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Nucleic Acids Research Dec 2020Efficient S phase entry is essential for development, tissue repair, and immune defences. However, hyperactive or expedited S phase entry causes replication stress, DNA... (Review)
Review
Efficient S phase entry is essential for development, tissue repair, and immune defences. However, hyperactive or expedited S phase entry causes replication stress, DNA damage and oncogenesis, highlighting the need for strict regulation. Recent paradigm shifts and conflicting reports demonstrate the requirement for a discussion of the G1/S transition literature. Here, we review the recent studies, and propose a unified model for the S phase entry decision. In this model, competition between mitogen and DNA damage signalling over the course of the mother cell cycle constitutes the predominant control mechanism for S phase entry of daughter cells. Mitogens and DNA damage have distinct sensing periods, giving rise to three Commitment Points for S phase entry (CP1-3). S phase entry is mitogen-independent in the daughter G1 phase, but remains sensitive to DNA damage, such as single strand breaks, the most frequently-occurring lesions that uniquely threaten DNA replication. To control CP1-3, dedicated hubs integrate the antagonistic mitogenic and DNA damage signals, regulating the stoichiometric cyclin: CDK inhibitor ratio for ultrasensitive control of CDK4/6 and CDK2. This unified model for the G1/S cell cycle transition combines the findings of decades of study, and provides an updated foundation for cell cycle research.
Topics: Cell Cycle; Cell Cycle Checkpoints; Cell Division; DNA Damage; DNA Replication; G1 Phase; Humans; S Phase; Signal Transduction
PubMed: 33166394
DOI: 10.1093/nar/gkaa1002 -
EMBO Reports Oct 2022Neutrophils are the most prevalent immune cells in circulation, but the repertoire of canonical inflammasomes in neutrophils and their respective involvement in...
Neutrophils are the most prevalent immune cells in circulation, but the repertoire of canonical inflammasomes in neutrophils and their respective involvement in neutrophil IL-1β secretion and neutrophil cell death remain unclear. Here, we show that neutrophil-targeted expression of the disease-associated gain-of-function Nlrp3 mutant suffices for systemic autoinflammatory disease and tissue pathology in vivo. We confirm the activity of the canonical NLRP3 and NLRC4 inflammasomes in neutrophils, and further show that the NLRP1b, Pyrin and AIM2 inflammasomes also promote maturation and secretion of interleukin (IL)-1β in cultured bone marrow neutrophils. Notably, all tested canonical inflammasomes promote GSDMD cleavage in neutrophils, and canonical inflammasome-induced pyroptosis and secretion of mature IL-1β are blunted in GSDMD-knockout neutrophils. In contrast, GSDMD is dispensable for PMA-induced NETosis. We also show that Salmonella Typhimurium-induced pyroptosis is markedly increased in Nox2/Gp91 -deficient neutrophils that lack NADPH oxidase activity and are defective in PMA-induced NETosis. In conclusion, we establish the canonical inflammasome repertoire in neutrophils and identify differential roles for GSDMD and the NADPH complex in canonical inflammasome-induced neutrophil pyroptosis and mitogen-induced NETosis, respectively.
Topics: Animals; Extracellular Traps; Inflammasomes; Interleukin-1beta; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mitogens; NADP; NADPH Oxidases; NLR Family, Pyrin Domain-Containing 3 Protein; Neutrophils; Phosphate-Binding Proteins; Pore Forming Cytotoxic Proteins; Pyrin; Pyroptosis
PubMed: 35899491
DOI: 10.15252/embr.202154277 -
Nature Jul 2023In mammalian cells, the decision to proliferate is thought to be irreversibly made at the restriction point of the cell cycle, when mitogen signalling engages a positive...
In mammalian cells, the decision to proliferate is thought to be irreversibly made at the restriction point of the cell cycle, when mitogen signalling engages a positive feedback loop between cyclin A2/cyclin-dependent kinase 2 (CDK2) and the retinoblastoma protein. Contrary to this textbook model, here we show that the decision to proliferate is actually fully reversible. Instead, we find that all cycling cells will exit the cell cycle in the absence of mitogens unless they make it to mitosis and divide first. This temporal competition between two fates, mitosis and cell cycle exit, arises because cyclin A2/CDK2 activity depends upon CDK4/6 activity throughout the cell cycle, not just in G1 phase. Without mitogens, mitosis is only observed when the half-life of cyclin A2 protein is long enough to sustain CDK2 activity throughout G2/M. Thus, cells are dependent on mitogens and CDK4/6 activity to maintain CDK2 activity and retinoblastoma protein phosphorylation throughout interphase. Consequently, even a 2-h delay in a cell's progression towards mitosis can induce cell cycle exit if mitogen signalling is lost. Our results uncover the molecular mechanism underlying the restriction point phenomenon, reveal an unexpected role for CDK4/6 activity in S and G2 phases and explain the behaviour of all cells following loss of mitogen signalling.
