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Article: Activation of the Anaphase Promoting Complex Reverses Multiple Drug Resistant Cancer in a Canine Model of Multiple Drug Resistant Lymphoma.

Arnason, Terra G / MacDonald-Dickinson, Valerie / Gaunt, Matthew Casey / Davies, Gerald F / Lobanova, Liubov / Trost, Brett / Gillespie, Zoe E / Waldner, Matthew / Baldwin, Paige / Borrowman, Devon / Marwood, Hailey / Vizeacoumar, Frederick S / Vizeacoumar, Franco J / Eskiw, Christopher H / Kusalik, Anthony / Harkness, Troy A A

Cancers

2022 Volume 14, Issue 17

Abstract: Like humans, canine lymphomas are treated by chemotherapy cocktails and frequently develop multiple drug resistance (MDR). Their shortened clinical timelines and tumor accessibility make canines excellent models to study MDR mechanisms. Insulin- ... ...

Abstract	Like humans, canine lymphomas are treated by chemotherapy cocktails and frequently develop multiple drug resistance (MDR). Their shortened clinical timelines and tumor accessibility make canines excellent models to study MDR mechanisms. Insulin-sensitizers have been shown to reduce the incidence of cancer in humans prescribed them, and we previously demonstrated that they also reverse and delay MDR development in vitro. Here, we treated canines with MDR lymphoma with metformin to assess clinical and tumoral responses, including changes in MDR biomarkers, and used mRNA microarrays to determine differential gene expression. Metformin reduced MDR protein markers in all canines in the study. Microarrays performed on mRNAs gathered through longitudinal tumor sampling identified a 290 gene set that was enriched in Anaphase Promoting Complex (APC) substrates and additional mRNAs associated with slowed mitotic progression in MDR samples compared to skin controls. mRNAs from a canine that went into remission showed that APC substrate mRNAs were decreased, indicating that the APC was activated during remission. In vitro validation using canine lymphoma cells selected for resistance to chemotherapeutic drugs confirmed that APC activation restored MDR chemosensitivity, and that APC activity was reduced in MDR cells. This supports the idea that rapidly pushing MDR cells that harbor high loads of chromosome instability through mitosis, by activating the APC, contributes to improved survival and disease-free duration.
Language	English
Publishing date	2022-08-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14174215
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Troglitazone reverses the multiple drug resistance phenotype in cancer cells.

Davies, Gerald F / Juurlink, Bernhard H J / Harkness, Troy A A

Drug design, development and therapy

2009 Volume 3, Page(s) 79–88

Abstract: A major problem in treating cancer is the development of drug resistance. We previously demonstrated doxorubicin (DOX) resistance in K562 human leukemia cells that was associated with upregulation of glyoxalase 1 (GLO-1) and histone H3 expression. The ... ...

Abstract	A major problem in treating cancer is the development of drug resistance. We previously demonstrated doxorubicin (DOX) resistance in K562 human leukemia cells that was associated with upregulation of glyoxalase 1 (GLO-1) and histone H3 expression. The thiazolidinedione troglitazone (TRG) downregulated GLO-1 expression and further upregulated histone H3 expression and post-translational modifications in these cells, leading to a regained sensitivity to DOX. Given the pleiotropic effects of epigenetic changes in cancer development, we hypothesized that TRG may downregulate the multiple drug resistance (MDR) phenotype in a variety of cancer cells. To test this, MCF7 human breast cancer cells and K562 cells were cultured in the presence of low-dose DOX to establish DOX-resistant cell lines (K562/DOX and MCF7/DOX). The MDR phenotype was confirmed by Western blot analysis of the 170 kDa P-glycoprotein (Pgp) drug efflux pump multiple drug resistance protein 1 (MDR-1), and the breast cancer resistance protein (BCRP). TRG markedly decreased expression of both MDR-1 and BCRP in these cells, resulting in sensitivity to DOX. Silencing of MDR-1 expression also sensitized MCF7/DOX cells to DOX. Use of the specific and irreversible peroxisome proliferator-activated receptor gamma (PPARgamma) inhibitor GW9662 in the nanomolar range not only demonstrated that the action of TRG on MCF/DOX was PPARgamma-independent, but indicated that PPARgamma may play a role in the MDR phenotype, which is antagonized by TRG. We conclude that TRG is potentially a useful adjunct therapy in chemoresistant cancers.
Language	English
Publishing date	2009-09-21
Publishing country	New Zealand
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451346-5
ISSN	1177-8881 ; 1177-8881
ISSN (online)	1177-8881
ISSN	1177-8881
DOI	10.2147/dddt.s3314
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Article ; Online: TFPI1 mediates resistance to doxorubicin in breast cancer cells by inducing a hypoxic-like response.

