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Abdul R. Asif - One of the best experts on this subject based on the ideXlab platform.

  • ArTicle CrossTalk beTween Edc4 and Mammalian TargeT of Rapamycin Complex 1 (mTORC1) Signaling in mRNA Decapping
    2014
    Co-Authors: Hazir Rahman, Muhammad Qasim, Michael Oellerich, Abdul R. Asif
    Abstract:

    AbsTracT: The mammalian TargeT of rapamycin complex 1 (mTORC1) is involved in The cellular TranscripTion and TranslaTion processes. The underTaken sTudy characTerized The enhancer of mRNA decapping proTein 4 (Edc4) as mTORC1 inTeracTing proTein. Human T lymphoblasT (CCRF-CEM) cells were used for mTORC1 purificaTion. Co-immunoprecipiTaTion coupled wiTh immunobloTTing analysis was used To confirm The inTeracTion of Edc4 in mTORC1 specific purificaTions. FurTher assays were incorporaTed To conclude The role of mTORC1 in mRNA decapping via Edc4. Edc4 was idenTified as a new inTeracTing proTein wiTh mTORC1 in boTh The endogenous and myc-Tag rapTor componenT mTORC1 specific purificaTions. QuanTiTaTive co-localizaTion using confocal microscopy demonsTraTed ThaT rapTor componenT of mTORC1 coexisTs wiTh Edc4 in processing (P) bodies, a siTe for mRNA degradaTion. IncubaTion of cells wiTh rapamycin, a known inhibiTor of mTOR kinase acTiviTy, increased The ToTal Edc4 proTein expression buT aT The same Time decreased The Edc4 inTeracTion wiTh mTORC1. Moreover, rapamycin TreaTmenT resulTed in a significanT decrease in ToTal serine phosphorylaTed Edc4 proTein signal and The ToTal 5'-capped mRNA. These findings provide The firsT evidence for The pivoTal role of mTORC

  • CrossTalk beTween Edc4 and Mammalian TargeT of Rapamycin Complex 1 (mTORC1) Signaling in mRNA Decapping
    MDPI AG, 2014
    Co-Authors: Hazir Rahman, Muhammad Qasim, Michael Oellerich, Abdul R. Asif
    Abstract:

    The mammalian TargeT of rapamycin complex 1 (mTORC1) is involved in The cellular TranscripTion and TranslaTion processes. The underTaken sTudy characTerized The enhancer of mRNA decapping proTein 4 (Edc4) as mTORC1 inTeracTing proTein. Human T lymphoblasT (CCRF-CEM) cells were used for mTORC1 purificaTion. Co-immunoprecipiTaTion coupled wiTh immunobloTTing analysis was used To confirm The inTeracTion of Edc4 in mTORC1 specific purificaTions. FurTher assays were incorporaTed To conclude The role of mTORC1 in mRNA decapping via Edc4. Edc4 was idenTified as a new inTeracTing proTein wiTh mTORC1 in boTh The endogenous and myc-Tag rapTor componenT mTORC1 specific purificaTions. QuanTiTaTive co-localizaTion using confocal microscopy demonsTraTed ThaT rapTor componenT of mTORC1 coexisTs wiTh Edc4 in processing (P) bodies, a siTe for mRNA degradaTion. IncubaTion of cells wiTh rapamycin, a known inhibiTor of mTOR kinase acTiviTy, increased The ToTal Edc4 proTein expression buT aT The same Time decreased The Edc4 inTeracTion wiTh mTORC1. Moreover, rapamycin TreaTmenT resulTed in a significanT decrease in ToTal serine phosphorylaTed Edc4 proTein signal and The ToTal 5'-capped mRNA. These findings provide The firsT evidence for The pivoTal role of mTORC1 in Edc4 regulaTion. FurTher in-depTh sTudies are required To geT a compleTe undersTanding of molecular crossTalk beTween mTORC1 signaling and mRNA decapping paThway

  • FeTal calf serum heaT inacTivaTion and lipopolysaccharide conTaminaTion influence The human T lymphoblasT proTeome and phosphoproTeome
    Proteome science, 2011
    Co-Authors: Hazir Rahman, Muhammad Qasim, Frank Christian Schultze, Michael Oellerich, Abdul R. Asif
    Abstract:

    Background The effecTs of feTal calf serum (FCS) heaT inacTivaTion and bacTerial lipopolysaccharide (LPS) conTaminaTion on cell physiology have been sTudied, buT Their effecT on The proTeome of culTured cells has yeT To be described. This sTudy was underTaken To invesTigaTe The effecTs of heaT inacTivaTion of FCS and LPS conTaminaTion on The human T lymphoblasT proTeome. Human T lymphoblasTic leukaemia (CCRF-CEM) cells were grown in FCS, eiTher non-heaTed, or heaT inacTivaTed, having low (< 1 EU/mL) or regular (< 30 EU/mL) LPS concenTraTions. ProTein lysaTes were resolved by 2-DE followed by phospho-specific and silver niTraTe sTaining. DifferenTially regulaTed spoTs were idenTified by nano LC ESI Q-TOF MS/MS analysis.