Topics: Animals; Cell Cycle; Cyclin A2; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; G2 Phase; Mitogens; Mitosis; Phosphorylation; Retinoblastoma Protein; Cyclin-Dependent Kinase 6; S Phase; G1 Phase
PubMed: 37407814
DOI: 10.1038/s41586-023-06274-3 -
Nature Jun 2023Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ1. PMR releases pro-inflammatory cytoplasmic...
Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ1. PMR releases pro-inflammatory cytoplasmic molecules, collectively called damage-associated molecular patterns (DAMPs), that activate immune cells. Therefore, inhibiting NINJ1 and PMR may limit the inflammation that is associated with excessive cell death. Here we describe an anti-NINJ1 monoclonal antibody that specifically targets mouse NINJ1 and blocks oligomerization of NINJ1, preventing PMR. Electron microscopy studies showed that this antibody prevents NINJ1 from forming oligomeric filaments. In mice, inhibition of NINJ1 or Ninj1 deficiency ameliorated hepatocellular PMR induced with TNF plus D-galactosamine, concanavalin A, Jo2 anti-Fas agonist antibody or ischaemia-reperfusion injury. Accordingly, serum levels of lactate dehydrogenase, the liver enzymes alanine aminotransaminase and aspartate aminotransferase, and the DAMPs interleukin 18 and HMGB1 were reduced. Moreover, in the liver ischaemia-reperfusion injury model, there was an attendant reduction in neutrophil infiltration. These data indicate that NINJ1 mediates PMR and inflammation in diseases driven by aberrant hepatocellular death.
Topics: Animals; Mice; Alanine Transaminase; Alarmins; Antibodies, Monoclonal; Aspartate Aminotransferases; Cell Adhesion Molecules, Neuronal; Cell Death; Cell Membrane; Concanavalin A; Galactosamine; Hepatocytes; Inflammation; Lactate Dehydrogenases; Liver; Microscopy, Electron; Nerve Growth Factors; Neutrophil Infiltration; Reperfusion Injury
PubMed: 37196676
DOI: 10.1038/s41586-023-06191-5 -
Molecular Cell Jan 2021Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the...
Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the cellular antioxidant systems. We report here that oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), transfer electrons from NAD(P)H to oxygen to generate hydrogen peroxide, which subsequently reacts with iron to generate reactive hydroxyl radicals for the peroxidation of the polyunsaturated fatty acid (PUFA) chains of membrane phospholipids, thereby disrupting membrane integrity during ferroptosis. Genetic knockout of POR and CYB5R1 decreases cellular hydrogen peroxide generation, preventing lipid peroxidation and ferroptosis. Moreover, POR knockdown in mouse liver prevents ConA-induced liver damage. Ferroptosis, therefore, is a result of incidental electron transfer carried out by POR/CYB5R1 oxidoreductase and thus needs to be constitutively countered by the antioxidant systems.
Topics: Animals; Cell Line, Tumor; Cell Membrane; Concanavalin A; Cytochrome P-450 Enzyme System; Cytochrome-B(5) Reductase; Electron Transport; Fatty Acids, Unsaturated; Ferroptosis; HEK293 Cells; HeLa Cells; Humans; Hydrogen Peroxide; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; NADP; Oxygen; Phenylurea Compounds; Piperazines; Pyridines; Sorafenib
PubMed: 33321093
DOI: 10.1016/j.molcel.2020.11.024 -
Nature Metabolism Jun 2022While fibroblast growth factor (FGF) 1 is expressed in multiple tissues, only adipose-derived and brain FGF1 have been implicated in the regulation of metabolism.... (Review)
Review
While fibroblast growth factor (FGF) 1 is expressed in multiple tissues, only adipose-derived and brain FGF1 have been implicated in the regulation of metabolism. Adipose FGF1 production is upregulated in response to dietary stress and is essential for adipose tissue plasticity in these conditions. Similarly, in the brain, FGF1 secretion into the ventricular space and the adjacent parenchyma is increased after a hypercaloric challenge induced by either feeding or glucose infusion. Potent anorexigenic properties have been ascribed to both peripheral and centrally injected FGF1. The ability of recombinant FGF1 and variants with reduced mitogenicity to lower glucose, suppress adipose lipolysis and promote insulin sensitization elevates their potential as candidates in the treatment of type 2 diabetes mellitus and associated comorbidities. Here, we provide an overview of the known metabolic functions of endogenous FGF1 and discuss its therapeutic potential, distinguishing between peripherally or centrally administered FGF1.