Davies, Gerald F / Berg, Arnie / Postnikoff, Spike D L / Wilson, Heather L / Arnason, Terra G / Kusalik, Anthony / Harkness, Troy A A

PloS one

2014 Volume 9, Issue 1, Page(s) e84611

Abstract: Thrombin and hypoxia are important players in breast cancer progression. Breast cancers often develop drug resistance, but mechanisms linking thrombin and hypoxia to drug resistance remain unresolved. Our studies using Doxorubicin (DOX) resistant MCF7 ... ...

Abstract	Thrombin and hypoxia are important players in breast cancer progression. Breast cancers often develop drug resistance, but mechanisms linking thrombin and hypoxia to drug resistance remain unresolved. Our studies using Doxorubicin (DOX) resistant MCF7 breast cancer cells reveals a mechanism linking DOX exposure with hypoxic induction of DOX resistance. Global expression changes between parental and DOX resistant MCF7 cells were examined. Westerns, Northerns and immunocytochemistry were used to validate drug resistance and differentially expressed genes. A cluster of genes involved in the anticoagulation pathway, with Tissue Factor Pathway Inhibitor 1 (TFPI1) the top hit, was identified. Plasmids overexpressing TFPI1 were utilized, and 1% O2 was used to test the effects of hypoxia on drug resistance. Lastly, microarray datasets from patients with drug resistant breast tumors were interrogated for TFPI1 expression levels. TFPI1 protein levels were found elevated in 3 additional DOX resistant cells lines, from humans and rats, indicating evolutionarily conservation of the effect. Elevated TFPI1 in DOX resistant cells was active, as thrombin protein levels were coincidentally low. We observed elevated HIF1α protein in DOX resistant cells, and in cells with forced expression of TFPI1, suggesting TFPI1 induces HIF1α. TFPI1 also induced c-MYC, c-SRC, and HDAC2 protein, as well as DOX resistance in parental cells. Growth of cells in 1% O2 induced elevated HIF1α, BCRP and MDR-1 protein, and these cells were resistant to DOX. Our in vitro results were consistent with in vivo patient datasets, as tumors harboring increased BCRP and MDR-1 expression also had increased TFPI1 expression. Our observations are clinically relevant indicating that DOX treatment induces an anticoagulation cascade, leading to inhibition of thrombin and the expression of HIF1α. This in turn activates a pathway leading to drug resistance.
MeSH term(s)	Animals ; Cell Hypoxia/genetics ; Cell Hypoxia/physiology ; Doxorubicin/pharmacology ; Drug Resistance, Neoplasm/genetics ; Drug Resistance, Neoplasm/physiology ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Lipoproteins/genetics ; Lipoproteins/metabolism ; MCF-7 Cells ; Tumor Cells, Cultured
Chemical Substances	Hypoxia-Inducible Factor 1, alpha Subunit ; Lipoproteins ; lipoprotein-associated coagulation inhibitor ; Doxorubicin (80168379AG)
Language	English
Publishing date	2014-01-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0084611
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Article ; Online: Human serum-derived hydroxy long-chain fatty acids exhibit anti-inflammatory and anti-proliferative activity.

Ritchie, Shawn A / Jayasinghe, Dushmanthi / Davies, Gerald F / Ahiahonu, Pearson / Ma, Hong / Goodenowe, Dayan B

Journal of experimental & clinical cancer research : CR

2011 Volume 30, Page(s) 59

Abstract: Background: Circulating levels of novel long-chain hydroxy fatty acids (called GTAs) were recently discovered in the serum of healthy subjects which were shown to be reduced in subjects with colorectal cancer (CRC), independent of tumor burden or ... ...

