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1.
Sci Rep ; 12(1): 14872, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050456

RESUMO

Records on the distribution of Rickettsia spp. in their natural hosts in Central Asia are incomplete. Rodents and small mammals are potential natural reservoirs for Rickettsiae in their natural lifecycle. Studies about the maintenance of Rickettsia in wild animals are available for Western nations, but-to our knowledge-no studies and data are available in the Republic of Kazakhstan so far. The first case description of Rickettsioses in Kazakhstan was made in the 1950ies in the Almaty region and now Kyzylorda, East Kazakhstan, Pavlodar and North Kazakhstan are endemic areas. The existence of murine and endemic typhus was proven in arthropod vectors in the regions Kyzylorda and Almaty. Here we show for the first time investigations on tick-borne Rickettsia species detected by a pan-rickettsial citrate synthase gene (gltA) real-time PCR in ear lobes of small mammals (n = 624) in Kazakhstan. From all analysed small mammals 2.72% were positive for Rickettsia raoultii, R. slovaca or R. conorii. Sequencing of the rickettsial gene OmpAIV and the 23S-5S interspacer region revealed a similar heritage of identified Rickettsia species that was observed in ticks in previous studies from the region. In summary, this study proves that rodents in Kazakhstan serve as a natural reservoir of Rickettsia spp.


Assuntos
Rickettsia , Rickettsiose do Grupo da Febre Maculosa , Carrapatos , Animais , Incidência , Cazaquistão/epidemiologia , Mamíferos/microbiologia , Camundongos , Rickettsia/genética , Rickettsiales , Roedores , Rickettsiose do Grupo da Febre Maculosa/epidemiologia , Rickettsiose do Grupo da Febre Maculosa/microbiologia , Carrapatos/microbiologia
3.
Cell Death Differ ; 22(11): 1803-11, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25857265

RESUMO

The receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD/CRADD) functions as a dual adaptor and is a constituent of different multi-protein complexes implicated in the regulation of inflammation and cell death. Within the PIDDosome complex, RAIDD connects the cell death-related protease, Caspase-2, with the p53-induced protein with a death domain 1 (PIDD1). As such, RAIDD has been implicated in DNA-damage-induced apoptosis as well as in tumorigenesis. As loss of Caspase-2 leads to an acceleration of tumor onset in the Eµ-Myc mouse lymphoma model, whereas loss of Pidd1 actually delays onset of this disease, we set out to interrogate the role of Raidd in cancer in more detail. Our data obtained analyzing Eµ-Myc/Raidd(-/-) mice indicate that Raidd is unable to protect from c-Myc-driven lymphomagenesis. Similarly, we failed to observe a modulatory effect of Raidd deficiency on DNA-damage-driven cancer. The role of Caspase-2 as a tumor suppressor and that of Pidd1 as a tumor promoter can therefore be uncoupled from their ability to interact with the Raidd scaffold, pointing toward the existence of alternative signaling modules engaging these two proteins in this context.


Assuntos
Proteína Adaptadora de Sinalização CRADD/metabolismo , Caspase 2/metabolismo , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Proteína Adaptadora de Sinalização CRADD/genética , Caspase 2/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética
4.
Oncogene ; 33(44): 5221-4, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-24213575

RESUMO

The antiapoptotic BCL-2 protein MCL-1, which opposes mitochondrial outer membrane permeabilization, was shown to have a crucial role in the survival of hematopoietic cells. We have previously shown that, upon loss of phosphatidylinositol 3-kinase signaling, S159 of MCL-1 is phosphorylated by glycogen synthase kinase-3 (GSK-3), earmarking MCL-1 for enhanced ubiquitylation and degradation. In this study, we introduced MCL-1(wt) or the phosphorylation-deficient mutant MCL-1(S159A) in mouse BM cells, followed by adoptive transfer to recipient mice. Mice expressing MCL-1(S159A) exhibited significantly elevated white blood cell and lymphocyte counts, whereas no effect was observed on the distribution of T and B lymphocyte subsets or the numbers of monocytes, red blood cells or platelets. Expression of MCL-1(S159A) in Eµ-Myc transgenic bone marrow significantly accelerated the onset of disease, and these mice displayed increased spleen weights compared with Eµ-Myc/MCL-1(wt) mice. Our data demonstrate that the absence of MCL-1 S159 phosphorylation provides a survival advantage for hematopoietic cells in vivo and facilitates oncogenesis.


Assuntos
Leucócitos/metabolismo , Linfoma/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Animais , Transplante de Medula Óssea , Sobrevivência Celular , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Leucócitos/patologia , Linfonodos/citologia , Linfoma/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Fosforilação , Baço/citologia
5.
Cell Death Dis ; 4: e942, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24309929

RESUMO

Much effort has been put in the discovery of ways to selectively kill p53-deficient tumor cells and targeting cell cycle checkpoint pathways has revealed promising candidates. Studies in zebrafish and human cell lines suggested that the DNA damage response kinase, checkpoint kinase 1 (Chk1), not only regulates onset of mitosis but also cell death in response to DNA damage in the absence of p53. This effect reportedly relies on ataxia telangiectasia mutated (ATM)-dependent and PIDDosome-mediated activation of Caspase-2. However, we show that genetic ablation of PIDDosome components in mice does not affect cell death in response to γ-irradiation. Furthermore, Chk1 inhibition largely failed to sensitize normal and malignant cells from p53(-/-) mice toward DNA damaging agents, and p53 status did not affect the death-inducing activity of DNA damage after Chk1 inhibition in human cancer cells. These observations argue against cross-species conservation of a Chk1-controlled cell survival pathway demanding further investigation of the molecular machinery responsible for cell death elicited by forced mitotic entry in the presence of DNA damage in different cell types and model organisms.


