recovery in the standard control group in phosphate-buffered saline without red light). This fast bone regeneration is attributed to the deep penetration strength of red light into cellular membranes via tissue and the resulting efficient cell stimulation by enhanced photocurrent upon two-photon excitation of C3N4 sheets near cells. Given that the photoinduced charge transfer can increase cytosolic Ca2+ accumulation, this increase would promote nucleotide synthesis and cellular proliferation/differentiation. The cell stimulation enhances hBMSC differentiation toward bone formation, demonstrating the therapeutic potential of near-infrared two-photon absorption of C3N4 sheets in bone regeneration and fracture healing.
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IJS, KILJ, NUK, PNG, UL, UM
Psychological stress is an emotion experienced when people are under mental pressure or encounter unexpected problems. Extreme or repetitive stress increases the risk of developing human disease, ...including cardiovascular disease (CVD), immune diseases, mental disorders, and cancer. Several studies have shown an association between psychological stress and cancer growth and metastasis in animal models and case studies of cancer patients. Stress induces the secretion of stress-related mediators, such as catecholamine, cortisol, and oxytocin, via the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic nervous system (SNS). These stress-related hormones and neurotransmitters adversely affect stress-induced tumor progression and cancer therapy. Catecholamine is the primary factor that influences tumor progression. It can regulate diverse cellular signaling pathways through adrenergic receptors (ADRs), which are expressed by several types of cancer cells. Activated ADRs enhance the proliferation and invasion abilities of cancer cells, alter cell activity in the tumor microenvironment, and regulate the interaction between cancer and its microenvironment to promote tumor progression. Additionally, other stress mediators, such as glucocorticoids and oxytocin, and their cognate receptors are involved in stress-induced cancer growth and metastasis. Here, we will review how each receptor-mediated signal cascade contributes to tumor initiation and progression and discuss how we can use these molecular mechanisms for cancer therapy.
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