Vascular Stress Signaling in Hypertension

2021 ◽  
Vol 128 (7) ◽  
pp. 969-992
Author(s):  
Stephanie M. Cicalese ◽  
Josiane Fernandes da Silva ◽  
Fernanda Priviero ◽  
R. Clinton Webb ◽  
Satoru Eguchi ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Molecular Mechanisms ◽  
Mitochondrial Fission ◽  
Antioxidant Response ◽  
Intracellular Accumulation ◽  
Unfolded Protein ◽  
Cell Death Pathways ◽  
Signaling Mechanisms ◽  
Survival Signaling

Cells respond to stress by activating a variety of defense signaling pathways, including cell survival and cell death pathways. Although cell survival signaling helps the cell to recover from acute insults, cell death or senescence pathways induced by chronic insults can lead to unresolved pathologies. Arterial hypertension results from chronic physiological maladaptation against various stressors represented by abnormal circulating or local neurohormonal factors, mechanical stress, intracellular accumulation of toxic molecules, and dysfunctional organelles. Hypertension and aging share common mechanisms that mediate or prolong chronic cell stress, such as endoplasmic reticulum stress and accumulation of protein aggregates, oxidative stress, metabolic mitochondrial stress, DNA damage, stress-induced senescence, and proinflammatory processes. This review discusses common adaptive signaling mechanisms against these stresses including unfolded protein responses, antioxidant response element signaling, autophagy, mitophagy, and mitochondrial fission/fusion, STING (signaling effector stimulator of interferon genes)-mediated responses, and activation of pattern recognition receptors. The main molecular mechanisms by which the vasculature copes with hypertensive and aging stressors are presented and recent advancements in stress-adaptive signaling mechanisms as well as potential therapeutic targets are discussed.

scholarly journals LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽  
2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Yu Geon Lee ◽  
Hui Won Kim ◽  
Yeji Nam ◽  
Kyeong Jin Shin ◽  
Yu Jin Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Cell Survival ◽  
Cancer Cell ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Mitochondrial Matrix ◽  
Mitochondrial Functions ◽  
Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

scholarly journals OTUD1 deubiquitylase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

2021 ◽  
Author(s):  
Daisuke Oikawa ◽  
Min Gi ◽  
Hidetaka Kosako ◽  
Kouhei Shimizu ◽  
Hirotaka Takahashi ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Stress Responses ◽  
Inflammatory Responses ◽  
Reactive Oxygen ◽  
Antioxidant Response ◽  
Oxygen Species ◽  
Ubiquitin Chain ◽  
Intrinsically Disordered ◽  
Cell Death Pathways

Deubiquitylating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolysing K63-linked ubiquitin chains from NF-κB signalling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. The N-terminal intrinsically disordered region of OTUD1, which contains an EGTE motif, is indispensable for KEAP1-binding and NF-κB suppression. OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1-/--mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.

scholarly journals Ca2+ signaling mechanisms of cell survival and cell death: An introduction

Cell Calcium ◽  
2011 ◽  
Vol 50 (3) ◽  
pp. 207-210 ◽  
Author(s):  
H. De Smedt ◽  
A. Verkhratsky ◽  
S. Muallem
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Signaling Mechanisms

scholarly journals Cell Death Pathways as Therapeutic Targets in Rhabdomyosarcoma

Sarcoma ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Aberrant Expression ◽  
Antiapoptotic Proteins ◽  
Cell Death Pathways ◽  
Rational Development ◽  
Current Therapies ◽  
Key Issues ◽  
Cytotoxic Therapies

Resistance of rhabdomyosarcoma to current therapies remains one of the key issues in pediatric oncology. Since the success of most cytotoxic therapies in the treatment of cancer, for example, chemotherapy, depends on intact signaling pathways that mediate programmed cell death (apoptosis), defects in apoptosis programs in cancer cells may result in resistance. Evasion of apoptosis in rhabdomyosarcoma may be caused by defects in the expression or function of critical mediators of apoptosis or in aberrant expression of antiapoptotic proteins. Therefore, the identification of the molecular mechanisms that confer primary or acquired resistance to apoptosis in rhabdomyosarcoma presents a critical step for the rational development of molecular targeted drugs. This approach will likely open novel perspectives for the treatment of rhabdomyosarcoma.

