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A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells.
Rasmussen ML, Kline LA, Park KP, Ortolano NA, Romero-Morales AI, Anthony CC, Beckermann KE, Gama V
(2018) Stem Cell Reports 10: 684-692
MeSH Terms: Apoptosis, Cell Differentiation, Cell Line, Cellular Reprogramming, Humans, Mitochondria, Mitochondrial Dynamics, Mitochondrial Membranes, Myeloid Cell Leukemia Sequence 1 Protein, Pluripotent Stem Cells, Proto-Oncogene Proteins c-bcl-2
Show Abstract · Added March 14, 2018
Human pluripotent stem cells (hPSCs) maintain a highly fragmented mitochondrial network, but the mechanisms regulating this phenotype remain unknown. Here, we describe a non-cell death function of the anti-apoptotic protein, MCL-1, in regulating mitochondrial dynamics and promoting pluripotency of stem cells. MCL-1 is induced upon reprogramming, and its inhibition or knockdown induces dramatic changes to the mitochondrial network as well as loss of the key pluripotency transcription factors, NANOG and OCT4. Aside from localizing at the outer mitochondrial membrane like other BCL-2 family members, MCL-1 is unique in that it also resides at the mitochondrial matrix in pluripotent stem cells. Mechanistically, we find MCL-1 to interact with DRP-1 and OPA1, two GTPases responsible for remodeling the mitochondrial network. Depletion of MCL-1 compromised the levels and activity of these key regulators of mitochondrial dynamics. Our findings uncover an unexpected, non-apoptotic function for MCL-1 in the maintenance of mitochondrial structure and stemness.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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11 MeSH Terms
Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy.
Kasper S, Reis H, Ziegler S, Nothdurft S, Mueller A, Goetz M, Wiesweg M, Phasue J, Ting S, Wieczorek S, Even A, Worm K, Pogorzelski M, Breitenbuecher S, Meiler J, Paul A, Trarbach T, Schmid KW, Breitenbuecher F, Schuler M
(2017) Oncotarget 8: 45898-45917
MeSH Terms: Antineoplastic Agents, Immunological, Apoptosis, Biomarkers, Cell Line, Tumor, Colorectal Neoplasms, Drug Resistance, Neoplasm, ErbB Receptors, Exons, Genes, ras, Humans, Mitogen-Activated Protein Kinases, Mutation, Odds Ratio, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Signal Transduction
Show Abstract · Added March 17, 2018
Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are a mainstay of metastatic colorectal cancer (mCRC) treatment. However, a significant number of patients suffer from primary or acquired resistance. RAS mutations are negative predictors of clinical efficacy of anti-EGFR antibodies in patients with mCRC. Oncogenic RAS activates the MAPK and PI3K/AKT pathways, which are considered the main effectors of resistance. However, the relative impact of these pathways in RAS-mutant CRC is less defined. A better mechanistic understanding of RAS-mediated resistance may guide development of rational intervention strategies. To this end we developed cancer models for functional dissection of resistance to anti-EGFR therapy in vitro and in vivo. To selectively activate MAPK- or AKT-signaling we expressed conditionally activatable RAF-1 and AKT in cancer cells. We found that either pathway independently protected sensitive cancer models against anti-EGFR antibody treatment in vitro and in vivo. RAF-1- and AKT-mediated resistance was associated with increased expression of anti-apoptotic BCL-2 proteins. Biomarkers of MAPK and PI3K/AKT pathway activation correlated with inferior outcome in a cohort of mCRC patients receiving cetuximab-based therapy. Dual pharmacologic inhibition of PI3K and MEK successfully sensitized primary resistant CRC models to anti-EGFR therapy. In conclusion, combined targeting of MAPK and PI3K/AKT signaling, but not single pathways, may be required to enhance the efficacy of anti-EGFR antibody therapy in patients with RAS-mutated CRC as well as in RAS wild type tumors with clinical resistance.
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17 MeSH Terms
Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade.
Williams MM, Lee L, Hicks DJ, Joly MM, Elion D, Rahman B, McKernan C, Sanchez V, Balko JM, Stricker T, Estrada MV, Cook RS
(2017) Mol Cancer Res 15: 259-268
MeSH Terms: Aniline Compounds, Antineoplastic Agents, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Estrogen Receptor alpha, Female, Humans, MCF-7 Cells, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasms, Proto-Oncogene Proteins c-bcl-2, RNA, Messenger, Sulfonamides, bcl-X Protein
Show Abstract · Added April 6, 2017
An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of as compared with or (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured using Mcl-1/Bim proximity ligation assays. Importantly, gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of or and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1-selective inhibitors for targeted tumor cell killing. Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. .
©2016 American Association for Cancer Research.
