Neuroglobin and Estrogen Receptors: A New Pathway of Cell Survival and Cell Death Balance

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.

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A Screen for Mutations That Suppress the Phenotype of Drosophila armadillo, the β-Catenin Homolog

Genetics ◽

10.1093/genetics/155.4.1725 ◽

2000 ◽

Vol 155 (4) ◽

pp. 1725-1740

Author(s):

Rachel T Cox ◽

Donald G McEwen ◽

Denise L Myster ◽

Robert J Duronio ◽

Joseph Loureiro ◽

...

Keyword(s):

Cell Death ◽

Cell Adhesion ◽

Programmed Cell Death ◽

Cell Survival ◽

Wnt Pathway ◽

Genetic Modifier ◽

Wnt Signaling Pathway ◽

Adherens Junction ◽

Cell Fates ◽

Wnt Signal

Abstract During development signaling pathways coordinate cell fates and regulate the choice between cell survival or programmed cell death. The well-conserved Wingless/Wnt pathway is required for many developmental decisions in all animals. One transducer of the Wingless/Wnt signal is Armadillo/β-catenin. Drosophila Armadillo not only transduces Wingless signal, but also acts in cell-cell adhesion via its role in the epithelial adherens junction. While many components of both the Wingless/Wnt signaling pathway and adherens junctions are known, both processes are complex, suggesting that unknown components influence signaling and junctions. We carried out a genetic modifier screen to identify some of these components by screening for mutations that can suppress the armadillo mutant phenotype. We identified 12 regions of the genome that have this property. From these regions and from additional candidate genes tested we identified four genes that suppress arm: dTCF, puckered, head involution defective (hid), and Dpresenilin. We further investigated the interaction with hid, a known regulator of programmed cell death. Our data suggest that Wg signaling modulates Hid activity and that Hid regulates programmed cell death in a dose-sensitive fashion.

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Steroid Hormone Control of Cell Death and Cell Survival: Molecular Insights Using RNAi

PLoS Genetics ◽

10.1371/journal.pgen.1000379 ◽

2009 ◽

Vol 5 (2) ◽

pp. e1000379 ◽

Cited By ~ 17

Author(s):

Suganthi Chittaranjan ◽

Melissa McConechy ◽

Ying-Chen Claire Hou ◽

J. Douglas Freeman ◽

Lindsay DeVorkin ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Steroid Hormone ◽

Hormone Control

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Pancreatic islet cell survival following islet isolation: the role of cellular interactions in the pancreas

Journal of Endocrinology ◽

10.1677/joe.0.1610357 ◽

1999 ◽

Vol 161 (3) ◽

pp. 357-364 ◽

Cited By ~ 102

Author(s):

A Ilieva ◽

S Yuan ◽

RN Wang ◽

D Agapitos ◽

DJ Hill ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Islet Cell ◽

Apoptotic Cell ◽

Specific Cell ◽

Cellular Interactions ◽

Pancreatic Islet Cell ◽

Beneficial Result ◽

Trophic Effect ◽

Ductal Epithelium

The purpose of this study was to characterize the trophic effect of pancreatic duct cells on the islets of Langerhans. Ductal epithelium and islets were isolated from hamster pancreata. In addition, duct-conditioned medium (DCM) was prepared from primary duct cultures that had been passaged twice to remove other cellular elements. Three experimental groups were then established: Group 1, 100 islets alone; Group 2, 100 islets+80 duct fragments; and Group 3, 100 islets in 25% DCM. All tissues were embedded in rat tail collagen for up to 12 days and the influence of pancreatic ductal epithelium on islet cell survival was examined. By day 12, 20.6+/-3. 0% (S.E.M.) of the islets cultured alone developed central necrosis, compared with 6.7+/-2.0% of the islets co-cultured with ducts and 5.6+/-1.5% of the islets cultured in DCM (P<0.05). The presence of apoptotic cell death was determined by a TdT-mediated dUTP-biotin nick end labelling (TUNEL) assay and by a specific cell death ELISA. DNA fragmentation in islets cultured alone was significantly increased compared with islets cultured either in the presence of duct epithelium or in DCM (P<0.05). More than 80% of TUNEL-positive cells were situated in the inner 80% of the islet area, suggesting that most were beta-cells. DCM was analysed for known growth factors. The presence of a large amount of IGF-II (34 ng/ml) and a much smaller quantity of nerve growth factor (4 ng/ml) was identified. When the apoptosis studies were repeated to compare islets alone, islets+DCM and islets+IGF-II, the cell death ELISA indicated that IGF-II produced the same beneficial result as DCM when compared with islets cultured alone. We conclude that pancreatic ductal epithelium promotes islet cell survival. This effect appears to be mediated in a paracrine manner by the release of IGF-II from cells in the ductal epithelium.

