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Centrosome
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- 4. Centrosome’s Function • Nucleateand organize microtubules • Conductors of interphase processes o Cell polarity o Organization of immunologic synapse o Cell locomotion (movement) o Mitosis conductors (cell division) o Assembly of mitotic spindle • Responsible for equal dividing of the replicated genome into daughter cells
- 5. Centrosome Dysfunction • Centrosomedysfunction o Linked to chromosome and aneuploidy instability (the presence of an unexpected number of chromosomes,45 or 47, not the normal 46) • These are both hall markers of cancer • Recent work has suggested: o Chromosomes that were separated incorrectly may experience: • Chromosomes can experience extensive DNA damage • Tumors due with extensive structural rearrangements in their genome and reshuffling of the chromosome domain are particularly prevalent when centrosome dysfunction is present o This is thought to occur at the level signaling cell division and strongly correlates to aberrant proliferation—tumors • Ongoing gene shuffling: o Encourages evasion of the immune system, continuous growth, and survival
- 6. Centrosome Therapy • Thisorganelle presents a target for anti-cancer therapy • Therapeutic intervention targets in regards to cancer o Manipulation of networks of molecules that control the centrosome function • Normal cells may be spared during targeted treatments o Centrosome-associated regulators of the G2/M checkpoint • This checkpoint stops mitosis from occurring if the DNA is found damaged—if irreparable the cell is supposed to undergo apoptosis. • Alteration of this cell-cycle control is a hall mark of cancer making it a potential target for study.
- 7. References Charts and Diagrams.2015. Diagram of a Centrosome Canvas Print. Retrieved on 4 October 2015 from: http://www.zazzle.com/diagram_of_a_centrosome_canvas_print-192559813004413576 Biology Discussion. 2013. Centrosome: Useful notes on Centrosome. Retrieved on 2 October 2015 from: http://www.biologydiscussion.com/centrosome/centrosome-useful-notes-on-centrosome-biology/763 Department of Pathology and Laboratory Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA. Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer. 12 November 2013. Retrieved on 4 Oct 2015 from: http://www.ncbi.nlm.nih.gov/pubmed/24282781 Front Yard Landscaping Ideas. 24 November 2014. What is the centrosome Diagram? Retrieved on 4 October 2015 from http://thegreatestgarden.com/what-is-centrosome-diagram/ Mazzorana M, Montoya G, Mortuza GB. Macromolecular Crystallography Group, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. The centrosome: a target for cancer therapy. 2011. Retrieved on 4 Oct 2015 from http://www.ncbi.nlm.nih.gov/pubmed/21486219 W.H. Freemand and Company. 2000. Aneuploidy. Retrieved on 4 October 2015 from http://www.ncbi.nlm.nih.gov/books/NBK21870/ Yingmei Wang, Ping Ji, Jinsong Liu, Russell R Braddus, Fenxia Xue, Wei Zhang. 2009. Centrosome-associated regulators of the G2/M checkpoint as targets for cancer therapy. Retrieved on 4 October 2015 from http://www.molecular-cancer.com/content/8/1/8
Editor's Notes
- #2 Front Yard Landscaping Ideas. 24 November 2014. What is the centrosome Diagram? Retrieved on 4 October 2015 from http://thegreatestgarden.com/what-is-centrosome-diagram/
- #3 Charts and Diagrams. 2015. Diagram of a Centrosome Canvas Print. Retrieved on 4 October 2015 from: http://www.zazzle.com/diagram_of_a_centrosome_canvas_print-192559813004413576
- #4 Biology Discussion. 2013. Centrosome: Useful notes on Centrosome. Retrieved on 2 October 2015 from: http://www.biologydiscussion.com/centrosome/centrosome-useful-notes-on-centrosome-biology/763
- #5 “The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered (Harvard, 2013).“ Department of Pathology and Laboratory Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA. Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer. 12 November 2013. Retrieved on 4 Oct 2015 from: http://www.ncbi.nlm.nih.gov/pubmed/24282781