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15 MeSH Terms
NADPH oxidase 4 deficiency increases tubular cell death during acute ischemic reperfusion injury.
Nlandu-Khodo S, Dissard R, Hasler U, Schäfer M, Pircher H, Jansen-Durr P, Krause KH, Martin PY, de Seigneux S
(2016) Sci Rep 6: 38598
MeSH Terms: Animals, Apoptosis, Cell Death, Creatinine, Disease Models, Animal, Gene Expression, Gene Expression Regulation, Genetic Predisposition to Disease, Glutathione, Kelch-Like ECH-Associated Protein 1, Kidney Diseases, Kidney Tubules, Mice, Mice, Knockout, Mitochondria, NADPH Oxidase 4, NF-E2-Related Factor 2, Oxidation-Reduction, Proto-Oncogene Proteins c-bcl-2, Reperfusion Injury
Show Abstract · Added December 26, 2018
NADPH oxidase 4 (NOX4) is highly expressed in kidney proximal tubular cells. NOX4 constitutively produces hydrogen peroxide, which may regulate important pro-survival pathways. Renal ischemia reperfusion injury (IRI) is a classical model mimicking human ischemic acute tubular necrosis. We hypothesized that NOX4 plays a protective role in kidney IRI. In wild type (WT) animals subjected to IRI, NOX4 protein expression increased after 24 hours. NOX4 KO (knock-out) and WT littermates mice were subjected to IRI. NOX4 KO mice displayed decreased renal function and more severe tubular apoptosis, decreased Bcl-2 expression and higher histologic damage scores compared to WT. Activation of NRF2 was decreased in NOX4 KO mice in response to IRI. This was related to decreased KEAP1 oxidation leading to decreased NRF2 stabilization. This resulted in decreased glutathione levels. In vitro silencing of NOX4 in cells showed an enhanced propensity to apoptosis, with reduced expression of NRF2, glutathione content and Bcl-2 expression, similar to cells derived from NOX4 KO mice. Overexpression of a constitutively active form of NRF2 (caNRF2) in NOX4 depleted cells rescued most of this phenotype in cultured cells, implying that NRF2 regulation by ROS issued from NOX4 may play an important role in its anti-apoptotic property.
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Histone Deacetylase 3 Is Required for Efficient T Cell Development.
Stengel KR, Zhao Y, Klus NJ, Kaiser JF, Gordy LE, Joyce S, Hiebert SW, Summers AR
(2015) Mol Cell Biol 35: 3854-65
MeSH Terms: Animals, CD4 Antigens, CD4-Positive T-Lymphocytes, CD8 Antigens, CD8-Positive T-Lymphocytes, Cell Differentiation, Gene Deletion, Gene Expression Regulation, Developmental, Histone Deacetylases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Proto-Oncogene Proteins c-bcl-2, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, bcl-X Protein
Show Abstract · Added September 28, 2015
Hdac3 is a key target for Hdac inhibitors that are efficacious in cutaneous T cell lymphoma. Moreover, the regulation of chromatin structure is critical as thymocytes transition from an immature cell with open chromatin to a mature T cell with tightly condensed chromatin. To define the phenotypes controlled by Hdac3 during T cell development, we conditionally deleted Hdac3 using the Lck-Cre transgene. This strategy inactivated Hdac3 in the double-negative stages of thymocyte development and caused a significant impairment at the CD8 immature single-positive (ISP) stage and the CD4/CD8 double-positive stage, with few mature CD4(+) or CD8(+) single-positive cells being produced. When Hdac3(-/-) mice were crossed with Bcl-xL-, Bcl2-, or TCRβ-expressing transgenic mice, a modest level of complementation was found. However, when the null mice were crossed with mice expressing a fully rearranged T cell receptor αβ transgene, normal levels of CD4 single-positive cells were produced. Thus, Hdac3 is required for the efficient transit from double-negative stage 4 through positive selection.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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18 MeSH Terms
Bcl-2 family proteins in breast development and cancer: could Mcl-1 targeting overcome therapeutic resistance?
Williams MM, Cook RS
(2015) Oncotarget 6: 3519-30
MeSH Terms: Animals, Apoptosis, Breast, Breast Neoplasms, Female, Humans, Mammary Glands, Animal, Myeloid Cell Leukemia Sequence 1 Protein, Proto-Oncogene Proteins c-bcl-2
Show Abstract · Added April 15, 2019
Apoptosis, cell death executed by caspases, is essential to normal breast development and homeostasis. Pro-apoptotic and anti-apoptotic signals are tightly regulated in normal breast epithelial cells. Dysregulation of this balance is required for breast tumorigenesis and increases acquired resistance to treatments, including molecularly targeted therapies, radiation and chemotherapies. The pro-apoptotic or anti-apoptotic Bcl-2 family members interact with each other to maintain mitochondrial integrity and regulate cellular commitment to apoptosis. Among the anti-apoptotic Bcl-2 family members, Mcl-1 is uniquely regulated by numerous oncogenic signaling pathways. This review will focus on the role of Bcl-2 family proteins in normal breast development, breast tumorigenesis and acquired resistance to breast cancer treatment strategies, while highlighting Mcl-1 as a promising target to improve breast cancer tumor cell killing.
