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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 -
Science (New York, N.Y.) May 2024Cell cycle events are coordinated by cyclin-dependent kinases (CDKs) to ensure robust cell division. CDK4/6 and CDK2 regulate the growth 1 (G) to synthesis (S) phase...
Cell cycle events are coordinated by cyclin-dependent kinases (CDKs) to ensure robust cell division. CDK4/6 and CDK2 regulate the growth 1 (G) to synthesis (S) phase transition of the cell cycle by responding to mitogen signaling, promoting E2F transcription and inhibition of the anaphase-promoting complex. We found that this mechanism was still required in G-arrested cells to prevent cell cycle exit after the S phase. This mechanism revealed a role for CDK4/6 in maintaining the G state, challenging the notion that the cell cycle is irreversible and that cells do not require mitogens after passing the restriction point. Exit from G occurred during ribotoxic stress and was actively mediated by stress-activated protein kinases. Upon relief of stress, a significant fraction of cells underwent a second round of DNA replication that led to whole-genome doubling.
Topics: Humans; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; E2F Transcription Factors; G2 Phase Cell Cycle Checkpoints; S Phase; Stress, Physiological; Cell Line; Endoreduplication
PubMed: 38696576
DOI: 10.1126/science.adi2421 -
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 -
Annual Review of Biochemistry Jun 2022Mitogen-activated protein kinase (MAPK)-activated protein kinases (MAPKAPKs) are defined by their exclusive activation by MAPKs. They can be activated by classical and... (Review)
Review
Mitogen-activated protein kinase (MAPK)-activated protein kinases (MAPKAPKs) are defined by their exclusive activation by MAPKs. They can be activated by classical and atypical MAPKs that have been stimulated by mitogens and various stresses. Genetic deletions of MAPKAPKs and availability of highly specific small-molecule inhibitors have continuously increased our functional understanding of these kinases. MAPKAPKs cooperate in the regulation of gene expression at the level of transcription; RNA processing, export, and stability; and protein synthesis. The diversity of stimuli for MAPK activation, the crosstalk between the different MAPKs and MAPKAPKs, and the specific substrate pattern of MAPKAPKs orchestrate immediate-early and inflammatory responses in space and time and ensure proper control of cell growth, differentiation, and cell behavior. Hence, MAPKAPKs are promising targets for cancer therapy and treatments for conditions of acute and chronic inflammation, such as cytokine storms and rheumatoid arthritis.
Topics: Humans; Inflammation; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Phosphorylation
PubMed: 35303787
DOI: 10.1146/annurev-biochem-081720-114505 -
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 -
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 -
International Journal of Molecular... Jul 2021The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid... (Review)
Review
The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.
Topics: Animals; Atherosclerosis; Humans; MAP Kinase Kinase 5; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 7; Neoplasms
PubMed: 34299213
DOI: 10.3390/ijms22147594 -
Biochemistry and Cell Biology =... Jun 2023The mitogen- and stress-activated protein kinases (MSK) are epigenetic modifiers that regulate gene expression in normal and disease cell states. MSK1 and 2 are involved... (Review)
Review
The mitogen- and stress-activated protein kinases (MSK) are epigenetic modifiers that regulate gene expression in normal and disease cell states. MSK1 and 2 are involved in a chain of signal transduction events bringing signals from the external environment of a cell to specific sites in the genome. MSK1/2 phosphorylate histone H3 at multiple sites, resulting in chromatin remodeling at regulatory elements of target genes and the induction of gene expression. Several transcription factors (RELA of NF-κB and CREB) are also phosphorylated by MSK1/2 and contribute to induction of gene expression. In response to signal transduction pathways, MSK1/2 can stimulate genes involved in cell proliferation, inflammation, innate immunity, neuronal function, and neoplastic transformation. Abrogation of the MSK-involved signaling pathway is among the mechanisms by which pathogenic bacteria subdue the host's innate immunity. Depending on the signal transduction pathways in play and the MSK-targeted genes, MSK may promote or hinder metastasis. Thus, depending on the type of cancer and genes involved, MSK overexpression may be a good or poor prognostic factor. In this review, we focus on mechanisms by which MSK1/2 regulate gene expression, and recent studies on their roles in normal and diseased cells.
Topics: Gene Expression; Histones; Mitogens; Phosphorylation; Protein Kinases; Humans; Animals
PubMed: 36812480
DOI: 10.1139/bcb-2022-0371