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The pro-cell death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia

International Journal of Cancer ◽

10.1002/ijc.21547 ◽

2006 ◽

Vol 118 (7) ◽

pp. 1660-1669 ◽

Cited By ~ 68

Author(s):

Teralee R. Burton ◽

Elizabeth S. Henson ◽

Priti Baijal ◽

David D. Eisenstat ◽

Spencer B. Gibson

Keyword(s):

Cell Death ◽

Glioblastoma Multiforme ◽

Tumor Cell ◽

Cell Survival ◽

Family Member ◽

Glial Cells ◽

Tumor Cell Survival

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Kinase cascades regulating entry into apoptosis

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.61.1.33-46.1997 ◽

1997 ◽

Vol 61 (1) ◽

pp. 33-46

Author(s):

P Anderson

Keyword(s):

Cell Death ◽

Cell Surface ◽

Cell Survival ◽

Tyrosine Kinases ◽

Uv Light ◽

Apoptotic Cell ◽

Paracrine Factors ◽

Surface Receptors ◽

Promote Cell Survival ◽

Necrosis Factor

All cells are constantly exposed to conflicting environment cues that signal cell survival or cell death. Survival signals are delivered by autocrine or paracrine factors that actively suppress a default death pathway. In addition to survival factor withdrawal, cell death can be triggered by environmental stresses such as heat, UV light, and hyperosmolarity or by dedicated death receptors (e.g., FAS/APO-1 and tumor necrosis factor [TNF] receptors) that are counterparts of growth factor or survival receptors at the cell surface. One of the ways that cells integrate conflicting exogenous stimuli is by phosphorylation (or dephosphorylation) of cellular constituents by interacting cascades of serine/threonine and tyrosine protein kinases (and phosphatases). Survival factors (e.g., growth factors and mitogens) activate receptor tyrosine kinases and selected mitogen-activated, cyclin-dependent, lipid-activated, nucleic acid-dependent, and cyclic AMP-dependent kinases to promote cell survival and proliferation, whereas environmental stress (or death factors such as FAS/APO-1 ligand and TNF-alpha) activates different members of these kinase families to inhibit cell growth and, under some circumstances, promote apoptotic cell death. Because individual kinase cascades can interact with one another, they are able to integrate conflicting exogenous stimuli and provide a link between cell surface receptors and the biochemical pathways leading to cell proliferation or cell death.

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Abstract 143: A Novel TAK1 Signaling Network Regulating Programmed Necrosis and Myocardial Remodeling

Circulation Research ◽

10.1161/res.113.suppl_1.a143 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Qinghang Liu ◽

Lei Li ◽

Yi Chen ◽

Jessica Doan ◽

Jeffery Molkentin

Keyword(s):

