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Article ; Online: Short hairpin RNA suppression of thymidylate synthase produces DNA mismatches and results in excellent radiosensitization.

Flanagan, Sheryl A / Cooper, Kristin S / Mannava, Sudha / Nikiforov, Mikhail A / Shewach, Donna S

International journal of radiation oncology, biology, physics

2012 Volume 84, Issue 5, Page(s) e613–20

Abstract: Purpose: To determine the effect of short hairpin ribonucleic acid (shRNA)-mediated suppression of thymidylate synthase (TS) on cytotoxicity and radiosensitization and the mechanism by which these events occur.: Methods and materials: shRNA ... ...

Abstract	Purpose: To determine the effect of short hairpin ribonucleic acid (shRNA)-mediated suppression of thymidylate synthase (TS) on cytotoxicity and radiosensitization and the mechanism by which these events occur. Methods and materials: shRNA suppression of TS was compared with 5-fluoro-2'-deoxyuridine (FdUrd) inactivation of TS with or without ionizing radiation in HCT116 and HT29 colon cancer cells. Cytotoxicity and radiosensitization were measured by clonogenic assay. Cell cycle effects were measured by flow cytometry. The effects of FdUrd or shRNA suppression of TS on dNTP deoxynucleotide triphosphate imbalances and consequent nucleotide misincorporations into deoxyribonucleic acid (DNA) were analyzed by high-pressure liquid chromatography and as pSP189 plasmid mutations, respectively. Results: TS shRNA produced profound (≥ 90%) and prolonged (≥ 8 days) suppression of TS in HCT116 and HT29 cells, whereas FdUrd increased TS expression. TS shRNA also produced more specific and prolonged effects on dNTPs deoxynucleotide triphosphates compared with FdUrd. TS shRNA suppression allowed accumulation of cells in S-phase, although its effects were not as long-lasting as those of FdUrd. Both treatments resulted in phosphorylation of Chk1. TS shRNA alone was less cytotoxic than FdUrd but was equally effective as FdUrd in eliciting radiosensitization (radiation enhancement ratio: TS shRNA, 1.5-1.7; FdUrd, 1.4-1.6). TS shRNA and FdUrd produced a similar increase in the number and type of pSP189 mutations. Conclusions: TS shRNA produced less cytotoxicity than FdUrd but was equally effective at radiosensitizing tumor cells. Thus, the inhibitory effect of FdUrd on TS alone is sufficient to elicit radiosensitization with FdUrd, but it only partially explains FdUrd-mediated cytotoxicity and cell cycle inhibition. The increase in DNA mismatches after TS shRNA or FdUrd supports a causal and sufficient role for the depletion of dTTP thymidine triphosphate and consequent DNA mismatches underlying radiosensitization. Importantly, shRNA suppression of TS avoids FP-mediated TS elevation and its negative prognostic role. These studies support the further exploration of TS suppression as a novel radiosensitizing strategy.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Antimetabolites, Antineoplastic/pharmacology ; Cell Line, Tumor ; Checkpoint Kinase 1 ; Cytidine Triphosphate/metabolism ; DNA Mismatch Repair ; Enzyme Activation/drug effects ; Floxuridine/pharmacology ; Guanosine Triphosphate/metabolism ; HT29 Cells ; Humans ; Phosphorylation ; Protein Kinases/metabolism ; RNA, Small Interfering/pharmacology ; Radiation Tolerance/genetics ; Thymidylate Synthase/antagonists & inhibitors ; Tumor Stem Cell Assay/methods
Chemical Substances	Antimetabolites, Antineoplastic ; RNA, Small Interfering ; Floxuridine (039LU44I5M) ; Cytidine Triphosphate (65-47-4) ; Guanosine Triphosphate (86-01-1) ; Adenosine Triphosphate (8L70Q75FXE) ; Thymidylate Synthase (EC 2.1.1.45) ; Protein Kinases (EC 2.7.-) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1)
Language	English
Publishing date	2012-08-03
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	197614-x
ISSN	1879-355X ; 0360-3016
ISSN (online)	1879-355X
ISSN	0360-3016
DOI	10.1016/j.ijrobp.2012.06.050
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Article ; Online: MLH1 deficiency enhances radiosensitization with 5-fluorodeoxyuridine by increasing DNA mismatches.