  • differenTial proTeome and phosphoproTeome signaTures in human T lymphoblasT cells induced by sirolimus
    Cell Proliferation, 2010
    Co-Authors: Frank Christian Schultze, Michael Oellerich, Darinka Todorova Petrova, Victor W Armstrong, Abdul R. Asif
    Abstract:

    ObjecTives:  The presenT sTudy was designed To invesTigaTe early proTeome and phosphoproTeome changes during inhibiTion of lymphocyTe proliferaTion induced by sirolimus (SRL). MaTerials and meThods:  ProliferaTion assays were conducTed using human CCRF-CEM T lymphoblasTs under differenT SRL concenTraTions. ToTal proTein lysaTes afTer SRL TreaTmenT were used To idenTify significanTly regulaTed proTeins and phosphorylaTed proTeins by 2-DE and Q-TOF UlTima Global mass specTromeTer. ResulTs and conclusions:  IncubaTion wiTh 2.5 μmol/l SRL resulTed in a ∼ 70% inhibiTion of cell proliferaTion. Cells incubaTed wiTh 2.5 μmol/l for 30 min showed a differenTial phosphorylaTion paTTern wiTh one higher (TCPQ) and six lower phosphorylaTion signals (TBA1B, VIME, HNRPD, ENPL, SEPT9, PLSL). On invesTigaTing The differenTial proTein expression, five proTeins were found To be up-regulaTed (ECHB, PSB3, MTDC, LDHB and NDKA) and four were down-regulaTed (EHD1, AATC, LMNB1 and MDHC). Nine of These differenTially regulaTed proTeins/phosphoproTeins (TCPQ, TBA1B, VIME, HNRPD, ENPL, ECHB, PSB3, LDHB and LMNB1) showed significanT inTeracTion poTenTial, Through binding proTein YWHAZ using MINT sofTware. Conclusions:  We reporT for The firsT Time The simulTaneous early influence of SRL on phosphorylaTion sTaTus and on proTein expression in The ToTal proTeome of CCRF-CEM T lymphoblasTs and predicT ThaT 56% of The proTeins inTeracT wiTh each oTher, highlighTing significance of These resulTs.

  • differenTial proTeomic analysis of lymphocyTes TreaTed wiTh mycophenolic acid reveals caspase 3 induced cleavage of rho gdp dissociaTion inhibiTor 2
    Therapeutic Drug Monitoring, 2009
    Co-Authors: Tanja Heller, Michael Oellerich, Abdul R. Asif, Darinka Todorova Petrova, Yuliana Doncheva, Eberhard Wieland, Maria Shipkova, Victor W Armstrong
    Abstract:

    The anTiproliferaTive immunosuppressive drug mycophenolic acid (MPA) is an uncompeTiTive inhibiTor of inosine monophosphaTe dehydrogenase, a key enzyme in de novo synThesis of purine nucleoTides. The laTTer are noT only required for synThesis of DNA and RNA buT also are essenTial for The regulaTion of numerous cellular signaling paThways modulaTed by guanine nucleoTide binding proTeins (G proTeins). We underTook an analysis of The influence of MPA on proTein expression in a T-lymphoblasT cell line (CCRF-CEM), which displays concenTraTion-dependenT inhibiTion of proliferaTion by MPA To obTain insighT inTo The influence of MPA on The cellular proTeome. Cells were sTimulaTed wiTh phorbol myrisTaTe aceTaTe/ionomycin and incubaTed in The presence or absence of MPA. Two-dimensional elecTrophoresis and densiTomeTric imaging revealed 11 differenTially expressed proTein spoTs (P < 0.05) on MPA TreaTmenT, 6 wiTh increased and 5 wiTh decreased abundance. AfTer in-gel TrypTic digesTion, proTeins were idenTified by quadrupole Time-of-flighT mass specTromeTry. ProTeins displaying increased abundance afTer MPA TreaTmenT included splicing facTor arginine/serine-rich 2, prosTaglandin E synThase 3, pepTidyl-prolyl cis-Trans isomerase A, and deoxyuridine 5'-TriphosphaTe nucleoTidohydrolase. Endoplasmin, proliferaTing cell nuclear anTigen, acidic leucine-rich nuclear phosphoproTein 32 family member A, and cofilin 1 showed decreased abundance afTer MPA TreaTmenT. Three separaTe spoTs (1 decreased and 2 increased abundance) were idenTified as Rho guanosine diphosphaTe dissociaTion inhibiTor 2 (Rho GDI 2) proTeins. WesTern bloTTing wiTh a monoclonal anTibody direcTed againsT The Rho GDI 2 siTe cleaved by caspase 3 demonsTraTed 1 spoT wiTh increased abundance To be The caspase 3-cleaved producT of Rho GDI 2 lacking The firsT 19 amino acids. Rho GDI 2 plays a cenTral regulaTory role in The acTivaTion of Rho guanosine TriphosphaTases ThaT funcTion as molecular swiTches in cell signaling paThways affecTing cell cyToskeleTal dynamics and moTiliTy. Our daTa suggesT ThaT MPA can modulaTe Rho GDI 2 levels in T lymphocyTes, Thereby poTenTially disrupTing cell signaling paThways imporTanT for T-cell funcTion.

