The mammalian ULK1 complex and autophagy initiation

Essays in Biochemistry, Journal Year: 2017, Volume and Issue: 61(6), P. 585 - 596

Published: Dec. 12, 2017

Autophagy is a vital lysosomal degradation pathway that serves as quality control mechanism. It rids the cell of damaged, toxic or excess cellular components, which if left to persist could be detrimental cell. also recycling maintain protein synthesis under starvation conditions. A key initial event in autophagy formation autophagosome, unique double-membrane organelle engulfs cytosolic cargo destined for degradation. This step mediated by serine/threonine kinase ULK1 (unc-51-like 1), functions complex with at least three partners: FIP200 (focal adhesion family interacting 200 kDa), ATG (autophagy-related protein) 13 (ATG13), and ATG101. In this artcile, we focus on regulation during initiation. The pattern upstream pathways converge suggests acts node, converting multiple signals into autophagosome formation. Here, review our current understanding turn discuss what happens downstream, once becomes activated.

Language: Английский

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Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 13, 2022

Regulated cell death (RCD), also well-known as programmed (PCD), refers to the form of that can be regulated by a variety biomacromolecules, which is distinctive from accidental (ACD). Accumulating evidence has revealed RCD subroutines are key features tumorigenesis, may ultimately lead establishment different potential therapeutic strategies. Hitherto, targeting with pharmacological small-molecule compounds been emerging promising avenue, rapidly progressed in many types human cancers. Thus, this review, we focus on summarizing not only apoptotic and autophagy-dependent signaling pathways, but crucial pathways other subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis lysosome-dependent (LCD) cancer. Moreover, further discuss current situation several improve cancer treatment, such single-target, dual or multiple-target compounds, drug combinations, some new strategies would together shed light future directions attack vulnerabilities drugs for purposes.

Language: Английский

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Mitochondrial DNA copy number in human disease: the more the better?

FEBS Letters, Journal Year: 2020, Volume and Issue: 595(8), P. 976 - 1002

Published: Dec. 12, 2020

Most of the genetic information has been lost or transferred to nucleus during evolution mitochondria. Nevertheless, mitochondria have retained their own genome that is essential for oxidative phosphorylation (OXPHOS). In mammals, a gene‐dense circular mitochondrial DNA (mtDNA) about 16.5 kb encodes 13 proteins, which constitute only 1% proteome. Mammalian mtDNA present in thousands copies per cell and mutations often affect fraction them. pathogenic human are recessive cause OXPHOS defects if above certain critical threshold. However, emerging evidence strongly suggests proportion mutated not determinant disease but also absolute copy number matters. this review, we critically discuss current knowledge role regulation various types diseases, including disorders, neurodegenerative disorders cancer, ageing. We provide an overview new exciting therapeutic strategies directly manipulate restore diseases.

Language: Английский

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Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Oct. 2, 2023

The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain homeostasis. mTOR signaling cascade consists two distinct multi-subunit complexes named complex 1/2 (mTORC1/2). catalyzes the phosphorylation several critical proteins like AKT, C, insulin growth factor receptor (IGF-1R), 4E binding 1 (4E-BP1), ribosomal S6 (S6K), transcription EB (TFEB), sterol-responsive element-binding (SREBPs), Lipin-1, Unc-51-like autophagy-activating kinases. plays central role in regulating translation, lipid synthesis, nucleotide biogenesis lysosomes, nutrient sensing, signaling. emerging pieces evidence have revealed constitutive activation pathway due mutations/amplification/deletion either its (mTORC1 mTORC2) or upstream targets responsible for aging, neurological diseases, human malignancies. Here, we provide detailed structure mTOR, complexes, comprehensive regulators, as well downstream effectors cascades biomolecules, autophagy. Additionally, summarize potential long noncoding RNAs (lncRNAs) an important modulator Importantly, highlighted disorders, cancers, cancer stem cells, drug resistance. discuss developments therapeutic targeting with improved anticancer efficacy benefit patients clinics.

Language: Английский

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Beclin 1 Phosphorylation – at the Center of Autophagy Regulation

Frontiers in Cell and Developmental Biology, Journal Year: 2018, Volume and Issue: 6

Published: Oct. 12, 2018

Autophagy is a tightly regulated catabolic process wherein cells under stress sequester cytosolic constituents like damaged proteins and organelles in double-membrane vesicles called autophagosomes. The autophagosomes degrade their cargo by lysosomal proteolysis generating raw materials for the biosynthesis of vital macromolecules. One initial steps assembly from pre-autophagic structures recruitment activation class III phosphatidylinositol 3-kinase complex consisting Beclin 1 (BECN1), VPS34, VPS15 ATG14 proteins. Evidence indicate that phosphorylation ubiquitination BECN1 at an array residues fine-tune responses to diverse autophagy modulating stimuli helps maintaining balance between pro-survival pro-apoptotic responses. In this mini-review we will discuss importance distinct events, signaling pathways kinases involved role regulation autophagy.