Flanagan, Sheryl A / Krokosky, Christina M / Mannava, Sudha / Nikiforov, Mikhail A / Shewach, Donna S

Molecular pharmacology

2008 Volume 74, Issue 3, Page(s) 863–871

Abstract: The antitumor drug 5-fluoro-2'-deoxyuridine (FdUrd) also sensitizes tumor cells to ionizing radiation in vitro and in vivo. Although radiosensitization with FdUrd requires dTTP depletion and S-phase arrest, the exact mechanism by which these events ... ...

Abstract	The antitumor drug 5-fluoro-2'-deoxyuridine (FdUrd) also sensitizes tumor cells to ionizing radiation in vitro and in vivo. Although radiosensitization with FdUrd requires dTTP depletion and S-phase arrest, the exact mechanism by which these events produce radiosensitization remains unknown. We hypothesized that the depletion of dTTP produces DNA mismatches that, if not repaired before irradiation, would result in radiosensitization. We evaluated this hypothesis in mismatch repair (MMR)-deficient HCT116 0-1 cells that lack the expression of the required MMR protein MLH1 (inactive MLH1), and in MMR-proficient (wild-type MLH1) HCT116 1-2 cells. Although HCT116 0-1 cells were less sensitive to FdUrd (IC(50) = 3.5 microM) versus HCT116 1-2 cells (IC(50) = 0.75 microM), when irradiation followed FdUrd (IC(50)) the MLH1-inactivated cells exhibited greater radiosensitization compared with MMR-wild-type cells [radiation enhancement ratio (RER) = 1.8 +/- 0.28 versus 1.1 +/- 0.1, respectively] and an increase (> or =8-fold) in nucleotide misincorporations. In SW620 cells and HCT116 1-2 MLH1-wild-type cells, FdUrd (IC(50)) did not produce radiosensitization nor did it increase the mutation frequency, but after short hairpin RNA-directed suppression of MLH1 this concentration produced excellent radiosensitization (RER = 1.6 +/- 0.10 and 1.5 +/- 0.06, respectively) and an increase in nucleotide misincorporations (8-fold and 6-fold, respectively). Incubation with higher concentrations of FdUrd (IC(90)) after suppression of MLH1 produced a further increase in ionizing radiation sensitivity in both SW620 and HCT116 1-2 cells (RER = 1.8 +/- 0.03 and 1.7 +/- 0.13, respectively) and nucleotide misincorporations (>10-fold in both cell lines). These results demonstrate an important role for MLH1 and implicate mismatches in radiosensitization by FdUrd.
MeSH term(s)	Adaptor Proteins, Signal Transducing/deficiency ; Base Pair Mismatch/drug effects ; Base Pair Mismatch/radiation effects ; Cell Cycle/drug effects ; Cell Cycle/radiation effects ; Cell Death/drug effects ; Cell Death/radiation effects ; Floxuridine/pharmacology ; HCT116 Cells ; Humans ; MutL Protein Homolog 1 ; Mutation/genetics ; Nuclear Proteins/deficiency ; Nucleotides/metabolism ; Plasmids/genetics ; RNA, Small Interfering/metabolism ; Radiation Tolerance/drug effects ; Radiation Tolerance/radiation effects ; Radiation, Ionizing
Chemical Substances	Adaptor Proteins, Signal Transducing ; MLH1 protein, human ; Nuclear Proteins ; Nucleotides ; RNA, Small Interfering ; Floxuridine (039LU44I5M) ; MutL Protein Homolog 1 (EC 3.6.1.3)
Language	English
Publishing date	2008-06-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/mol.107.043349
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Article ; Online: Ribonucleotide reductase and thymidylate synthase or exogenous deoxyribonucleosides reduce DNA damage and senescence caused by C-MYC depletion.