Heart Failure ◽

Cell Death ◽

Cell Survival ◽

Cardiac Fibrosis ◽

Signaling Network ◽

Specific Gene ◽

Caspase 8 ◽

Programmed Necrosis ◽

Genetic Ablation ◽

Cell Death Pathway

We recently identified a novel signaling molecule, TAK1 (TGFβ-activated kinase 1, also known as MAP3K7), as a key regulator of the hypertrophic signaling network. Importantly, TAK1 is activated in mouse models of heart failure as well as in diseased human myocardium. Here, we defined a previously unidentified, novel role for TAK1 in promoting cardiac cell survival and homeostasis using cardiac-specific gene-targeted mice. Indeed, cardiac-specific ablation of TAK1 in mice using a Cre-LoxP system showed enhanced pathological cardiac remodeling and massive cell death, and these mice gradually developed heart failure and spontaneous death. Remarkably, ablation of TNF receptor 1 (TNFR1) largely rescued the pathological phenotype of TAK1-deficient mice, preventing early lethality and cardiac fibrosis, suggesting that TNFR1 signaling is critical in mediating adverse remodeling and heart failure associated with TAK1 deficiency. Genetic or pharmacological inactivation of TAK1 in cardiomyocytes markedly induced programmed necrosis and apoptosis in response to TNFα. Conversely, overexpression of the constitutively active TAK1 mutant, or TAK1 plus its activator TAB1, protected cardiomyocytes from TNFα-induced cell death. Mechanistically, inactivation of TAK1 promoted formation of the necroptotic cell death complex consisting of RIP1, RIP3, caspase 8, and FADD. Genetic ablation of RIP1, RIP3, caspase 8, or FADD largely blocked TNFα-induced cell death in TAK1-deficient cells, whereas deletion of Bax/Bak or cyclophilin D showed no effects. Further, IKK/NFκB-mediated cell survival signaling was greatly impaired in TAK1-deficient cardiomyocytes. Taken together, our data indicate that TAK1 functions as a critical “molecular switch” in TNFα-induced programmed necrosis in cardiomyocytes, by interacting with the RIP1/3-caspase 8-FADD cell death pathway as well as the IKK-NFκB cell survival pathway. These findings thus define an important TAK1-mediated cardio-protective signaling network in the heart, which may suggest new therapeutic strategies in the treatment of heart disease.

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Overexpression of human Hsp27 inhibits serum-induced proliferation in airway smooth muscle myocytes and confers resistance to hydrogen peroxide cytotoxicity

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00453.2006 ◽

2007 ◽

Vol 293 (5) ◽

pp. L1194-L1207 ◽

Cited By ~ 26

Author(s):

Sonemany Salinthone ◽

Mariam Ba ◽

Lisa Hanson ◽

Jody L. Martin ◽

Andrew J. Halayko ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Cell Death ◽

Smooth Muscle ◽

Cell Survival ◽

Airway Smooth Muscle ◽

Apoptotic Cell ◽

Airway Remodeling ◽

Small Heat Shock Protein ◽

Nonmuscle Cells ◽

Myocyte Proliferation

Airway smooth muscle (ASM) hypertrophy and hyperplasia are characteristics of asthma that lead to thickening of the airway wall and obstruction of airflow. Very little is known about mechanisms underlying ASM remodeling, but in vascular smooth muscle, it is known that progression of atherosclerosis depends on the balance of myocyte proliferation and cell death. Small heat shock protein 27 (Hsp27) is antiapoptotic in nonmuscle cells, but its role in ASM cell survival is unknown. Our hypothesis was that phosphorylation of Hsp27 may regulate airway remodeling by modifying proliferation, cell survival, or both. To test this hypothesis, adenoviral vectors were used to overexpress human Hsp27 in ASM cells. Cells were infected with empty vector (Ad5) or wild-type Hsp27 (AdHsp27 WT), and proliferation and death were assessed. Overexpressing Hsp27 WT caused a 50% reduction in serum-induced proliferation and increased cell survival after exposure to 100 μM hydrogen peroxide (H2O2) compared with mock-infected controls. Overexpression studies utilizing an S15A, S78A, and S82A non-phosphorylation mutant (AdHsp27 3A) and an S15D, S78D, and S82D pseudo-phosphorylation mutant (AdHsp27 3D) showed phosphorylation of Hsp27 was necessary for regulation of ASM proliferation, but not survival. Hsp27 provided protection against H2O2-induced cytotoxicity by upregulating cellular glutathione levels and preventing necrotic cell death, but not apoptotic cell death. The results support the notion that ASM cells can be stimulated to undergo proliferation and death and that Hsp27 may regulate these processes, thereby contributing to airway remodeling in asthmatics.