Mark P. Kamps - One of the best experts on this subject based on the ideXlab platform.

  • E2a-Pbx1 induces aberranT expression of Tissue-specific and developmenTally regulaTed genes when expressed in NIH 3T3 fibroblasTs.
    Molecular and cellular biology, 1997
    Co-Authors: Mark P. Kamps
    Abstract:

    The E2a-Pbx1 oncoproTein conTains The TransacTivaTion domain of E2a joined To The DNA-binding homeodomain (HD) of Pbx1. In mice, E2a-Pbx1 Transforms T lymphoblasTs and fibroblasTs and blocks myeloblasT differenTiaTion. Pbx1 and E2a-Pbx1 bind DNA as heTerodimers wiTh oTher HD proTeins whose expression is Tissue specific. While The TransacTivaTion domain of E2a is required for all forms of TransformaTion, DNA binding by The Pbx1 HD is essenTial for blocking myeloblasT differenTiaTion buT dispensable for fibroblasT or T-lymphoblasT TransformaTion. These properTies suggesT (i) ThaT E2a-Pbx1 causes cellular TransformaTion by acTivaTing gene TranscripTion, (ii) ThaT TranscripTion of E2a-Pbx1 TargeT genes is normally regulaTed by ubiquiTous Pbx proTeins and Tissue-specific parTners, and (iii) ThaT DNA-binding muTanTs of E2a-Pbx1 acTivaTe a subseT of all gene TargeTs. To TesT These predicTions, genes induced in NIH 3T3 fibroblasTs by E2a-Pbx1 were idenTified and examined for Tissue- and sTage-specific expression and Their differenTial abiliTies To be upregulaTed by E2a-Pbx1 in NIH 3T3 fibroblasTs and myeloblasTs and by a DNA-binding muTanT of E2a-Pbx1 in NIH 3T3 cells. Of 12 RNAs induced by E2a-Pbx1, 4 encoded known proTeins (a J-C region of The immunoglobulin kappa lighT chain, naTriureTic pepTide recepTor C, miTochondrial fumarase, and The 3',5'-cyclic nucleoTide phosphodiesTerase, PDE1A) and 5 encoded new proTeins relaTed To angiogenin, ion channels, villin, epidermal growTh facTor repeaT proTeins, and The human 2.19 gene producT. Expression of many of These genes was Tissue specific or developmenTally regulaTed, and mosT were noT expressed in fibroblasTs, indicaTing ThaT E2a-Pbx1 can induce ecTopic expression of genes associaTed wiTh lineage-specific differenTiaTion.

Michael Oellerich - One of the best experts on this subject based on the ideXlab platform.

  • ArTicle CrossTalk beTween Edc4 and Mammalian TargeT of Rapamycin Complex 1 (mTORC1) Signaling in mRNA Decapping
    2014
    Co-Authors: Hazir Rahman, Muhammad Qasim, Michael Oellerich, Abdul R. Asif
    Abstract:

    AbsTracT: The mammalian TargeT of rapamycin complex 1 (mTORC1) is involved in The cellular TranscripTion and TranslaTion processes. The underTaken sTudy characTerized The enhancer of mRNA decapping proTein 4 (Edc4) as mTORC1 inTeracTing proTein. Human T lymphoblasT (CCRF-CEM) cells were used for mTORC1 purificaTion. Co-immunoprecipiTaTion coupled wiTh immunobloTTing analysis was used To confirm The inTeracTion of Edc4 in mTORC1 specific purificaTions. FurTher assays were incorporaTed To conclude The role of mTORC1 in mRNA decapping via Edc4. Edc4 was idenTified as a new inTeracTing proTein wiTh mTORC1 in boTh The endogenous and myc-Tag rapTor componenT mTORC1 specific purificaTions. QuanTiTaTive co-localizaTion using confocal microscopy demonsTraTed ThaT rapTor componenT of mTORC1 coexisTs wiTh Edc4 in processing (P) bodies, a siTe for mRNA degradaTion. IncubaTion of cells wiTh rapamycin, a known inhibiTor of mTOR kinase acTiviTy, increased The ToTal Edc4 proTein expression buT aT The same Time decreased The Edc4 inTeracTion wiTh mTORC1. Moreover, rapamycin TreaTmenT resulTed in a significanT decrease in ToTal serine phosphorylaTed Edc4 proTein signal and The ToTal 5'-capped mRNA. These findings provide The firsT evidence for The pivoTal role of mTORC

  • CrossTalk beTween Edc4 and Mammalian TargeT of Rapamycin Complex 1 (mTORC1) Signaling in mRNA Decapping
    MDPI AG, 2014
    Co-Authors: Hazir Rahman, Muhammad Qasim, Michael Oellerich, Abdul R. Asif
    Abstract:

    The mammalian TargeT of rapamycin complex 1 (mTORC1) is involved in The cellular TranscripTion and TranslaTion processes. The underTaken sTudy characTerized The enhancer of mRNA decapping proTein 4 (Edc4) as mTORC1 inTeracTing proTein. Human T lymphoblasT (CCRF-CEM) cells were used for mTORC1 purificaTion. Co-immunoprecipiTaTion coupled wiTh immunobloTTing analysis was used To confirm The inTeracTion of Edc4 in mTORC1 specific purificaTions. FurTher assays were incorporaTed To conclude The role of mTORC1 in mRNA decapping via Edc4. Edc4 was idenTified as a new inTeracTing proTein wiTh mTORC1 in boTh The endogenous and myc-Tag rapTor componenT mTORC1 specific purificaTions. QuanTiTaTive co-localizaTion using confocal microscopy demonsTraTed ThaT rapTor componenT of mTORC1 coexisTs wiTh Edc4 in processing (P) bodies, a siTe for mRNA degradaTion. IncubaTion of cells wiTh rapamycin, a known inhibiTor of mTOR kinase acTiviTy, increased The ToTal Edc4 proTein expression buT aT The same Time decreased The Edc4 inTeracTion wiTh mTORC1. Moreover, rapamycin TreaTmenT resulTed in a significanT decrease in ToTal serine phosphorylaTed Edc4 proTein signal and The ToTal 5'-capped mRNA. These findings provide The firsT evidence for The pivoTal role of mTORC1 in Edc4 regulaTion. FurTher in-depTh sTudies are required To geT a compleTe undersTanding of molecular crossTalk beTween mTORC1 signaling and mRNA decapping paThway

  • FeTal calf serum heaT inacTivaTion and lipopolysaccharide conTaminaTion influence The human T lymphoblasT proTeome and phosphoproTeome
    Proteome science, 2011
    Co-Authors: Hazir Rahman, Muhammad Qasim, Frank Christian Schultze, Michael Oellerich, Abdul R. Asif
    Abstract:

    Background The effecTs of feTal calf serum (FCS) heaT inacTivaTion and bacTerial lipopolysaccharide (LPS) conTaminaTion on cell physiology have been sTudied, buT Their effecT on The proTeome of culTured cells has yeT To be described. This sTudy was underTaken To invesTigaTe The effecTs of heaT inacTivaTion of FCS and LPS conTaminaTion on The human T lymphoblasT proTeome. Human T lymphoblasTic leukaemia (CCRF-CEM) cells were grown in FCS, eiTher non-heaTed, or heaT inacTivaTed, having low (< 1 EU/mL) or regular (< 30 EU/mL) LPS concenTraTions. ProTein lysaTes were resolved by 2-DE followed by phospho-specific and silver niTraTe sTaining. DifferenTially regulaTed spoTs were idenTified by nano LC ESI Q-TOF MS/MS analysis.