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EGF receptor deletion in podocytes attenuates diabetic nephropathy.
Chen J, Chen JK, Harris RC
(2015) J Am Soc Nephrol 26: 1115-25
MeSH Terms: Albuminuria, Animals, Caspase 3, Diabetic Nephropathies, ErbB Receptors, Hyperglycemia, Male, Mice, Knockout, Podocytes, Proto-Oncogene Proteins c-bcl-2, Reactive Oxygen Species, Signal Transduction, Smad Proteins, Receptor-Regulated, Transforming Growth Factor beta, src-Family Kinases
Show Abstract · Added October 27, 2014
The generation of reactive oxygen species (ROS), particularly superoxide, by damaged or dysfunctional mitochondria has been postulated to be an initiating event in the development of diabetes complications. The glomerulus is a primary site of diabetic injury, and podocyte injury is a classic hallmark of diabetic glomerular lesions. In streptozotocin-induced type 1 diabetes, podocyte-specific EGF receptor (EGFR) knockout mice (EGFR(podKO)) and their wild-type (WT) littermates had similar levels of hyperglycemia and polyuria, but EGFR(podKO) mice had significantly less albuminuria and less podocyte loss compared with WT diabetic mice. Furthermore, EGFR(podKO) diabetic mice had less TGF-β1 expression, Smad2/3 phosphorylation, and glomerular fibronectin deposition. Immunoblotting of isolated glomerular lysates revealed that the upregulation of cleaved caspase 3 and downregulation of Bcl2 in WT diabetic mice were attenuated in EGFR(podKO) diabetic mice. Administration of the SOD mimetic mito-tempol or the NADPH oxidase inhibitor apocynin attenuated the upregulation of p-c-Src, p-EGFR, p-ERK1/2, p-Smad2/3, and TGF-β1 expression and prevented the alteration of cleaved caspase 3 and Bcl2 expression in glomeruli of WT diabetic mice. High-glucose treatment of cultured mouse podocytes induced similar alterations in the production of ROS; phosphorylation of c-Src, EGFR, and Smad2/3; and expression of TGF-β1, cleaved caspase 3, and Bcl2. These alterations were inhibited by treatment with mito-tempol or apocynin or by inhibiting EGFR expression or activity. Thus, results of our studies utilizing mice with podocyte-specific EGFR deletion demonstrate that EGFR activation has a major role in activating pathways that mediate podocyte injury and loss in diabetic nephropathy.
Copyright © 2015 by the American Society of Nephrology.
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15 MeSH Terms
The impact of anti-apoptotic gene Bcl-2∆ expression on CHO central metabolism.
Templeton N, Lewis A, Dorai H, Qian EA, Campbell MP, Smith KD, Lang SE, Betenbaugh MJ, Young JD
(2014) Metab Eng 25: 92-102
MeSH Terms: Animals, Apoptosis Regulatory Proteins, CHO Cells, Cricetinae, Cricetulus, Lactic Acid, Metabolic Flux Analysis, Mitochondrial Proteins, Proto-Oncogene Proteins c-bcl-2, Pyruvic Acid, Signal Transduction
Show Abstract · Added January 23, 2015
Anti-apoptosis engineering is an established technique to prolong the viability of mammalian cell cultures used for industrial production of recombinant proteins. However, the effect of overexpressing anti-apoptotic proteins on central carbon metabolism has not been systematically studied. We transfected CHO-S cells to express Bcl-2∆, an engineered anti-apoptotic gene, and selected clones that differed in their Bcl-2∆ expression and caspase activity. (13)C metabolic flux analysis (MFA) was then applied to elucidate the metabolic alterations induced by Bcl-2∆. Expression of Bcl-2Δ reduced lactate accumulation by redirecting the fate of intracellular pyruvate toward mitochondrial oxidation during the lactate-producing phase, and it significantly increased lactate re-uptake during the lactate-consuming phase. This flux redistribution was associated with significant increases in biomass yield, peak viable cell density (VCD), and integrated VCD. Additionally, Bcl-2∆ expression was associated with significant increases in isocitrate dehydrogenase and NADH oxidase activities, both rate-controlling mitochondrial enzymes. This is the first comprehensive (13)C MFA study to demonstrate that expression of anti-apoptotic genes has a significant impact on intracellular metabolic fluxes, especially in controlling the fate of pyruvate carbon, which has important biotechnology applications for reducing lactate accumulation and enhancing productivity in mammalian cell cultures.