Mannava, Sudha / Moparthy, Kalyana C / Wheeler, Linda J / Leonova, Katerina I / Wawrzyniak, Joseph A / Bianchi-Smiraglia, Anna / Berman, Albert E / Flanagan, Sheryl / Shewach, Donna S / Zeitouni, Nathalie C / Gudkov, Andrei V / Mathews, Christopher K / Nikiforov, Mikhail A

Aging

2012 Volume 4, Issue 12, Page(s) 917–922

Abstract: The down-regulation of dominant oncogenes, including C-MYC, in tumor cells often leads to the induction of senescence via mechanisms that are not completely identified. In the current study, we demonstrate that MYC-depleted melanoma cells undergo ... ...

Abstract	The down-regulation of dominant oncogenes, including C-MYC, in tumor cells often leads to the induction of senescence via mechanisms that are not completely identified. In the current study, we demonstrate that MYC-depleted melanoma cells undergo extensive DNA damage that is caused by the underexpression of thymidylate synthase (TS) and ribonucleotide reductase (RR) and subsequent depletion of deoxyribonucleoside triphosphate pools. Simultaneous genetic inhibition of TS and RR in melanoma cells induced DNA damage and senescence phenotypes very similar to the ones caused by MYC-depletion. Reciprocally, overexpression of TS and RR in melanoma cells or addition of deoxyribo-nucleosides to culture media substantially inhibited DNA damage and senescence-associated phenotypes caused by C-MYC depletion. Our data demonstrate the essential role of TS and RR in C-MYC-dependent suppression of senescence in melanoma cells.
MeSH term(s)	Cell Line, Tumor ; Cellular Senescence/drug effects ; DNA Damage/drug effects ; Deoxyribonucleosides/pharmacology ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Genotype ; Humans ; Melanoma/enzymology ; Melanoma/genetics ; Melanoma/pathology ; Phenotype ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; RNA Interference ; Ribonucleoside Diphosphate Reductase/metabolism ; Ribonucleotide Reductases/genetics ; Ribonucleotide Reductases/metabolism ; Skin Neoplasms/enzymology ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Thymidylate Synthase/genetics ; Thymidylate Synthase/metabolism ; Time Factors ; Transfection ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Deoxyribonucleosides ; MYC protein, human ; Proto-Oncogene Proteins c-myc ; Tumor Suppressor Proteins ; Ribonucleotide Reductases (EC 1.17.4.-) ; ribonucleotide reductase M2 (EC 1.17.4.-) ; RRM1 protein, human (EC 1.17.4.1) ; Ribonucleoside Diphosphate Reductase (EC 1.17.4.1) ; Thymidylate Synthase (EC 2.1.1.45)
Language	English
Publishing date	2012-12-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1945-4589
ISSN (online)	1945-4589
DOI	10.18632/aging.100512
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Article ; Online: Depletion of deoxyribonucleotide pools is an endogenous source of DNA damage in cells undergoing oncogene-induced senescence.

Mannava, Sudha / Moparthy, Kalyana C / Wheeler, Linda J / Natarajan, Venkatesh / Zucker, Shoshanna N / Fink, Emily E / Im, Michael / Flanagan, Sheryl / Burhans, William C / Zeitouni, Nathalie C / Shewach, Donna S / Mathews, Christopher K / Nikiforov, Mikhail A

The American journal of pathology

2012 Volume 182, Issue 1, Page(s) 142–151

Abstract: In normal human cells, oncogene-induced senescence (OIS) depends on induction of DNA damage response. Oxidative stress and hyperreplication of genomic DNA have been proposed as major causes of DNA damage in OIS cells. Here, we report that down-regulation ...

