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Centrosomes mature as cells enter mitosis, accumulating gamma-tubulin and other pericentriolar material (PCM) components. This occurs concomitant with an increase in the number of centrosomally organized microtubules (MTs). Here, we use RNA-mediated interference (RNAi) to examine the role of the aurora-A kinase, AIR-1, during centrosome maturation in Caenorhabditis elegans. In air-1(RNAi) embryos, centrosomes separate normally, an event that occurs before maturation in C. elegans. After nuclear envelope breakdown, the separated centrosomes collapse together, and spindle assembly fails. In mitotic air-1(RNAi) embryos, centrosomal alpha-tubulin fluorescence intensity accumulates to only 40% of wild-type levels, suggesting a defect in the maturation process. Consistent with this hypothesis, we find that AIR-1 is required for the increase in centrosomal gamma-tubulin and two other PCM components, ZYG-9 and CeGrip, as embryos enter mitosis. Furthermore, the AIR-1-dependent increase in centrosomal gamma-tubulin does not require MTs. These results suggest that aurora-A kinases are required to execute a MT-independent pathway for the recruitment of PCM during centrosome maturation.
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PMID:Aurora-A kinase is required for centrosome maturation in Caenorhabditis elegans. 1174 51

The weak spindle integrity checkpoint in Drosophila spermatocytes has revealed a novel function of the gamma-tubulin ring complex (gammaTuRC) in maintaining spindle bipolarity throughout meiosis. Bipolar and bi-astral spindles could form in Drosophila mutants for dd4, the gene encoding the 91 kDa subunit of gammaTuRC. However, these spindles collapsed around metaphase and began to elongate as if attempting anaphase B. The microtubules of the collapsing spindle folded back on themselves, their putative plus ends forming the focused apexes of biconical figures. Cells with such spindles were unable to undergo cytokinesis. A second type of spindle, monopolar hemi-spindles, also formed as a result of either spindle collapse at an earlier stage or failure of centrosome separation. Multiple centrosome-like bodies at the foci of hemi-spindles nucleated robust asters of microtubules in the absence of detectable gamma-tubulin. Time-lapse imaging revealed these to be intermediates that developed into cones, structures that also had putative plus ends of microtubules focused at their tips. Unlike biconical figures, however, cones seemed to contain a central spindle-like structure at their apexes and undergo cytokinesis. We conclude that spermatocytes do not need astral microtubules nucleated by opposite poles to intersect in order to form a central spindle and a cleavage furrow.
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PMID:Drosophila dd4 mutants reveal that gammaTuRC is required to maintain juxtaposed half spindles in spermatocytes. 1257 Dec 90

Neurodegenerative disorders are characterized by progressive loss of specific neurons in the central nervous system. Although they have different etiologies and clinical manifestations, most of them share similar histopathologic characteristics such as the presence of inclusion bodies in both neurons and glial cells, which represent intracellular aggregation of misfolded or aberrant proteins. In Parkinson's disease, formation of inclusion bodies has been associated with the aggresome-related process and consequently with the centrosome. However, the significance of the centrosome in the neurodegenerative process remains obscure. In the present study, the morphological and functional changes in the centrosome induced by rotenone, a common insecticide used to produce experimental Parkinsonism, were examined both in vitro and in vivo. Aggregation of gamma-tubulin protein, which is a component of the centrosome matrix and recently identified in Lewy bodies of Parkinson's disease, was observed in primary cultures of mesencephalic cells treated with rotenone. Rotenone-treated neurons and astrocytes showed enlarged and multiple centrosomes. These centrosomes also displayed multiple aggregates of alpha-synuclein protein. Neurons with disorganized centrosomes exhibited neurite retraction and microtubule destabilization, and astrocytes showed disturbances of mitotic spindles. The Golgi apparatus, which is closely related to the centrosome, was dispersed in both rotenone-treated neuronal cells and the substantia nigra of rotenone-treated rats. Our findings suggested that recruitment of abnormal proteins in the centrosome contributed to the formation of inclusion bodies, and that rotenone markedly affected the structure and function of the centrosome with consequent induction of cytoskeleton disturbances, disassembly of the Golgi apparatus and collapse of neuronal cells.
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PMID:Rotenone induces aggregation of gamma-tubulin protein and subsequent disorganization of the centrosome: relevance to formation of inclusion bodies and neurodegeneration. 1589 36

The centrosome is the major organelle responsible for the nucleation and organization of microtubules into arrays. Recent studies demonstrate that microtubules can nucleate outside the centrosome. The molecular mechanisms controlling acentrosomal microtubule nucleation are currently poorly defined, and the function of this type of microtubule regulation in tumor cell biology is particularly unclear. Since microtubule nucleation is initiated by the gamma-tubulin protein, we examined the regulation of gamma-tubulin in a panel of human breast tumor cell lines, ranging from non-tumorigenic to highly aggressive. We have identified a more dispersive subcellular localization of gamma-tubulin in aggressive breast cancer cell lines, while gamma-tubulin localization remains largely centrosomal in non-aggressive cell lines. Delocalization of gamma-tubulin occurs independently from changes in protein expression and is therefore regulated at the post-translational level. Subcellular fractionation revealed that tumor cell lines show an aberrantly increased release of gamma-tubulin into a soluble cytoplasmic fraction, with the most dramatic changes observed in tumor cell lines of greater aggressiveness. Extraction of soluble gamma-tubulin revealed acentrosomal incorporation of gamma-tubulin in cytoplasmic microtubules and along cell junctions. Moreover, acentrosomal delocalization of gamma-tubulin yielded resistance to colchicine-mediated microtubule collapse. These findings support a model where the solubility of gamma-tubulin can be altered through post-translational modification and provides a new mechanism for microtubule dysregulation in breast cancer. Gamma-tubulin that is delocalized from the centrosome can still clearly be incorporated into filaments, and defines a novel mechanism for tumor cells to develop resistance to microtubule-targeted chemotherapies.
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PMID:Delocalization of gamma-tubulin due to increased solubility in human breast cancer cell lines. 2000 67