Copyright © 2014 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.
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11 MeSH Terms
Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway.
Zhang B, Zhang B, Chen X, Bae S, Singh K, Washington MK, Datta PK
(2014) Br J Cancer 110: 946-57
MeSH Terms: Animals, Antimetabolites, Antineoplastic, Cell Cycle Proteins, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Chromones, Colorectal Neoplasms, Drug Resistance, Neoplasm, Enzyme Activation, Enzyme Inhibitors, Fluorouracil, Humans, Inhibitor of Apoptosis Proteins, Mice, Mice, Inbred BALB C, Morpholines, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Transplantation, Neovascularization, Pathologic, Phosphatidylinositol 3-Kinase, Phosphatidylinositol 3-Kinases, Phosphorylation, Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Repressor Proteins, Retinoblastoma Protein, Smad4 Protein, Survivin, Up-Regulation, Vascular Endothelial Growth Factor A, Wound Healing, Xenograft Model Antitumor Assays
Show Abstract · Added April 12, 2016
BACKGROUND - Higher frequency of Smad4 inactivation or loss of expression is observed in metastasis of colorectal cancer (CRC) leading to unfavourable survival and contributes to chemoresistance. However, the molecular mechanism of how Smad4 regulates chemosensitivity of CRC is unknown.
METHODS - We evaluated how the loss of Smad4 in CRC enhanced chemoresistance to 5-fluorouracil (5-FU) using two CRC cell lines in vitro and in vivo. Immunoblotting with cell and tumour lysates and immunohistochemical analyses with tissue microarray were performed.
RESULTS - Knockdown or loss of Smad4 induced tumorigenicity, migration, invasion, angiogenesis, metastasis, and 5-FU resistance. Smad4 expression in mouse tumours regulated cell-cycle regulatory proteins leading to Rb phosphorylation. Loss of Smad4 activated Akt pathway that resulted in upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-w, and Survivin. Suppression of phosphatidylinositol-3-kinase (PI3K)/Akt pathway by LY294002 restored chemosensitivity of Smad4-deficient cells to 5-FU. Vascular endothelial growth factor-induced angiogenesis in Smad4-deficient cells might also lead to chemoresistance. Low levels of Smad4 expression in CRC tissues correlated with higher levels of Bcl-2 and Bcl-w and with poor overall survival as observed in immunohistochemical staining of tissue microarrays.
CONCLUSION - Loss of Smad4 in CRC patients induces resistance to 5-FU-based therapy through activation of Akt pathway and inhibitors of this pathway may sensitise these patients to 5-FU.
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36 MeSH Terms
Association of genetic markers in the BCL-2 family of apoptosis-related genes with endometrial cancer risk in a Chinese population.
Dorjgochoo T, Xiang YB, Long J, Shi J, Deming S, Xu WH, Cai H, Cheng J, Cai Q, Zheng W, Shu XO
(2013) PLoS One 8: e60915
MeSH Terms: Adult, Aged, Apoptosis, Asian Continental Ancestry Group, Case-Control Studies, Endometrial Neoplasms, Female, Genetic Markers, Genetic Predisposition to Disease, Humans, Middle Aged, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-bcl-2
Show Abstract · Added December 10, 2013
BACKGROUND - In vitro studies have demonstrated the role of the BCL-2 family of genes in endometrial carcinogenesis. The role of genetic variants in BCL-2 genes and their interactions with non-genetic factors in the development of endometrial cancer has not been investigated in epidemiological studies.
PATIENTS AND METHODS - We examined the relationship between BCL-2 gene family variants and endometrial cancer risk among 1,028 patients and 1,922 age-matched community controls from Shanghai, China. We also investigated possible interactions between genetic variants and established risk factors (demographic, lifestyle and clinical). Individuals were genotyped for 86 tagging single nucleotide polymorphisms (SNPs) in the BCL2, BAX, BAD and BAK1 genes.
RESULTS - Significant associations with endometrial cancer risk were found for 9 SNPs in the BCL2 gene (P trend<0.05 for all). For SNPs rs17759659 and rs7243091 (minor allele for both: G), the associations were independent. The odds ratio was 1.27 (95% CI: 1.04-1.53) for women with AG genotype for the SNP rs17759659 and 1.82 (95% CI: 1.21-2.73) for women with the GG genotype for the SNP rs7243091. No interaction between these two SNPs and established non-genetic risk factors of endometrial cancer was noticed.
CONCLUSION - Genetic polymorphisms in the BCL2 gene may be associated with the risk of endometrial cancer in Chinese women.
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13 MeSH Terms