Abstract	In normal human cells, oncogene-induced senescence (OIS) depends on induction of DNA damage response. Oxidative stress and hyperreplication of genomic DNA have been proposed as major causes of DNA damage in OIS cells. Here, we report that down-regulation of deoxyribonucleoside pools is another endogenous source of DNA damage in normal human fibroblasts (NHFs) undergoing HRAS(G12V)-induced senescence. NHF-HRAS(G12V) cells underexpressed thymidylate synthase (TS) and ribonucleotide reductase (RR), two enzymes required for the entire de novo deoxyribonucleotide biosynthesis, and possessed low dNTP levels. Chromatin at the promoters of the genes encoding TS and RR was enriched with retinoblastoma tumor suppressor protein and histone H3 tri-methylated at lysine 9. Importantly, ectopic coexpression of TS and RR or addition of deoxyribonucleosides substantially suppressed DNA damage, senescence-associated phenotypes, and proliferation arrest in two types of NHF-expressing HRAS(G12V). Reciprocally, short hairpin RNA-mediated suppression of TS and RR caused DNA damage and senescence in NHFs, although less efficiently than HRAS(G12V). However, overexpression of TS and RR in quiescent NHFs did not overcome proliferation arrest, suggesting that unlike quiescence, OIS requires depletion of dNTP pools and activated DNA replication. Our data identify a previously unknown role of deoxyribonucleotides in regulation of OIS.
MeSH term(s)	Cell Proliferation ; Cells, Cultured ; Cellular Senescence/genetics ; Cellular Senescence/physiology ; DNA Damage/genetics ; DNA Replication/genetics ; Deoxyribonucleotides/genetics ; Deoxyribonucleotides/metabolism ; Fibroblasts/metabolism ; Fibroblasts/physiology ; Humans ; Oncogenes/physiology ; Proto-Oncogene Proteins p21(ras)/physiology ; Ribonucleotide Reductases/biosynthesis ; Ribonucleotide Reductases/physiology ; Thymidylate Synthase/biosynthesis ; Thymidylate Synthase/physiology
Chemical Substances	Deoxyribonucleotides ; Ribonucleotide Reductases (EC 1.17.4.-) ; Thymidylate Synthase (EC 2.1.1.45) ; HRAS protein, human (EC 3.6.5.2) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2012-12-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2012.09.011
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Article ; Online: KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells.

Mannava, Sudha / Zhuang, DaZhong / Nair, Jayakumar R / Bansal, Rajat / Wawrzyniak, Joseph A / Zucker, Shoshanna N / Fink, Emily E / Moparthy, Kalyana C / Hu, Qiang / Liu, Song / Boise, Lawrence H / Lee, Kelvin P / Nikiforov, Mikhail A

Blood

2011 Volume 119, Issue 6, Page(s) 1450–1458

Abstract: Bortezomib, a therapeutic agent for multiple myeloma (MM) and mantle cell lymphoma, suppresses proteosomal degradation leading to substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators ... ...