Abstract	Background: Circulating levels of novel long-chain hydroxy fatty acids (called GTAs) were recently discovered in the serum of healthy subjects which were shown to be reduced in subjects with colorectal cancer (CRC), independent of tumor burden or disease stage. The levels of GTAs were subsequently observed to exhibit an inverse association with age in the general population. The current work investigates the biological activity of these fatty acids by evaluating the effects of enriched human serum extracts on cell growth and inflammation. Methods: GTAs were extracted from commercially available bulk human serum and then chromatographically separated into enriched (GTA-positive) and depleted (GTA-negative) fractions. SW620, MCF7 and LPS stimulated RAW264.7 cells were treated with various concentrations of the GTA-positive and GTA-negative extracts, and the effects on cell growth and inflammation determined. Results: Enriched fractions resulted in poly-ADP ribose polymerase (PARP) cleavage, suppression of NFκB, induction of IκBα, and reduction in NOS2 mRNA transcript levels. In RAW264.7 mouse macrophage cells, incubation with enriched fractions prior to treatment with LPS blocked the induction of several pro-inflammatory markers including nitric oxide, TNFα, IL-1β, NOS2 and COX2. Conclusions: Our results show that human serum extracts enriched with endogenous long-chain hydroxy fatty acids possess anti-inflammatory and anti-proliferative activity. These findings support a hypothesis that the reduction of these metabolites with age may result in a compromised ability to defend against uncontrolled cell growth and inflammation, and could therefore represent a significant risk for the development of CRC.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/isolation & purification ; Anti-Inflammatory Agents/pharmacology ; Antineoplastic Agents/isolation & purification ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Fatty Acids/isolation & purification ; Fatty Acids/pharmacology ; Humans ; Inflammation Mediators/antagonists & inhibitors ; Mice ; Poly(ADP-ribose) Polymerases/metabolism
Chemical Substances	Anti-Inflammatory Agents ; Antineoplastic Agents ; Fatty Acids ; Inflammation Mediators ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
Language	English
Publishing date	2011-05-17
Publishing country	England
Document type	Journal Article
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/1756-9966-30-59
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Article ; Online: Human serum-derived hydroxy long-chain fatty acids exhibit anti-inflammatory and anti-proliferative activity

Ahiahonu Pearson / Davies Gerald F / Jayasinghe Dushmanthi / Ritchie Shawn A / Ma Hong / Goodenowe Dayan B

Journal of Experimental & Clinical Cancer Research, Vol 30, Iss 1, p

2011 Volume 59

Abstract: Abstract Background Circulating levels of novel long-chain hydroxy fatty acids (called GTAs) were recently discovered in the serum of healthy subjects which were shown to be reduced in subjects with colorectal cancer (CRC), independent of tumor burden or ...

Abstract	Abstract Background Circulating levels of novel long-chain hydroxy fatty acids (called GTAs) were recently discovered in the serum of healthy subjects which were shown to be reduced in subjects with colorectal cancer (CRC), independent of tumor burden or disease stage. The levels of GTAs were subsequently observed to exhibit an inverse association with age in the general population. The current work investigates the biological activity of these fatty acids by evaluating the effects of enriched human serum extracts on cell growth and inflammation. Methods GTAs were extracted from commercially available bulk human serum and then chromatographically separated into enriched (GTA-positive) and depleted (GTA-negative) fractions. SW620, MCF7 and LPS stimulated RAW264.7 cells were treated with various concentrations of the GTA-positive and GTA-negative extracts, and the effects on cell growth and inflammation determined. Results Enriched fractions resulted in poly-ADP ribose polymerase (PARP) cleavage, suppression of NFκB, induction of IκBα, and reduction in NOS2 mRNA transcript levels. In RAW264.7 mouse macrophage cells, incubation with enriched fractions prior to treatment with LPS blocked the induction of several pro-inflammatory markers including nitric oxide, TNFα, IL-1β, NOS2 and COX2. Conclusions Our results show that human serum extracts enriched with endogenous long-chain hydroxy fatty acids possess anti-inflammatory and anti-proliferative activity. These findings support a hypothesis that the reduction of these metabolites with age may result in a compromised ability to defend against uncontrolled cell growth and inflammation, and could therefore represent a significant risk for the development of CRC.
Keywords	Long-chain fatty acid ; colorectal cancer ; aging ; screening ; inflammation ; NFκB ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	571
Language	English
Publishing date	2011-05-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells.