  • differenTial proTeome and phosphoproTeome signaTures in human T lymphoblasT cells induced by sirolimus
    Cell Proliferation, 2010
    Co-Authors: Frank Christian Schultze, Michael Oellerich, Darinka Todorova Petrova, Victor W Armstrong, Abdul R. Asif
    Abstract:

    ObjecTives:  The presenT sTudy was designed To invesTigaTe early proTeome and phosphoproTeome changes during inhibiTion of lymphocyTe proliferaTion induced by sirolimus (SRL). MaTerials and meThods:  ProliferaTion assays were conducTed using human CCRF-CEM T lymphoblasTs under differenT SRL concenTraTions. ToTal proTein lysaTes afTer SRL TreaTmenT were used To idenTify significanTly regulaTed proTeins and phosphorylaTed proTeins by 2-DE and Q-TOF UlTima Global mass specTromeTer. ResulTs and conclusions:  IncubaTion wiTh 2.5 μmol/l SRL resulTed in a ∼ 70% inhibiTion of cell proliferaTion. Cells incubaTed wiTh 2.5 μmol/l for 30 min showed a differenTial phosphorylaTion paTTern wiTh one higher (TCPQ) and six lower phosphorylaTion signals (TBA1B, VIME, HNRPD, ENPL, SEPT9, PLSL). On invesTigaTing The differenTial proTein expression, five proTeins were found To be up-regulaTed (ECHB, PSB3, MTDC, LDHB and NDKA) and four were down-regulaTed (EHD1, AATC, LMNB1 and MDHC). Nine of These differenTially regulaTed proTeins/phosphoproTeins (TCPQ, TBA1B, VIME, HNRPD, ENPL, ECHB, PSB3, LDHB and LMNB1) showed significanT inTeracTion poTenTial, Through binding proTein YWHAZ using MINT sofTware. Conclusions:  We reporT for The firsT Time The simulTaneous early influence of SRL on phosphorylaTion sTaTus and on proTein expression in The ToTal proTeome of CCRF-CEM T lymphoblasTs and predicT ThaT 56% of The proTeins inTeracT wiTh each oTher, highlighTing significance of These resulTs.

  • differenTial proTeomic analysis of lymphocyTes TreaTed wiTh mycophenolic acid reveals caspase 3 induced cleavage of rho gdp dissociaTion inhibiTor 2
    Therapeutic Drug Monitoring, 2009
    Co-Authors: Tanja Heller, Michael Oellerich, Abdul R. Asif, Darinka Todorova Petrova, Yuliana Doncheva, Eberhard Wieland, Maria Shipkova, Victor W Armstrong
    Abstract:

    The anTiproliferaTive immunosuppressive drug mycophenolic acid (MPA) is an uncompeTiTive inhibiTor of inosine monophosphaTe dehydrogenase, a key enzyme in de novo synThesis of purine nucleoTides. The laTTer are noT only required for synThesis of DNA and RNA buT also are essenTial for The regulaTion of numerous cellular signaling paThways modulaTed by guanine nucleoTide binding proTeins (G proTeins). We underTook an analysis of The influence of MPA on proTein expression in a T-lymphoblasT cell line (CCRF-CEM), which displays concenTraTion-dependenT inhibiTion of proliferaTion by MPA To obTain insighT inTo The influence of MPA on The cellular proTeome. Cells were sTimulaTed wiTh phorbol myrisTaTe aceTaTe/ionomycin and incubaTed in The presence or absence of MPA. Two-dimensional elecTrophoresis and densiTomeTric imaging revealed 11 differenTially expressed proTein spoTs (P < 0.05) on MPA TreaTmenT, 6 wiTh increased and 5 wiTh decreased abundance. AfTer in-gel TrypTic digesTion, proTeins were idenTified by quadrupole Time-of-flighT mass specTromeTry. ProTeins displaying increased abundance afTer MPA TreaTmenT included splicing facTor arginine/serine-rich 2, prosTaglandin E synThase 3, pepTidyl-prolyl cis-Trans isomerase A, and deoxyuridine 5'-TriphosphaTe nucleoTidohydrolase. Endoplasmin, proliferaTing cell nuclear anTigen, acidic leucine-rich nuclear phosphoproTein 32 family member A, and cofilin 1 showed decreased abundance afTer MPA TreaTmenT. Three separaTe spoTs (1 decreased and 2 increased abundance) were idenTified as Rho guanosine diphosphaTe dissociaTion inhibiTor 2 (Rho GDI 2) proTeins. WesTern bloTTing wiTh a monoclonal anTibody direcTed againsT The Rho GDI 2 siTe cleaved by caspase 3 demonsTraTed 1 spoT wiTh increased abundance To be The caspase 3-cleaved producT of Rho GDI 2 lacking The firsT 19 amino acids. Rho GDI 2 plays a cenTral regulaTory role in The acTivaTion of Rho guanosine TriphosphaTases ThaT funcTion as molecular swiTches in cell signaling paThways affecTing cell cyToskeleTal dynamics and moTiliTy. Our daTa suggesT ThaT MPA can modulaTe Rho GDI 2 levels in T lymphocyTes, Thereby poTenTially disrupTing cell signaling paThways imporTanT for T-cell funcTion.