Abstract	Bortezomib, a therapeutic agent for multiple myeloma (MM) and mantle cell lymphoma, suppresses proteosomal degradation leading to substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators required for bortezomib-induced apoptosis in MM cells are largely unknown. Using gene expression profiling, we identified 36 transcription factors that displayed altered expression in MM cells treated with bortezomib. Analysis of a publically available database identified Kruppel-like family factor 9 (KLF9) as the only transcription factor with significantly higher basal expression in MM cells from patients who responded to bortezomib compared with nonresponders. We demonstrated that KLF9 in cultured MM cells was up-regulated by bortezomib; however, it was not through the induction of endoplasmic reticulum stress. Instead, KLF9 levels correlated with bortezomib-dependent inhibition of histone deacetylases (HDAC) and were increased by the HDAC inhibitor LBH589 (panobinostat). Furthermore, bortezomib induced binding of endogenous KLF9 to the promoter of the proapoptotic gene NOXA. Importantly, KLF9 knockdown impaired NOXA up-regulation and apoptosis caused by bortezomib, LBH589, or a combination of theses drugs, whereas KLF9 overexpression induced apoptosis that was partially NOXA-dependent. Our data identify KLF9 as a novel and potentially clinically relevant transcriptional regulator of drug-induced apoptosis in MM cells.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Boronic Acids/pharmacology ; Bortezomib ; Cell Line, Tumor ; Cell Survival/drug effects ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hydroxamic Acids/pharmacology ; Indoles ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Multiple Myeloma/genetics ; Multiple Myeloma/metabolism ; Multiple Myeloma/pathology ; Oligonucleotide Array Sequence Analysis ; Panobinostat ; Promoter Regions, Genetic/genetics ; Protein Binding ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyrazines/pharmacology ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Antineoplastic Agents ; Boronic Acids ; Hydroxamic Acids ; Indoles ; KLF9 protein, human ; Kruppel-Like Transcription Factors ; PMAIP1 protein, human ; Proto-Oncogene Proteins c-bcl-2 ; Pyrazines ; Transcription Factors ; Bortezomib (69G8BD63PP) ; Panobinostat (9647FM7Y3Z)
Language	English
Publishing date	2011-12-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2011-04-346676
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Article ; Online: Nrf2 amplifies oxidative stress via induction of Klf9.

Molecular cell

2014 Volume 53, Issue 6, Page(s) 916–928

Abstract: Reactive oxygen species (ROS) activate NF-E2-related transcription factor 2 (Nrf2), a key transcriptional regulator driving antioxidant gene expression and protection from oxidant injury. Here, we report that in response to elevation of intracellular ROS ...

Abstract	Reactive oxygen species (ROS) activate NF-E2-related transcription factor 2 (Nrf2), a key transcriptional regulator driving antioxidant gene expression and protection from oxidant injury. Here, we report that in response to elevation of intracellular ROS above a critical threshold, Nrf2 stimulates expression of transcription Kruppel-like factor 9 (Klf9), resulting in further Klf9-dependent increases in ROS and subsequent cell death. We demonstrated that Klf9 independently causes increased ROS levels in various types of cultured cells and in mouse tissues and is required for pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Mechanistically, Klf9 binds to the promoters and alters the expression of several genes involved in the metabolism of ROS, including suppression of thioredoxin reductase 2, an enzyme participating in ROS clearance. Our data reveal an Nrf2-dependent feedforward regulation of ROS and identify Klf9 as a ubiquitous regulator of oxidative stress and lung injury.
MeSH term(s)	Animals ; Binding Sites ; Bleomycin ; Cell Line, Tumor ; Gene Expression Regulation ; Genes, Reporter ; Humans ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Luciferases/genetics ; Luciferases/metabolism ; Lung/metabolism ; Lung/pathology ; Mice ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; NIH 3T3 Cells ; Oxidative Stress ; Promoter Regions, Genetic ; Protein Binding ; Pulmonary Fibrosis/chemically induced ; Pulmonary Fibrosis/genetics ; Pulmonary Fibrosis/metabolism ; Pulmonary Fibrosis/pathology ; Reactive Oxygen Species ; Signal Transduction
Chemical Substances	KLF9 protein, human ; Klf9 protein, mouse ; Kruppel-Like Transcription Factors ; NF-E2-Related Factor 2 ; NFE2L2 protein, human ; Nfe2l2 protein, mouse ; Reactive Oxygen Species ; Bleomycin (11056-06-7) ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2014-03-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2014.01.033
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Article ; Online: A purine nucleotide biosynthesis enzyme guanosine monophosphate reductase is a suppressor of melanoma invasion.