- #6 “Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegregated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies (Harvard, 2013).” Department of Pathology and Laboratory Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA. Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer. 12 November 2013. Retrieved on 4 Oct 2015 from: http://www.ncbi.nlm.nih.gov/pubmed/24282781 Mazzorana M, Montoya G, Mortuza GB. Macromolecular Crystallography Group, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. The centrosome: a target for cancer therapy. 2011. Retrieved on 4 Oct 2015 from http://www.ncbi.nlm.nih.gov/pubmed/21486219 W.H. Freemand and Company. 2000. Aneuploidy. Retrieved on 4 October 2015 from http://www.ncbi.nlm.nih.gov/books/NBK21870/
- #7 Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies (Harvard, 2013).” “The centrosome plays an essential role in cell cycle progression and cell polarity, organizing the microtubule network in interphase and mitosis. During cell division, the centrosome undergoes a series of structural and functional transitions and forms the two poles of the bipolar mitotic spindle. It is the microtubule cytoskeleton that is reorganized to form the two poles, ensuring accurate separation of the two daughter cells. To achieve this a large number of signalling proteins located at the centrosome, undergo precise time-dependent modulation. Protein kinases such as Aurora A, Polo and Neks, trigger and regulate events such as centrosome duplication, maturation and division. These enzymes are also involved in recruiting other proteins in cell division, thus they are likely to mediate the crosstalk between the cell and the centrosome cycle. In its function of microtubule organization, macromolecular complexes also have an important role. Tubulin polymerization confers the structural backbone to cell division, while other proteins may interact with it and/or mediate its recruitment to the centrosome. The interactions of these components regulate centrosome maturation and microtubule growth, essential mechanisms for cell division. Furthermore, dysregulation of this organelle, both at the level of signalling or as a structural element strongly correlates to aberrant proliferation, and the onset of tumours. Therefore, the centrosome represents an attractive target for anti-cancer therapy. Here we review the most important centrosomal proteins and their therapeutic potential. In addition, we summarize the current strategies of intervention and report the present stage of anti-cancer drug development targeting the centrosome (Mazzorana, 2011).” Mazzorana M, Montoya G, Mortuza GB. Macromolecular Crystallography Group, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. The centrosome: a target for cancer therapy. 2011. Retrieved on 4 Oct 2015 from http://www.ncbi.nlm.nih.gov/pubmed/21486219 Department of Pathology and Laboratory Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA. Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer. 12 November 2013. Retrieved on 4 Oct 2015 from: http://www.ncbi.nlm.nih.gov/pubmed/24282781 Yingmei Wang, Ping Ji, Jinsong Liu, Russell R Braddus, Fenxia Xue, Wei Zhang. 2009. Centrosome-associated regulators of the G2/M checkpoint as targets for cancer therapy. Retrieved on 4 October 2015 from http://www.molecular-cancer.com/content/8/1/8
- #8 Charts and Diagrams. 2015. Diagram of a Centrosome Canvas Print. Retrieved on 4 October 2015 from: http://www.zazzle.com/diagram_of_a_centrosome_canvas_print-192559813004413576 Biology Discussion. 2013. Centrosome: Useful notes on Centrosome. Retrived on 2 October 2015 from: http://www.biologydiscussion.com/centrosome/centrosome-useful-notes-on-centrosome-biology/763 Department of Pathology and Laboratory Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA. Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer. 12 November 2013. Retrieved on 4 Oct 2015 from: http://www.ncbi.nlm.nih.gov/pubmed/24282781 Front Yard Landscaping Ideas. 24 November 2014. What is the centrosome Diagram? Retrieved on 4 October 2015 from http://thegreatestgarden.com/ what-is-centrosome-diagram/ Mazzorana M, Montoya G, Mortuza GB. Macromolecular Crystallography Group, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. The centrosome: a target for cancer therapy. 2011. Retrieved on 4 Oct 2015 from http://www.ncbi.nlm.nih.gov/pubmed/21486219 W.H. Freemand and Company. 2000. Aneuploidy. Retrieved on 4 October 2015 from http://www.ncbi.nlm.nih.gov/books/NBK21870/ Yingmei Wang, Ping Ji, Jinsong Liu, Russell R Braddus, Fenxia Xue, Wei Zhang. 2009. Centrosome-associated regulators of the G2/M checkpoint as targets for cancer therapy. Retrieved on 4 October 2015 from http://www.molecular-cancer.com/content/8/1/8