Topics: Fibroblast Growth Factor 1; Fibroblast Growth Factors
PubMed: 35681108
DOI: 10.1038/s42255-022-00580-2 -
Life (Basel, Switzerland) May 2023A widely discussed topic in the pathophysiology of thyroid nodules is the role of obesity, a state that leads to increased systemic inflammatory markers. Leptin plays a... (Review)
Review
A widely discussed topic in the pathophysiology of thyroid nodules is the role of obesity, a state that leads to increased systemic inflammatory markers. Leptin plays a vital role in forming thyroid nodules and cancer through several mechanisms. Together with chronic inflammation, there is an augmentation in the secretion of tumor necrosis factor (TNF) and the cytokine interleukin 6 (IL-6), which contributed to cancer development, progression and metastasis. In addition, leptin exerts a modulatory action in the growth, proliferation and invasion of thyroid carcinoma cell lines via activating various signal pathways, such as Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) and/or phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt). Through several proposed mechanisms, aberrant endogenous estrogen levels have been suggested to play a vital role in the development of both benign and malignant nodules. Metabolic syndrome triggers the development of thyroid nodules by stimulating thyroid proliferation and angiogenesis due to hyperinsulinemia, hyperglycemia and dyslipidemia. Insulin resistance influences the distribution and structure of the thyroid blood vessels. Insulin growth factor 1 (IGF-1) and insulin affect the regulation of the expression of thyroid genes and the proliferation and differentiation of thyroid cells. TSH can promote the differentiation of pre-adipocytes to mature adipocytes but also, in the presence of insulin, TSH possesses mitogenic properties. This review aims to summarize the underlying mechanisms explaining the role of obesity in the pathophysiology of thyroid nodules and discuss potential clinical implications.
PubMed: 37374075
DOI: 10.3390/life13061292 -
International Journal of Molecular... Dec 2020Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein... (Review)
Review
Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics. Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition. Dysregulation of protein methylation is linked to various diseases, including cancer, inflammation, and genetic disorders. In this review, we cover biomolecular studies on the role of trimethyllysine in carnitine biosynthesis, different enzymatic reactions involved in the synthesis and removal of trimethyllysine, trimethyllysine recognition by reader proteins, and the role of trimethyllysine on the nucleosome assembly.
Topics: Animals; Carnitine; Epigenesis, Genetic; Histone-Lysine N-Methyltransferase; Humans; Lysine; Protein Processing, Post-Translational
PubMed: 33322546
DOI: 10.3390/ijms21249451 -
Mayo Clinic Proceedings. Innovations,... Jun 2020An understanding of the molecular basis of liver regeneration will open new horizons for the development of novel therapies for chronic liver failure. Such therapies... (Review)
Review
An understanding of the molecular basis of liver regeneration will open new horizons for the development of novel therapies for chronic liver failure. Such therapies would solve the drawbacks associated with liver transplant, including the shortage of donor organs, long waitlist time, high medical costs, and lifelong use of immunosuppressive agents. Regeneration after partial hepatectomy has been studied in animal models, particularly fumarylacetoacetate hydrolase-deficient ( ) mice and pigs. The process of regeneration is distinctive, complex, and well coordinated, and it depends on the interplay among several signaling pathways (eg, nuclear factor κβ, Notch, Hippo), cytokines (eg, tumor necrosis factor α, interleukin 6), and growth factors (eg, hepatocyte growth factor, epidermal growth factor, vascular endothelial growth factor), and other components. Furthermore, endocrinal hormones (eg, norepinephrine, growth hormone, insulin, thyroid hormones) also can influence the aforementioned pathways and factors. We believe that these endocrinal hormones are important hepatic mitogens that strongly induce and accelerate hepatocyte proliferation (regeneration) by directly and indirectly triggering the activity of the involved signaling pathways, cytokines, growth factors, and transcription factors. The subsequent induction of cyclins and associated cyclin-dependent kinase complexes allow hepatocytes to enter the cell cycle. In this review article, we comprehensively summarize the current knowledge regarding the roles and mechanisms of these hormones in liver regeneration. Articles used for this review were identified by searching MEDLINE and EMBASE databases from inception through June 1, 2019.
PubMed: 32542223
DOI: 10.1016/j.mayocpiqo.2020.02.001 -
Cancer Letters Sep 2019Phosphatidylinositol 3-kinase (PI3K)/AKT pathway regulates cell growth, proliferation, survival, mobility and invasion. Mitogen-activated protein kinase... (Review)
Review
Phosphatidylinositol 3-kinase (PI3K)/AKT pathway regulates cell growth, proliferation, survival, mobility and invasion. Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is also an important mitogenic signaling pathway involved in various cellular progresses. AKT, also named protein kinase B (PKB), is a primary mediator of the PI3K signaling pathway; and ERK at the end of MAPK signaling is the unique substrate and downstream effector of mitogen-activated protein/extracellular signal-regulated kinase (MEK). The AKT and ERK signaling are both aberrantly activated in a wide range of human cancers and have long been targeted for cancer therapy, but the clinical benefits of these targeted therapies have been limited due to complex cross-talk. Novel strategies, such as AKT/ERK dual inhibitors, may be needed.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Extracellular Signal-Regulated MAP Kinases; Humans; MAP Kinase Signaling System; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Randomized Controlled Trials as Topic; Xenograft Model Antitumor Assays
PubMed: 31128213
DOI: 10.1016/j.canlet.2019.05.025