scholarly journals The actin nucleation factors JMY and WHAMM enable a rapid p53-dependent pathway of apoptosis

2020 ◽  
Author(s):  
Virginia L. King ◽  
Nathan K. Leclair ◽  
Kenneth G. Campellone
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Actin Cytoskeleton ◽  
Cell Survival ◽  
G Protein ◽  
Actin Nucleation ◽  
Caspase Cleavage ◽  
Cell Death Pathways ◽  
Small G Protein

AbstractThe actin cytoskeleton is a well-known player in most vital cellular processes, but comparably little is understood about how the actin assembly machinery impacts programmed cell death pathways. In the current study, we explored roles for the human Wiskott-Aldrich Syndrome Protein (WASP) family of actin nucleation factors in DNA damage-induced apoptosis. Inactivation of each WASP-family gene revealed that two, JMY and WHAMM, are required for rapid apoptotic responses. JMY and WHAMM enable p53-dependent cell death by enhancing mitochondrial permeabilization, initiator caspase cleavage, and executioner caspase activation. The loss of JMY additionally results in significant changes in gene expression, including upregulation of the small G-protein RhoD. Depletion or deletion of RHOD increases cell death, suggesting that RhoD normally plays a key role in cell survival. These results give rise to a model in which JMY and WHAMM promote intrinsic cell death responses that can be opposed by RhoD.Author SummaryThe actin cytoskeleton is a collection of protein polymers that assemble and disassemble within cells at specific times and locations. Cytoskeletal regulators called nucleation-promoting factors ensure that actin polymerizes when and where it is needed, and many of these factors are members of the Wiskott-Aldrich Syndrome Protein (WASP) family. Humans express 8 WASP-family proteins, but whether the different factors function in programmed cell death pathways is not well understood. In this study, we explored roles for each WASP-family member in apoptosis and found that a subfamily consisting of JMY and WHAMM are critical for a rapid pathway of cell death. Furthermore, the loss of JMY results in changes in gene expression, including a dramatic upregulation of the small G-protein RhoD, which appears to be crucial for cell survival. Collectively, our results point to the importance of JMY and WHAMM in driving intrinsic cell death responses plus a distinct function for RhoD in maintaining cell viability.

scholarly journals Loss of αA or αB-Crystallin Accelerates Photoreceptor Cell Death in a Mouse Model of P23H Autosomal Dominant Retinitis Pigmentosa

2021 ◽  
Vol 23 (1) ◽  
pp. 70
Author(s):  
Tiantian Wang ◽  
Jingyu Yao ◽  
Lin Jia ◽  
Patrice E. Fort ◽  
David N. Zacks
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Unfolded Protein ◽  
Retinal Degenerations ◽  
Light Sensing ◽  
Cell Death Pathways ◽  
Αb Crystallin ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Photoreceptor Death

Inherited retinal degenerations (IRD) are a leading cause of visual impairment and can result from mutations in any one of a multitude of genes. Mutations in the light-sensing protein rhodopsin (RHO) is a leading cause of IRD with the most common of those being a missense mutation that results in substitution of proline-23 with histidine. This variant, also known as P23H-RHO, results in rhodopsin misfolding, initiation of endoplasmic reticulum stress, the unfolded protein response, and activation of cell death pathways. In this study, we investigate the effect of α-crystallins on photoreceptor survival in a mouse model of IRD secondary to P23H-RHO. We find that knockout of either αA- or αB-crystallin results in increased intraretinal inflammation, activation of apoptosis and necroptosis, and photoreceptor death. Our data suggest an important role for the ⍺-crystallins in regulating photoreceptor survival in the P23H-RHO mouse model of IRD.

scholarly journals Diterpenoid Vinigrol activates ATF4/DDIT3-mediated PERK/eIF2α arm of unfolded protein response to drive breast cancer cell death

2021 ◽  
Author(s):  
Wencheng Wei ◽  
Yunfei Li ◽  
Chuanxi Wang ◽  
Sanxing Gao ◽  
Hao Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Unfolded Protein Response ◽  
Molecular Mechanisms ◽  
Death Process ◽  
Mcf7 Cells ◽  
Multiple Cancer ◽  
Unfolded Protein ◽  
Mechanistic Investigation ◽  
Anti Cancer ◽  
Protein Response