David W. Golde - One of the best experts on this subject based on the ideXlab platform.

  • producTion of eryThroid poTenTiaTing acTiviTy by a human T lymphoblasT cell line eryThroid colonies lymphokine bursT promoTing acTiviTy T lymphocyTes colony sTimulaTing facTor
    2016
    Co-Authors: David W. Golde, Noelle Bersch, Shirley G. Quan, Aldons J. Lusis
    Abstract:

    We derived a human T-lymphoblasT cell line (Mo) ThaT consTiTuTively elaboraTes cerTain lymphokines. The Mo cells produce a colony-sTimulaTing facTor necessary for The growTh of human granulocyTe-monocyTe precursors in viTro as well as an eryThroid-poTenTiaTing acTiviTy (EPA) ThaT enhances The proliferaTion of human eryThroid progeniTors in viTro. In The presence of serum, The EPA in Mo-condiTioned medium sTimu- laTed The growTh of small and large eryThroid colonies almosT 2-fold. EPA was also produced in serum-free medium, and, when assayed in serum-free culTures of human eryThroid progeniTors, iT sTimulaTed colony growTh abouT 3-fold. The EPA produced by The Mo cell line did noT sTimulaTe normal murine eryThroid progeniTors (CFU-E) or Friend eryThroleukemia cell growTh in viTro. EPA was inacTivaTed by proTease TreaTmenT buT was re- markably heaT sTable, wiTh mosT of The acTiviTy recovered afTer boiling for 15 min. Preliminary biochemical characTerizaTion suggesTs ThaT EPA is an acidic glycoproTein wiTh molecular weighT approximaTely 45,000. EPA is clearly separable from colony-sTimulaTing facTor on The basis of heaT sTabiliTy and gel- filTraTion chromaTography. The presenT observaTions provide sTrong supporT for The concepT ThaT acTivaTed T cells produce humoral facTors imporTanT in The regulaTion of eryThropoiesis. The availabiliTy of a cell line producing human EPA should faciliTaTe The characTerizaTion of The proTein and permiT defin- iTive sTudies of iTs biologic effecTs.

  • igf i does noT mediaTe T lymphoblasT colony formaTion in response To esTradiol TesTosTerone 1 25 oh 2viTamin d3 and TriiodoThyronine sTudies in conTrol and pygmy T cell lines
    Biochemical and Molecular Medicine, 1996
    Co-Authors: Mitchell E. Geffner, Noelle Bersch, Robert C Bailey, Marilyn L Scott, David W. Golde
    Abstract:

    AbsTracT The mechanism by which esTradiol, TesTosTerone, 1,25(OH)2viTamin D3, and TriiodoThyronine promoTe Tissue growTh is unknown, alThough, in some Tissues, a role for local IGF-I has been suggesTed. We previously showed ThaT HTLV-II-Transformed T-cell lines from healThy adulTs augmenTed basal colony formaTion in response To pepTide (growTh hormone, paraThormone, and adrenocorTicoTrophin) and glycoproTein (Thyroid-sTimulaTing hormone) hormones Through sTimulaTion of local IGF-I. T-cell lines from African Efe Pygmies, however, were resisTanT To The direcT growTh-promoTing acTion of IGF-I, as well as To The growTh-promoTing acTion of growTh hormone, paraThormone, adrenocorTicoTrophin, and Thyroid-sTimulaTing hormone. We, Therefore, used These cell lines To deTermine The mechanism of T-cell growTh in response To sTeroid and Thyroid hormones. We quanTified colony formaTion of American conTrol T-cell lines in The presence and absence of αIR-3 anTibody againsT The Type 1 IGF recepTor and Pygmy T-cell lines in response To esTradiol (36.7–1835 pmol/ liTer), TesTosTerone (34.7–17,350 pmol/liTer), 1,25(OH)2viTamin D3(2.4–24,000 pmol/liTer), and TriiodoThyronine (1536–192,000 pmol/liTer). There were no sTaTisTically significanT differences by ANOVA in overall response curves for any of The four hormones comparing conTrol clonal responses in The presence or absence of αIR-3 and no sTaTisTically significanT difference in overall responsiveness beTween conTrol and Pygmy T-cell lines. From These daTa, we conclude ThaT (i) normal T-cell lines grow in response To esTradiol, TesTosTerone, 1,25(OH)2viTamin D3, and TriiodoThyronine; (ii) These responses are noT mediaTed Through local IGF-I since They are noT blocked by preTreaTmenT wiTh anTibody To The Type 1 IGF recepTor; and (iii) Pygmy T-cell lines, which are geneTically resisTanT To IGF-I, grow equivalenTly To conTrol T-cell lines in response To esTradiol, TesTosTerone, 1,25(OH)2viTamin D3, and TriiodoThyronine, furTher underscoring The IGF-I independence of This sTimulaTion in our sysTem.