Goldberg, Alexander A / Beach, Adam / Davies, Gerald F / Harkness, Troy A A / Leblanc, Andréa / Titorenko, Vladimir I

Oncotarget

2011 Volume 2, Issue 10, Page(s) 761–782

Abstract: Aging is one of the major risk factors of cancer. The onset of cancer can be postponed by pharmacological and dietary anti-aging interventions. We recently found in yeast cellular models of aging that lithocholic acid (LCA) extends longevity. Here we ... ...

Abstract	Aging is one of the major risk factors of cancer. The onset of cancer can be postponed by pharmacological and dietary anti-aging interventions. We recently found in yeast cellular models of aging that lithocholic acid (LCA) extends longevity. Here we show that, at concentrations that are not cytotoxic to primary cultures of human neurons, LCA kills the neuroblastoma (NB) cell lines BE(2)-m17, SK-n-SH, SK-n-MCIXC and Lan-1. In BE(2)-m17, SK-n-SH and SK-n-MCIXC cells, the LCA anti-tumor effect is due to apoptotic cell death. In contrast, the LCA-triggered death of Lan-1 cells is not caused by apoptosis. While low concentrations of LCA sensitize BE(2)-m17 and SK-n-MCIXC cells to hydrogen peroxide-induced apoptotic cell death controlled by mitochondria, these LCA concentrations make primary cultures of human neurons resistant to such a form of cell death. LCA kills BE(2)-m17 and SK-n-MCIXC cell lines by triggering not only the intrinsic (mitochondrial) apoptotic cell death pathway driven by mitochondrial outer membrane permeabilization and initiator caspase-9 activation, but also the extrinsic (death receptor) pathway of apoptosis involving activation of the initiator caspase-8. Based on these data, we propose a mechanism underlying a potent and selective anti-tumor effect of LCA in cultured human NB cells. Moreover, our finding that LCA kills cultured human breast cancer and rat glioma cells implies that it has a broad anti-tumor effect on cancer cells derived from different tissues and organisms.
MeSH term(s)	Animals ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Caspase 3/metabolism ; Caspase 6/metabolism ; Cells, Cultured ; Detergents/pharmacology ; Female ; Glioma/drug therapy ; Glioma/metabolism ; Glioma/pathology ; Histones/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Immunoblotting ; Lithocholic Acid/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Mitochondria/metabolism ; Neuroblastoma/drug therapy ; Neuroblastoma/metabolism ; Neuroblastoma/pathology ; Neurons/cytology ; Neurons/drug effects ; Phosphorylation/drug effects ; Rats
Chemical Substances	Detergents ; H2AX protein, human ; Histones ; Lithocholic Acid (5QU0I8393U) ; Hydrogen Peroxide (BBX060AN9V) ; Caspase 3 (EC 3.4.22.-) ; Caspase 6 (EC 3.4.22.-)
Language	English
Publishing date	2011-10-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.338
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Article: Troglitazone reduces heat shock protein 70 content in primary rat hepatocytes by a ubiquitin proteasome independent mechanism.

Davies, Gerald F / Roesler, William J / Ovsenek, Nick / Bharadwaj, Lalita A

Pharmacological research

2003 Volume 48, Issue 1, Page(s) 119–126

Abstract: Troglitazone (TRG) is an antidiabetic agent that increases the insulin sensitivity of target tissues in non-insulin-dependent diabetes mellitus. Therapy with troglitazone has been associated with severe hepatic injury in a small percentage of patients ... ...

