RESUMO
The mitotic spindle is a self-organizing structure that is constructed primarily from microtubules. Among the most important spindle microtubules are those that bind to kinetochores and form the fibers along which chromosomes move. Chemotherapeutics such as taxol and the vinca alkaloids perturb kinetochore-microtubule attachment and disrupt chromosome segregation. This activates a checkpoint pathway that delays cell cycle progression and induces programmed cell death. Recent work has identified at least four mammalian spindle assembly checkpoint proteins.
Assuntos
Apoptose/fisiologia , Divisão Celular/fisiologia , Microtúbulos/fisiologia , Aneuploidia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Microtúbulos/efeitos dos fármacos , Modelos Biológicos , Fuso Acromático/fisiologiaRESUMO
The B cell activating factor BAFF (BlyS/TALL-1/zTNF4) is a tumor necrosis factor (TNF)-related ligand that promotes B cell survival and binds to three receptors (BCMA, TACI, and the recently described BAFF-R). Here we report an absolute requirement for BAFF in normal B cell development. Examination of secondary lymphoid organs from BAFF-deficient mice revealed an almost complete loss of follicular and marginal zone B lymphocytes. In contrast, mice lacking BCMA had normal-appearing B lymphocyte compartments. BAFF therefore plays a crucial role in B cell development and can function through receptors other than BCMA.
Assuntos
Linfócitos B/fisiologia , Proteínas de Membrana/fisiologia , Receptores do Fator de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Antígenos CD/análise , Fator Ativador de Células B , Antígeno de Maturação de Linfócitos B , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/fisiologia , Linfócitos B/citologia , Linfócitos B/imunologia , Células da Medula Óssea/citologia , Separação Celular , Sobrevivência Celular , Citometria de Fluxo , Imunoglobulinas/sangue , Leucopoese , Linfonodos/citologia , Linfonodos/imunologia , Contagem de Linfócitos , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos A , Camundongos Knockout , Fenótipo , Receptores do Fator de Necrose Tumoral/deficiência , Receptores do Fator de Necrose Tumoral/genética , Transdução de Sinais , Baço/citologia , Baço/imunologia , Timo/citologia , Timo/imunologia , Fator de Necrose Tumoral alfa/deficiência , Fator de Necrose Tumoral alfa/genéticaRESUMO
The initiation of chromosome segregation at anaphase is linked by the spindle assembly checkpoint to the completion of chromosome-microtubule attachment during metaphase. To determine the function of the mitotic checkpoint protein Mad2 during normal cell division and when mitosis goes awry, we have knocked out Mad2 in mice. We find that E5.5 embryonic cells lacking Mad2, like mad2 yeast, grow normally but are unable to arrest in response to spindle disruption. At E6.5, the cells of the epiblast begin rapid cell division and the absence of a checkpoint results in widespread chromosome missegregation and apoptosis. In contrast, the postmitotic trophoblast giant cells survive without Mad2. Thus, the spindle assembly checkpoint is required for accurate chromosome segregation in mitotic mouse cells, and for embryonic viability, even in the absence of spindle damage.
Assuntos
Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas de Transporte , Segregação de Cromossomos , Proteínas Fúngicas/genética , Sequência de Aminoácidos , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ciclo Celular , Proteínas Fúngicas/metabolismo , Regulação da Expressão Gênica , Proteínas Mad2 , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Proteínas Nucleares , Homologia de Sequência de AminoácidosRESUMO
The mitotic checkpoint protein hsMad2 is required to arrest cells in mitosis when chromosomes are unattached to the mitotic spindle. The presence of a single, lagging chromosome is sufficient to activate the checkpoint, producing a delay at the metaphase-anaphase transition until the last spindle attachment is made. Complete loss of the mitotic checkpoint results in embryonic lethality owing to chromosome mis-segregation in various organisms. Whether partial loss of checkpoint control leads to more subtle rates of chromosome instability compatible with cell viability remains unknown. Here we report that deletion of one MAD2 allele results in a defective mitotic checkpoint in both human cancer cells and murine primary embryonic fibroblasts. Checkpoint-defective cells show premature sister-chromatid separation in the presence of spindle inhibitors and an elevated rate of chromosome mis-segregation events in the absence of these agents. Furthermore, Mad2+/- mice develop lung tumours at high rates after long latencies, implicating defects in the mitotic checkpoint in tumorigenesis.