Cell reports

2013 Volume 5, Issue 2, Page(s) 493–507

Abstract: Melanoma is one of the most aggressive types of human cancers, and the mechanisms underlying melanoma invasive phenotype are not completely understood. Here, we report that expression of guanosine monophosphate reductase (GMPR), an enzyme involved in de ... ...

Abstract	Melanoma is one of the most aggressive types of human cancers, and the mechanisms underlying melanoma invasive phenotype are not completely understood. Here, we report that expression of guanosine monophosphate reductase (GMPR), an enzyme involved in de novo biosynthesis of purine nucleotides, was downregulated in the invasive stages of human melanoma. Loss- and gain-of-function experiments revealed that GMPR downregulates the amounts of several GTP-bound (active) Rho-GTPases and suppresses the ability of melanoma cells to form invadopodia, degrade extracellular matrix, invade in vitro, and grow as tumor xenografts in vivo. Mechanistically, we demonstrated that GMPR partially depletes intracellular GTP pools. Pharmacological inhibition of de novo GTP biosynthesis suppressed whereas addition of exogenous guanosine increased invasion of melanoma cells as well as cells from other cancer types. Our data identify GMPR as a melanoma invasion suppressor and establish a link between guanosine metabolism and Rho-GTPase-dependent melanoma cell invasion.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Movement ; Extracellular Matrix/metabolism ; GMP Reductase/antagonists & inhibitors ; GMP Reductase/genetics ; GMP Reductase/metabolism ; Guanosine Triphosphate/metabolism ; HCT116 Cells ; Humans ; IMP Dehydrogenase/metabolism ; Melanoma/enzymology ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Phenotype ; Purine Nucleosides/biosynthesis ; RNA Interference ; RNA, Small Interfering/metabolism ; Transplantation, Heterologous ; rac1 GTP-Binding Protein/genetics ; rac1 GTP-Binding Protein/metabolism ; rho GTP-Binding Proteins/metabolism
Chemical Substances	Purine Nucleosides ; RNA, Small Interfering ; Guanosine Triphosphate (86-01-1) ; IMP Dehydrogenase (EC 1.1.1.205) ; IMPDH2 protein, human (EC 1.1.1.205) ; GMP Reductase (EC 1.7.1.7) ; rac1 GTP-Binding Protein (EC 3.6.5.2) ; rho GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2013-10-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2013.09.015
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Article ; Online: Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells.

Mannava, Sudha / Grachtchouk, Vladimir / Wheeler, Linda J / Im, Michael / Zhuang, Dazhong / Slavina, Elena G / Mathews, Christopher K / Shewach, Donna S / Nikiforov, Mikhail A

Cell cycle (Georgetown, Tex.)

2008 Volume 7, Issue 15, Page(s) 2392–2400

Abstract: To identify C-MYC targets rate-limiting for proliferation of malignant melanoma, we stably inhibited C-MYC in several human metastatic melanoma lines via lentivirus-based shRNAs approximately to the levels detected in normal melanocytes. C-MYC depletion ... ...