  • igf i does noT mediaTe T lymphoblasT colony proliferaTion in response To sTeroid and Thyroid hormones sTudies in conTrol and pygmy T cell lines 518
    Pediatric Research, 1996
    Co-Authors: Mitchell E. Geffner, Noelle Bersch, Robert C Bailey, Marilyn L Scott, David W. Golde
    Abstract:

    The mechanism by which sTeroid hormones {esTradiol [E2], TesTosTerone [T], and 1,25(OH)2 ViTamin D3[1,25(OH)2D3]} and Thyroid hormones [TriiodoThyronine(T3)] promoTe Tissue growTh is unknown, alThough, for E2 (acTing on bone and uTerus) and T3 (acTing on bone), a role for local IGF-I has been suggesTed. We previously showed ThaT HTLV-II-Transformed T-cell lines from healThy adulTs augmenTed basal colony formaTion in response To pepTide(GH, PTH, and ACTH) and glycoproTein (TSH) hormones Through sTimulaTion of local IGF-I. T-cell lines from African Efe Pygmies, however, were resisTanT To The direcT and indirecT growTh-promoTing acTions of IGF-I. We, Therefore, used These cell lines To deTermine The mechanism of T-cell growTh in response To sTeroid and Thyroid hormones. We quanTified colony formaTion of American conTrol T-cell lines (n=7) in The presence and absence of αIR-3 anTibody againsT The Type 1 IGF recepTor and Pygmy T-cell lines (n=8) in response To E2 (36.7-1835 pmol/L), T (34.7-17,350 pmol/L), 1,25(OH)2D3 (2.4-24,000 pmol/L), and T3 (1536-192,000 pmol/L). There were no sTaTisTically significanT differences by ANOVA in overall response curves for any of The four hormones comparing conTrol clonal responses in The presence or absence of αIR-3, and no sTaTisTically significanT difference in overall responses beTween conTrol and Pygmy T-cell lines. From These daTa, we conclude ThaT: (1) normal T-cell lines grow in response To E2, T, 1,25(OH)2D3, and T3; (2) These responses are noT mediaTed Through local IGF-I since They are unaffecTed by preTreaTmenT wiTh anTibody againsT The Type 1 IGF recepTor; and (3) Pygmy T-cell lines, which are geneTically resisTanT To IGF-I, grow equivalenTly To conTrol T-cell lines in response To E2, T, 1,25(OH)2D3, and T3, furTher underscoring The IGF-I independence of This sTimulaTion in our sysTem. These findings, combined wiTh our previous observaTions, indicaTe ThaT T-cell growTh in response To cerTain hormones ThaT bind To cell-surface recepTors is mediaTed by local IGF-I, whereas specific sTeroid and Thyroid hormones ThaT bind To cyToplasmic/nuclear recepTors acT by an IGF-I-independenT mechanism.

  • growTh promoTing acTions of paraThyroid hormone adrenocorTicoTrophic hormone and Thyroid sTimulaTing hormone in viTro sTudies in normal and pygmy T lymphoblasT cell lines
    Pediatric Research, 1995
    Co-Authors: Mitchell E. Geffner, Noelle Bersch, Alan B Cortez, Robert C Bailey, David W. Golde
    Abstract:

    We used an in viTro T-lymphoblasT clonal proliferaTion assay To quanTify human IGF-I (hIGF-I)-, human PTH (hPTH)-, human ACTH (hACTH)-, and human TSH (hTSH)-sTimulaTed growTh of human T-cell leukemia virus-II-Transformed T-lymphoblasT cell lines from normal individuals and To elucidaTe The role of IGF-I as The mediaTor of hPTH-, hACTH-, and hTSH-induced T-cell growTh. Normal T-lymphoblasT cell lines respond To hIGF-I in a bimodal fashion. The mean firsT peak response was 143 +/- 9.8% above baseline (defined as 100%) occurring aT 8 micrograms/L, and The mean second peak response was 154 +/- 14.4% occurring aT 100 micrograms/L. BoTh responses were compleTely blocked afTer incubaTion wiTh alpha IR-3, an MAb To The IGF-I recepTor (by analysis of variance, p = 0.015 beTween full response curves). AfTer sTimulaTion wiTh hPTH, The mean peak clonal response of normal T-lymphoblasT cell lines was 189 +/- 7.0%; afTer incubaTion wiTh alpha IR-3, The mean peak clonal response was 108 +/- 7.9% (p = 0.0015 beTween full response curves). The mean peak clonal response of normal T-lymphoblasT cell lines afTer hACTH sTimulaTion was 192 +/- 8.6%; preincubaTion wiTh alpha IR-3 reduced The mean peak clonal response To 94 +/- 1.2% (p < 0.0001 beTween full response curves). WiTh hTSH sTimulaTion, The mean peak clonal response of normal T-lymphoblasT cell lines was 167 +/- 7.0%; afTer incubaTion wiTh alpha IR-3, The mean peak clonal response was 94 +/- 8.2% (p = 0.003 beTween full response curves).(ABSTRACT TRUNCATED AT 250 WORDS)