Abstract	Troglitazone (TRG) is an antidiabetic agent that increases the insulin sensitivity of target tissues in non-insulin-dependent diabetes mellitus. Therapy with troglitazone has been associated with severe hepatic injury in a small percentage of patients and the mechanism of TRG-induced hepatotoxicity remains unclear. A family of highly conserved stress proteins identified as heat shock proteins (Hsps), are well-known to protect cells against a wide variety of toxic conditions such as extreme temperature changes, oxidative stress and toxic drugs. The stress-inducible Hsp 70 protein is one of the best-known endogenous factors protecting cells from injury under various stress conditions. Here we examined the effects of TRG on Hsp 70 mRNA and protein expression in primary cultures of rat hepatocytes. We also investigated the effects of TRG in an in vivo model by examining Hsp 70 protein levels in livers prepared from C57 mice fed a 0.2% dietary admixture of TRG. Levels of Hsp 70 mRNA increased in a concentration-dependent manner in rat hepatocytes treated for 8h with increasing concentrations of TRG. However, Hsp 70 protein levels decreased significantly in cells treated with increasing concentrations of TRG. C57 mice fed a 0.2% admixture of TRG for 10 days, also demonstrated decreased liver Hsp 70 protein levels. To investigate whether TRG decreased Hsp 70 protein levels by activating the ubiquitin-proteasome pathway, cells were pretreated with 10 microM lactacystin, a potent and specific inhibitor of this pathway. Lactacystin pretreatment failed to prevent TRG-induced decrease in Hsp 70 protein. The data suggests that TRG-induced effects may be mediated through another system of regulated proteolysis or may involve a post-transcriptional regulator mechanism. The mechanism of TRG-induced hepatotoxicity remains unclear, however, the effects induced by TRG on Hsp 70 may, in part, play a role.
MeSH term(s)	Acetylcysteine/analogs & derivatives ; Acetylcysteine/pharmacology ; Animals ; Blotting, Northern ; Blotting, Western ; Cells, Cultured ; Chemical and Drug Induced Liver Injury ; Chromans/adverse effects ; Chromans/pharmacology ; Cysteine Endopeptidases/metabolism ; Dose-Response Relationship, Drug ; Gene Expression/drug effects ; Heat-Shock Proteins/drug effects ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Hepatocytes/drug effects ; Hepatocytes/enzymology ; Hepatocytes/metabolism ; Histones/drug effects ; Histones/metabolism ; Liver Diseases/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Multienzyme Complexes/metabolism ; Proteasome Endopeptidase Complex ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Thiazolidinediones/adverse effects ; Thiazolidinediones/pharmacology ; Ubiquitin/metabolism
Chemical Substances	Chromans ; Heat-Shock Proteins ; Histones ; Multienzyme Complexes ; RNA, Messenger ; Thiazolidinediones ; Ubiquitin ; lactacystin (133343-34-7) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; troglitazone (I66ZZ0ZN0E) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2003-07
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1003347-6
ISSN	1096-1186 ; 1043-6618 ; 0031-6989
ISSN (online)	1096-1186
ISSN	1043-6618 ; 0031-6989
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Article ; Online: The Saccharomyces cerevisiae anaphase-promoting complex interacts with multiple histone-modifying enzymes to regulate cell cycle progression.

Turner, Emma L / Malo, Mackenzie E / Pisclevich, Marnie G / Dash, Megan D / Davies, Gerald F / Arnason, Terra G / Harkness, Troy A A

Eukaryotic cell

2010 Volume 9, Issue 10, Page(s) 1418–1431

Abstract: The anaphase-promoting complex (APC), a large evolutionarily conserved ubiquitin ligase complex, regulates cell cycle progression through mitosis and G(1). Here, we present data suggesting that APC-dependent cell cycle progression relies on a specific ... ...