Abstract	To identify C-MYC targets rate-limiting for proliferation of malignant melanoma, we stably inhibited C-MYC in several human metastatic melanoma lines via lentivirus-based shRNAs approximately to the levels detected in normal melanocytes. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation. shRNA-mediated suppression of TS, IMPDH2 or PRPS2 resulted in the decrease of dNTP pools and retardation of the cell cycle progression of melanoma cells in a manner similar to that of C-MYC-depletion in those cells. Reciprocally, concurrent overexpression of cDNAs for TS, IMPDH2 and PRPS2 delayed proliferative arrest caused by inhibition of C-MYC in melanoma cells. Overexpression of C-MYC in normal melanocytes enhanced expression of the above enzymes and increased individual dNTP pools. Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. Moreover, all three proteins express at higher levels in cells from several metastatic melanoma lines compared to normal melanocytes. Our data establish a novel functional link between C-MYC and dNTP metabolism and identify its role in proliferation of tumor cells.
MeSH term(s)	Cell Proliferation/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; IMP Dehydrogenase/genetics ; IMP Dehydrogenase/metabolism ; IMP Dehydrogenase/physiology ; Melanocytes/metabolism ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Nucleotides/biosynthesis ; Promoter Regions, Genetic ; Protein Binding ; Proto-Oncogene Proteins c-myc/antagonists & inhibitors ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Proto-Oncogene Proteins c-myc/physiology ; RNA, Small Interfering/pharmacology ; Ribose-Phosphate Pyrophosphokinase/genetics ; Ribose-Phosphate Pyrophosphokinase/metabolism ; Ribose-Phosphate Pyrophosphokinase/physiology ; Thymidylate Synthase/genetics ; Thymidylate Synthase/metabolism ; Thymidylate Synthase/physiology ; Transfection ; Tumor Cells, Cultured
Chemical Substances	Nucleotides ; Proto-Oncogene Proteins c-myc ; RNA, Small Interfering ; IMP Dehydrogenase (EC 1.1.1.205) ; IMPDH2 protein, human (EC 1.1.1.205) ; Thymidylate Synthase (EC 2.1.1.45) ; Ribose-Phosphate Pyrophosphokinase (EC 2.7.6.1)
Language	English
Publishing date	2008-06-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.6390
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Article ; Online: A Purine Nucleotide Biosynthesis Enzyme Guanosine Monophosphate Reductase Is a Suppressor of Melanoma Invasion

Cell Reports, Vol 5, Iss 2, Pp 493-

2013 Volume 507

Abstract	Melanoma is one of the most aggressive types of human cancers, and the mechanisms underlying melanoma invasive phenotype are not completely understood. Here, we report that expression of guanosine monophosphate reductase (GMPR), an enzyme involved in de novo biosynthesis of purine nucleotides, was downregulated in the invasive stages of human melanoma. Loss- and gain-of-function experiments revealed that GMPR downregulates the amounts of several GTP-bound (active) Rho-GTPases and suppresses the ability of melanoma cells to form invadopodia, degrade extracellular matrix, invade in vitro, and grow as tumor xenografts in vivo. Mechanistically, we demonstrated that GMPR partially depletes intracellular GTP pools. Pharmacological inhibition of de novo GTP biosynthesis suppressed whereas addition of exogenous guanosine increased invasion of melanoma cells as well as cells from other cancer types. Our data identify GMPR as a melanoma invasion suppressor and establish a link between guanosine metabolism and Rho-GTPase-dependent melanoma cell invasion.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2013-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Nrf2 Amplifies Oxidative Stress via Induction of Klf9

Molecular cell. 2014 Mar. 20, v. 53

2014

Abstract	Reactive oxygen species (ROS) activate NF-E2-related transcription factor 2 (Nrf2), a key transcriptional regulator driving antioxidant gene expression and protection from oxidant injury. Here, we report that in response to elevation of intracellular ROS above a critical threshold, Nrf2 stimulates expression of transcription Kruppel-like factor 9 (Klf9), resulting in further Klf9-dependent increases in ROS and subsequent cell death. We demonstrated that Klf9 independently causes increased ROS levels in various types of cultured cells and in mouse tissues and is required for pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Mechanistically, Klf9 binds to the promoters and alters the expression of several genes involved in the metabolism of ROS, including suppression of thioredoxin reductase 2, an enzyme participating in ROS clearance. Our data reveal an Nrf2-dependent feedforward regulation of ROS and identify Klf9 as a ubiquitous regulator of oxidative stress and lung injury.
Keywords	antioxidants ; cell death ; cultured cells ; fibrosis ; gene expression ; genes ; metabolism ; mice ; oxidants ; oxidative stress ; pathogenesis ; reactive oxygen species ; tissues ; transcription factors
Language	English
Dates of publication	2014-0320
Size	p. 916-928.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2014.01.033
Database	NAL-Catalogue (AGRICOLA)

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