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Death Receptor-Induced Activation of Initiator Caspase 8 Is Antagonized by Serine/Threonine Kinase PAK4

Molecular and Cellular Biology ◽

10.1128/mcb.23.21.7838-7848.2003 ◽

2003 ◽

Vol 23 (21) ◽

pp. 7838-7848 ◽

Cited By ~ 67

Author(s):

Nerina Gnesutta ◽

Audrey Minden

Keyword(s):

Cell Death ◽

Cell Survival ◽

Intracellular Signaling ◽

Death Receptor ◽

Caspase 8 ◽

Death Domain ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

Different Types ◽

Promote Cell Survival

ABSTRACT Normal cell growth requires a precisely controlled balance between cell death and survival. This involves activation of different types of intracellular signaling cascades within the cell. While some types of signaling proteins regulate apoptosis, or programmed cell death, other proteins within the cell can promote survival. The serine/threonine kinase PAK4 can protect cells from apoptosis in response to several different types of stimuli. As is the case for other members of the p21-activated kinase (PAK) family, one way that PAK4 may promote cell survival is by phosphorylating and thereby inhibiting the proapoptotic protein Bad. This leads in turn to the inhibition of effector caspases such as caspase 3. Here we show that in response to cytokines which activate death domain-containing receptors, such as the tumor necrosis factor and Fas receptors, PAK4 can inhibit the death signal by a different mechanism. Under these conditions, PAK4 inhibits apoptosis early in the caspase cascade, antagonizing the activation of initiator caspase 8. This inhibition, which does not require PAK4's kinase activity, may involve inhibition of caspase 8 recruitment to the death domain receptors. This role in regulating initiator caspases is an entirely novel role for the PAK proteins and suggests a new mechanism by which these proteins promote cell survival.

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Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts

Biochemical Journal ◽

10.1042/bj20130414 ◽

2013 ◽

Vol 454 (2) ◽

pp. 249-257 ◽

Cited By ~ 43

Author(s):

Qiuli Liang ◽

Gloria A. Benavides ◽

Athanassios Vassilopoulos ◽

David Gius ◽

Victor Darley-Usmar ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Mitochondrial Respiration ◽

Energy Demand ◽

Mammalian Target Of Rapamycin ◽

Protective Role ◽

Nutrient Deprivation ◽

Autophagy Flux ◽

Jnk Pathway ◽

Mouse Muscle

Sirt3 (sirtuin 3) is an NAD-dependent deacetylase localized to mitochondria. Sirt3 expression is increased in mouse muscle and liver by starvation, which could protect against the starvation-dependent increase in oxidative stress and protein damage. Damaged proteins and organelles depend on autophagy for removal and this is critical for cell survival, but the role of Sirt3 is unclear. To examine this, we used Sirt3-KO (knockout) mouse embryonic fibroblast cells, and found that, under basal conditions, Sirt3-KO cells exhibited increased autophagy flux compared with WT (wild-type) cells. In response to nutrient deprivation, both WT and KO cells exhibited increased basal and ATP-linked mitochondrial respiration, indicating an increased energy demand. Both cells exhibited lower levels of phosphorylated mTOR (mammalian target of rapamycin) and higher autophagy flux, with KO cells exhibiting lower maximal mitochondrial respiration and reserve capacity, and higher levels of autophagy than WT cells. KO cells exhibit higher phospho-JNK (c-Jun N-terminal kinase) and phospho-c-Jun than WT cells under starvation conditions. However, inhibition of JNK activity in Sirt3-KO cells did not affect LC3-I (light chain 3-I) and LC3-II levels, indicating that Sirt3-regulated autophagy is independent of the JNK pathway. Caspase 3 activation and cell death are significantly higher in Sirt3-KO cells compared with WT cells in response to nutrient deprivation. Inhibition of autophagy by chloroquine exacerbated cell death in both WT and Sirt3-KO cells, and by 3-methyadenine exacerbated cell death in Sirt3-KO cells. These data suggest that nutrient deprivation-induced autophagy plays a protective role in cell survival, and Sirt3 decreases the requirement for enhanced autophagy and improves cellular bioenergetics.

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