Abstract	The anaphase-promoting complex (APC), a large evolutionarily conserved ubiquitin ligase complex, regulates cell cycle progression through mitosis and G(1). Here, we present data suggesting that APC-dependent cell cycle progression relies on a specific set of posttranslational histone-modifying enzymes. Multiple APC subunit mutants were impaired in total and modified histone H3 protein content. Acetylated H3K56 (H3K56(Ac)) levels were as reduced as those of total H3, indicating that loading histones with H3K56(Ac) is unaffected in APC mutants. However, under restrictive conditions, H3K9(Ac) and dimethylated H3K79 (H3K79(me2)) levels were more greatly reduced than those of total H3. In a screen for histone acetyltransferase (HAT) and histone deacetylase (HDAC) mutants that genetically interact with the apc5(CA) (chromatin assembly) mutant, we found that deletion of GCN5 or ELP3 severely hampered apc5(CA) temperature-sensitive (ts) growth. Further analyses showed that (i) the elp3Δ gcn5Δ double mutant ts defect was epistatic to that observed in apc5(CA) cells; (ii) gcn5Δ and elp3Δ mutants accumulate in mitosis; and (iii) turnover of the APC substrate Clb2 is not impaired in elp3Δ gcn5Δ cells. Increased expression of ELP3 and GCN5, as well as genes encoding the HAT Rtt109 and the chromatin assembly factors Msi1 and Asf1, suppressed apc5(CA) defects, while increased APC5 expression partially suppressed elp3Δ gcn5Δ growth defects. Finally, we demonstrate that Gcn5 is unstable during G(1) and following G(1) arrest and is stabilized in APC mutants. We present our working model in which Elp3/Gcn5 and the APC work together to facilitate passage through mitosis and G(1). To progress into S, we propose that at least Gcn5 must then be targeted for degradation in an APC-dependent fashion.
MeSH term(s)	Anaphase-Promoting Complex-Cyclosome ; Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome ; Cell Cycle/genetics ; Cell Cycle/physiology ; Chromatin Assembly and Disassembly ; Gene Expression Regulation, Fungal ; Histone Acetyltransferases/genetics ; Histone Acetyltransferases/metabolism ; Histones/metabolism ; Mitosis/physiology ; Saccharomyces cerevisiae/cytology ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Ubiquitin-Protein Ligase Complexes/genetics ; Ubiquitin-Protein Ligase Complexes/metabolism
Chemical Substances	APC5 protein, S cerevisiae ; Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome ; Histones ; Saccharomyces cerevisiae Proteins ; Elp3 protein, S cerevisiae (EC 2.3.1.48) ; GCN5 protein, S cerevisiae (EC 2.3.1.48) ; Histone Acetyltransferases (EC 2.3.1.48) ; Ubiquitin-Protein Ligase Complexes (EC 2.3.2.23) ; Anaphase-Promoting Complex-Cyclosome (EC 2.3.2.27)
Language	English
Publishing date	2010-08-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2077635-4
ISSN	1535-9786 ; 1535-9778
ISSN (online)	1535-9786
ISSN	1535-9778
DOI	10.1128/EC.00097-10
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Article: l-carnosine and verapamil inhibit hypoxia-induced expression of hypoxia inducible factor (HIF-1 alpha) in H9c2 cardiomyoblasts.

Bharadwaj, Lalita A / Davies, Gerald F / Xavier, Ilungo J / Ovsenek, Nick

Pharmacological research

2002 Volume 45, Issue 3, Page(s) 175–181

Abstract: Contractile failure of myocardial cells is a common cause of mortality in ischemic heart disease. In response to hypoxic conditions, cells upregulate the activity of hypoxia-inducible factor 1 (HIF-1) and express a number of genes encoding proteins that ... ...

