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  1. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.140: Show issues Location:
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  4. Article ; Online: A purine nucleotide biosynthesis enzyme guanosine monophosphate reductase is a suppressor of melanoma invasion.

    Wawrzyniak, Joseph A / Bianchi-Smiraglia, Anna / Bshara, Wiam / Mannava, Sudha / Ackroyd, Jeff / Bagati, Archis / Omilian, Angela R / Im, Michael / Fedtsova, Natalia / Miecznikowski, Jeffrey C / Moparthy, Kalyana C / Zucker, Shoshanna N / Zhu, Qianqian / Kozlova, Nadezhda I / Berman, Albert E / Hoek, Keith S / Gudkov, Andrei V / Shewach, Donna S / Morrison, Carl D /
    Nikiforov, Mikhail A

    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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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