AbstractVinigrol is a natural diterpenoid with unprecedented chemical structure, driving great efforts into its total synthesis and the chemical analogs in the past decades. Despite its pharmacological efficacies reported on anti-hypertension and anti-clot, comprehensive functional investigations on Vinigrol and the underlying molecular mechanisms are entirely missing. In this study, we carried out a complete functional prediction of Vinigrol using a transcriptome-based strategy, Connectivity Map, and identified “anti-cancer” as the most prominent biofunction ahead of anti-hypertension and anti-depression/psychosis. A broad cytotoxicity was subsequently confirmed on multiple cancer types. Further mechanistic investigation on MCF7 cells revealed that its anti-cancer effect is mainly through activating PERK/eIF2α arm of unfolded protein response (UPR) and subsequent upregulation of p53/p21 to halt the cell cycle. The other two branches of UPR, IRE1α and ATF6, are functionally irrelevant to Vinigrol-induced cell death. CRISPR/Cas9-based gene activation, repression, and knockout systems identified essential contribution of ATF4/DDIT3 not ATF6 to the death process. This study unraveled a broad anti-cancer function of Vinigrol and its underlying targets and regulatory mechanisms, and also paved the way for further inspection on the structure-efficacy relationship of the whole compound family, making them a novel cluster of chemical hits for cancer therapy.

Mitochondrial morphology and distribution in mammalian cells

2006 ◽  
Vol 387 (12) ◽  
pp. 1551-1558 ◽  
Author(s):  
Ann E. Frazier ◽  
Clement Kiu ◽  
Diana Stojanovski ◽  
Nicholas J. Hoogenraad ◽  
Michael T. Ryan
Keyword(s):  
Cell Death ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Morphological Changes ◽  
Mitochondrial Fission ◽  
Gene Mutations ◽  
Current Understanding ◽  
Mitochondrial Morphology ◽  
Cell Death Pathways ◽  
Mitochondrial Distribution

Abstract It is now appreciated that mitochondria form tubular networks that adapt to the requirements of the cell by undergoing changes in their shape through fission and fusion. Proper mitochondrial distribution also appears to be required for ATP delivery and calcium regulation, and, in some cases, for cell development. While we now realise the great importance of mitochondria for the cell, we are only beginning to work out how these organelles undergo the drastic morphological changes that are essential for cellular function. Of the few known components involved in shaping mitochondria, some have been found to be essential to life and their gene mutations are linked to neurological disorders, while others appear to be recruited in the activation of cell death pathways. Here we review our current understanding of the functions of the main players involved in mitochondrial fission, fusion and distribution in mammalian cells.

scholarly journals Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Arnaud Tauffenberger ◽  
Hubert Fiumelli ◽  
Salam Almustafa ◽  
Pierre J. Magistretti
Keyword(s):  
Oxidative Stress ◽  
Cell Survival ◽  
Stress Resistance ◽  
Molecular Mechanisms ◽  
Antioxidant Defenses ◽  
Related Factor ◽  
Cell Protection ◽  
Unfolded Protein ◽  
Ros Burst

Abstract L-lactate was long considered a glycolytic by-product but is now being recognized as a signaling molecule involved in cell survival. In this manuscript, we report the role of L-lactate in stress resistance and cell survival mechanisms using neuroblastoma cells (SH-SY5Y) as well as the C. elegans model. We observed that L-lactate promotes cellular defense mechanisms, including Unfolded Protein Response (UPR) and activation of nuclear factor erythroid 2–related factor 2 (NRF2), by promoting a mild Reactive Oxygen Species (ROS) burst. This increase in ROS triggers antioxidant defenses and pro-survival pathways, such as PI3K/AKT and Endoplasmic Reticulum (ER) chaperones. These results contribute to the understanding of the molecular mechanisms involved in beneficial effects of L-lactate, involving mild ROS burst, leading to activation of unfolded protein responses and detoxification mechanisms. We present evidence that this hormetic mechanism induced by L-lactate protects against oxidative stress in vitro and in vivo. This work contributes to the identification of molecular mechanisms, which could serve as targets for future therapeutic approaches for cell protection and aging-related disorders.

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