Abstract	Contractile failure of myocardial cells is a common cause of mortality in ischemic heart disease. In response to hypoxic conditions, cells upregulate the activity of hypoxia-inducible factor 1 (HIF-1) and express a number of genes encoding proteins that either enhance O (2)delivery or increase cellular ATP levels. HIF-1 is a heterodimer of bHLH-PAS proteins, HIF-1 alpha and HIF-1 beta. Both subunits are constitutively expressed under normoxic conditions, but HIF-1 alpha levels are kept low by proteolytic degradation, then stabilized under conditions of low O (2)by a mechanism that is poorly understood. Here we tested the hypothesis that expression of HIF-1 alpha in cardiac cells may be affected by two known cardioprotective agents. We tested l-carnosine, a naturally occurring dipeptide which has been shown to improve myocardial contractility during hypoxia, and verapamil, a calcium channel blocker frequently prescribed for the treatment of heart disease. The levels of HIF-1 alphamRNA remained relatively stable during time course hypoxia (1% O (2)) in H9c2 cardiomyoblasts, then increased slightly after 24 h. In cells pretreated with 1 microM carnosine, the levels of mRNA were transiently reduced, but then increased after 24 h similar to the controls. The levels of HIF-1 alpha protein increased rapidly in H9c2 cells within 30 min of hypoxia, but this induction was significantly reduced in cells treated with either carnosine or verapamil. In addition, treatment of cells with these agents further reduced the low levels of HIF-1 under normoxic conditions. These results suggest that l-carnosine and verapamil may affect the regulated proteolytic degradation of HIF-1 alpha in heart cells during hypoxia.
MeSH term(s)	Animals ; Blotting, Northern ; Cardiotonic Agents/pharmacology ; Carnosine/pharmacology ; Cell Hypoxia/drug effects ; Cells, Cultured ; Hypoxia-Inducible Factor 1, alpha Subunit ; Myoblasts, Cardiac/drug effects ; Myoblasts, Cardiac/metabolism ; RNA, Messenger/metabolism ; Rats ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/metabolism ; Verapamil/pharmacology
Chemical Substances	Cardiotonic Agents ; Hypoxia-Inducible Factor 1, alpha Subunit ; RNA, Messenger ; Transcription Factors ; Carnosine (8HO6PVN24W) ; Verapamil (CJ0O37KU29)
Language	English
Publishing date	2002-03
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1003347-6
ISSN	1096-1186 ; 1043-6618 ; 0031-6989
ISSN (online)	1096-1186
ISSN	1043-6618 ; 0031-6989
DOI	10.1006/phrs.2001.0911
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Article: The ubiquitin-dependent targeting pathway in Saccharomyces cerevisiae plays a critical role in multiple chromatin assembly regulatory steps.

Harkness, Troy A A / Davies, Gerald F / Ramaswamy, Vijay / Arnason, Terra G

Genetics

2001 Volume 162, Issue 2, Page(s) 615–632

Abstract: In a screen designed to isolate Saccharomyces cerevisiae strains defective for in vitro chromatin assembly, two temperature-sensitive (ts) mutants were obtained: rmc1 and rmc3 (remodeling of chromatin). Cloning of RMC1 and RMC3 revealed a broad role for ... ...

Abstract	In a screen designed to isolate Saccharomyces cerevisiae strains defective for in vitro chromatin assembly, two temperature-sensitive (ts) mutants were obtained: rmc1 and rmc3 (remodeling of chromatin). Cloning of RMC1 and RMC3 revealed a broad role for the ubiquitin-dependent targeting cascade as the ubiquitin-protein ligases (E3s), the anaphase promoting complex (APC; RMC1 encodes APC5) and Rsp5p, respectively, were identified. Genetic studies linked the rmc1/apc5 chromatin assembly defect to APC function: rmc1/apc5 genetically interacted with apc9Delta, apc10Delta, and cdc26Delta mutants. Furthermore, phenotypes associated with the rmc1/apc5 allele were consistent with defects in chromatin metabolism and in APC function: (i) UV sensitivity, (ii) plasmid loss, (iii) accumulation of G2/M cells, and (iv) suppression of the ts defect by growth on glucose-free media and by expression of ubiquitin. On the other hand, the multifunctional E3, Rsp5p, was shown to be required for both in vitro and in vivo chromatin assembly, as well as for the proper transcriptional and translational control of at least histone H3. The finding that the distinctly different E3 enzymes, APC and Rsp5p, both play roles in regulating chromatin assembly highlight the depth of the regulatory networks at play. The significance of these findings will be discussed.
MeSH term(s)	Anaphase-Promoting Complex-Cyclosome ; Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome ; Chromatin/metabolism ; Histones/metabolism ; Ligases/genetics ; Ligases/metabolism ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligase Complexes ; Ubiquitin-Protein Ligases
Chemical Substances	APC5 protein, S cerevisiae ; Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome ; Chromatin ; Histones ; Saccharomyces cerevisiae Proteins ; Ubiquitin ; Ubiquitin-Protein Ligase Complexes (EC 2.3.2.23) ; Anaphase-Promoting Complex-Cyclosome (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Ligases (EC 6.-)
Language	English
Publishing date	2001-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2167-2
ISSN	1943-2631 ; 0016-6731
ISSN (online)	1943-2631
ISSN	0016-6731
DOI	10.1093/genetics/162.2.615
Database	MEDical Literature Analysis and Retrieval System OnLINE

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