Assuntos
Caspase 2/metabolismo , Dano ao DNA/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Caspase 2/genética , Ciclo Celular/genética , Ciclo Celular/fisiologia , Dano ao DNA/genética , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Immunoblotting , Camundongos , Camundongos Endogâmicos C57BL , Mitose/genética , Mitose/fisiologia , Proteína Supressora de Tumor p53/genética
6.
Cell Death Differ ; 20(4): 546-57, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23238565

RESUMO

Activation of NF-κB (nuclear factor of kappa light chain gene enhancer in B cells) in response to DNA damage is considered to contribute to repair of genetic lesions, increased cell survival and cytokine release. The molecular mechanisms orchestrating this cytoplasmic event involve core components of the nuclear DNA damage response machinery, including ATM-kinase (ataxia telangiectasia mutated kinase) and PARP-1 (poly (ADP-ribose) polymerase 1). The physiological consequences of defective NF-κB activation in this context, however, remain poorly investigated. Here we report on the role of the 'p53-induced protein with a death domain', PIDD, which appears rate limiting in this process, as is PARP-1. Despite impaired NF-κB activation, DNA damage did not increase cell death or reduce clonal survival of various cell types lacking PIDD, such as mouse embryonic fibroblasts or stem and progenitor cells of the hematopoietic system. Furthermore, lymphomagenesis induced by γ-irradiation (IR) was unaffected by deficiency for PIDD or PARP-1, indicating that loss of DNA damage-triggered NF-κB signalling does not affect IR-driven tumorigenesis. However, loss of either gene compromised cytokine release after acute IR injury. Hence, we propose that NF-κB's most notable function after DNA damage in primary cells is related to the release of cytokines, thereby contributing to sterile inflammation.


Assuntos
Citocinas/metabolismo , Dano ao DNA , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , NF-kappa B/metabolismo , Animais , Apoptose/efeitos da radiação , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos da radiação , Células Cultivadas , Dano ao DNA/efeitos da radiação , Proteínas de Ligação a DNA/metabolismo , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Fator Estimulador de Colônias de Granulócitos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Camundongos , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Radiação Ionizante , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Transcrição Gênica , Proteínas Supressoras de Tumor/metabolismo
7.
Cell Death Differ ; 19(10): 1722-32, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22595758

RESUMO

The PIDDosome, a multiprotein complex constituted of the 'p53-induced protein with a death domain (PIDD), 'receptor-interacting protein (RIP)-associated ICH-1/CED-3 homologous protein with a death domain' (RAIDD) and pro-Caspase-2 has been defined as an activating platform for this apoptosis-related protease. PIDD has been implicated in p53-mediated cell death in response to DNA damage but also in DNA repair and nuclear factor kappa-light-chain enhancer (NF-κB) activation upon genotoxic stress, together with RIP-1 kinase and Nemo/IKKγ. As all these cellular responses are critical for tumor suppression and deregulated expression of individual PIDDosome components has been noted in human cancer, we investigated their role in oncogenesis induced by DNA damage or oncogenic stress in gene-ablated mice. We observed that Pidd or Caspase-2 failed to suppress lymphoma formation triggered by γ-irradiation or 3-methylcholanthrene-driven fibrosarcoma development. In contrast, Caspase-2 showed tumor suppressive capacity in response to aberrant c-Myc expression, which did not rely on PIDD, the BH3-only protein Bid (BH3 interacting domain death agonist) or the death receptor ligand Trail (TNF-related apoptosis-inducing ligand), but associated with reduced rates of p53 loss and increased extranodal dissemination of tumor cells. In contrast, Pidd deficiency associated with abnormal M-phase progression and delayed disease onset, indicating that both proteins are differentially engaged upon oncogenic stress triggered by c-Myc, leading to opposing effects on tumor-free survival.


Assuntos
Proteína Adaptadora de Sinalização CRADD/metabolismo , Caspase 2/metabolismo , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Proteína Adaptadora de Sinalização CRADD/antagonistas & inibidores , Proteína Adaptadora de Sinalização CRADD/genética , Caspase 2/deficiência , Caspase 2/genética , Linhagem Celular , Dano ao DNA , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/antagonistas & inibidores , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Proteínas Ativadoras de GTPase/metabolismo , Raios gama , Células HCT116 , Humanos , Quinase I-kappa B/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metilcolantreno/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína Supressora de Tumor p53/metabolismo
8.
Oncogene ; 31(45): 4733-9, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-22266869

RESUMO

P53-induced protein with a death domain (PIDD) has been described as primary p53 target gene, induced upon DNA damage. More than 10 years after its discovery, its physiological role in the DNA damage response remains enigmatic, as it seems to be able to execute life-death decisions in vitro, yet genetic ablation in mice failed to reveal an obvious phenotype. Nonetheless, evidence is accumulating that it contributes to the fine-tuning of the DNA-damage response by orchestrating critical processes such as caspase activation or nuclear factor κB translocation and can also exert additional nuclear functions, for example, the modulation of translesion synthesis. In this review, we aim to integrate these observations and propose possible unexplored functions of PIDD.


Assuntos
Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Processamento Alternativo , Animais , Apoptose , Caspase 2/metabolismo , Sobrevivência Celular , Reparo do DNA , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática , Humanos , NF-kappa B/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Ligação Proteica , Isoformas de Proteínas/genética , Proteólise , Proteína Supressora de Tumor p53/genética
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