Language: Английский

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Roles of Autophagy in Oxidative Stress

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(9), P. 3289 - 3289

Published: May 6, 2020

Autophagy is a catabolic process for unnecessary or dysfunctional cytoplasmic contents by lysosomal degradation pathways. implicated in various biological processes such as programmed cell death, stress responses, elimination of damaged organelles and development. The role autophagy crucial mediator has been clarified expanded the pathological response to redox signalling. major sensor Reactive oxygen species (ROS) are highly reactive molecules that generated by-products cellular metabolism, principally mitochondria. Mitochondrial ROS (mROS) beneficial detrimental cells depending on their concentration location. mROS function messengers intracellular signalling at physiologically low level, whereas excessive production causes oxidative damage constituents thus incurs death. Hence, balance autophagy-related adaptation death important comprehend signalling-related pathogenesis. In this review, we attempt provide an overview basic mechanism context pathology.

Language: Английский

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Metabolism of Amino Acids in Cancer

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 8

Published: Jan. 12, 2021

Metabolic reprogramming has been widely recognized as a hallmark of malignancy. The uptake and metabolism amino acids are aberrantly upregulated in many cancers that display addiction to particular acids. Amino facilitate the survival proliferation cancer cells under genotoxic, oxidative, nutritional stress. Thus, targeting acid is becoming potential therapeutic strategy for patients. In this review, we will systematically summarize recent progress malignancy discuss their interconnection with mammalian target rapamycin complex 1 (mTORC1) signaling, epigenetic modification, tumor growth immunity, ferroptosis. Finally, highlight applications.

Language: Английский

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The Emerging Roles of mTORC1 in Macromanaging Autophagy

Cancers, Journal Year: 2019, Volume and Issue: 11(10), P. 1422 - 1422

Published: Sept. 24, 2019

Autophagy is a process of self-degradation that enables the cell to survive when faced with starvation or stressful conditions. The mechanistic target rapamycin (mTOR), also known as mammalian rapamycin, plays critical role in maintaining balance between cellular anabolism and catabolism. mTOR complex 1 (mTORC1) was unveiled master regulator autophagy since inhibition mTORC1 required initiate process. Evidence has emerged recent years indicate directly regulates subsequent steps process, including nucleation, autophagosome elongation, maturation termination. By phosphorylating select protein targets core machinery and/or their regulators, can alter functions, increase proteasomal degradation modulate acetylation status, which key switch Moreover, it phosphorylates alters subcellular localization transcription factors suppress expression genes needed for formation lysosome biogenesis. purpose this review article critically analyze current literatures provide an integrated view how various

Language: Английский

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Molecular regulation of autophagy machinery by mTOR‐dependent and ‐independent pathways

Annals of the New York Academy of Sciences, Journal Year: 2020, Volume and Issue: 1467(1), P. 3 - 20

Published: Jan. 27, 2020

Abstract Macroautophagy is a lysosomal degradative pathway or recycling process that maintains cellular homeostasis. This autophagy involves series of sequential processing events, such as initiation; elongation and nucleation the isolation membrane; cargo recruitment maturation autophagosome (AP); transport AP; docking fusion AP with late endosome lysosome; regeneration lysosome by autophagic reformation cycle. These events are critically coordinated action set several key components, including autophagy‐related proteins (Atg), regulated intricate networks, mechanistic target rapamycin (mTOR), master regulator autophagy, well mTOR‐independent signaling pathways. Among pathways, transient receptor potential (TRP) calcium ion channel TRPML (mucolipin) subfamily emerging an important to modulate biogenesis autophagy. review discusses recent advances in elucidating molecular mechanisms regulation process. Understanding these may ultimately allow scientists clinicians control this order improve human health.

Language: Английский

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Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR

Journal of Oncology, Journal Year: 2020, Volume and Issue: 2020, P. 1 - 11

Published: March 9, 2020

Breast cancer is the with highest prevalence in women and number-one cause of mortality worldwide. Cell transduction a fundamental process development progression cancer. Modifications various cell signalling pathways promote tumour proliferation, progression, survival. The PI3K/Akt/mTOR pathway an example that, it involved growth, survival, motility, metabolism, immune response regulation. Activation this one main causes resistance to antitumour therapies. This makes crucial object study for understanding disease. Thus, may have role as potential therapeutic target, well prognostic diagnostic value, patients breast Despite existence selective inhibitors current clinical trials, cellular mechanisms are not yet known. present review aims understand state important disease paths that must be forged.

Language: Английский

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