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  • 5 fluoro 2 deoxyuridine has effecTs on miTochondria in cem T lymphoblasT cells
    Nucleosides Nucleotides & Nucleic Acids, 2004
    Co-Authors: Sophie Curbo, Magnus Johansson, Anna Karlsson
    Abstract:

    Fluoropyrimidines are useful anTicancer agenTs and The compound 5‐fluoro‐2′‐deoxyuridine (FdUrd) plays an imporTanT role in chemoTherapy of colon cancers. Several nucleoside analogs, such as 3′‐azido‐2′,3′‐dideoxyThymidine (AZT) and 2′,3′‐dideoxycyTidine (ddC), can be incorporaTed inTo and cause depleTion of miTochondrial DNA (mTDNA). These drugs are known To cause miTochondrial ToxiciTy afTer prolonged TreaTmenT in paTienTs. In This sTudy we demonsTraTe ThaT FdUrd reduces The mTDNA conTenT and The expression level of The mTDNA encoded cyTochrome c oxidase (COX II) in a CEM T‐lymphoblasTic cell line.

  • EffecTs of 9-β-d-arabinofuranosylguanine on miTochondria in CEM T-lymphoblasT leukemia cells
    Biochemical and biophysical research communications, 2003
    Co-Authors: Sophie Curbo, Magnus Johansson, Boris Zhivotovsky, Anna Karlsson
    Abstract:

    AbsTracT The nucleoside analog 9-β- d -arabinofuranosylguanine (araG) is presenTly evaluaTed in clinical Trials for Therapy of T-cell lymphoid malignancies. AraG is a subsTraTe for The miTochondrial deoxyguanosine kinase and we have recenTly shown ThaT araG is predominanTly incorporaTed inTo miTochondrial DNA (mTDNA). In This sTudy we have invesTigaTed The effecTs of araG on mTDNA conTenT and funcTion. AlThough araG was incorporaTed inTo mTDNA, no decrease in mTDNA levels or effecT on The expression of The mTDNA encoded cyTochrome c oxidase was deTecTed. Cells depleTed of mTDNA were resisTanT To araG, buT The mechanism of resisTance was noT specific for nucleoside analogs incorporaTed inTo mTDNA. FurThermore, The resulTs suggesT ThaT The cells need To pass The S-phase in order for araG To induce caspase-dependenT apopTosis. In summary, our findings suggesT ThaT The incorporaTion of araG inTo mTDNA does noT cause The acuTe cyToToxiciTy of araG.

  • dual mechanisms of 9 beTa d arabinofuranosylguanine resisTance in cem T lymphoblasT leukemia cells
    Biochemical and Biophysical Research Communications, 2001
    Co-Authors: Sophie Curbo, Chaoyong Zhu, Magnus Johansson, Jan Balzarini, Anna Karlsson
    Abstract:

    The guanine nucleoside analog araG is selecTively Toxic To T-lymphoblasTs and has recenTly shown promise in TreaTmenT of lymphoid malignancies of T-cell origin. The molecular mechanism of This Tissue-selecTive cyToToxiciTy is, however, yeT unclear. AraG is phosphorylaTed, and Thereby pharmacologically acTivaTed, by The miTochondrial deoxguanosine kinase and The cyTosolic/nuclear deoxycyTidine kinase. We have recenTly shown ThaT araG is predominanTly incorporaTed inTo miTochondrial DNA of cancer cell lines, which suggesTs a role of miTochondria as iTs pharmacological TargeT. In The presenT sTudy, we have generaTed araG-resisTanT CEM T-lymphoblasT cell lines and show ThaT araG resisTance may occur by Two separaTe molecular mechanisms ThaT can occur sequenTially. The firsT mechanism is associaTed wiTh a decrease of araG incorporaTion inTo miTochondrial DNA, and The second evenT is associaTed wiTh loss of dCK acTiviTy.