MTOC FUNCTION
Microtubule organizing centers and microtubule nucleation in mitosis
| Coordinatore | FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Organization address
address: CARRER BALDIRI REIXAC 10-12 PARC SCIENTIFIC DE BARCELONA contact info |
| Nazionalità Coordinatore | Spain [ES] |
| Totale costo | 100˙000 € |
| EC contributo | 100˙000 € |
| Programma | FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) |
| Code Call | FP7-PEOPLE-2007-4-3-IRG |
| Funding Scheme | MC-IRG |
| Anno di inizio | 2008 |
| Periodo (anno-mese-giorno) | 2008-07-21 - 2012-07-20 |
Partecipanti
| # | ||||
|---|---|---|---|---|
| 1 |
FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Organization address
address: CARRER BALDIRI REIXAC 10-12 PARC SCIENTIFIC DE BARCELONA contact info |
ES (BARCELONA) | coordinator | 0.00 |
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Obiettivo del progetto (Objective)
'Centrosomes are multifunctional organelles crucial for a large number of cellular functions including the organization of microtubules. In mitosis centrosomes contribute to assembly, orientation and function of the mitotic spindle, which is important for proper segregation of the chromosomes. Defects in centrosome number and function are strongly associated with the cancer phenotype and centrosomes offer potential new targets for anti-mitotic cancer drugs. Recent data suggests that microtubule organization at centrosomes also has implications for aspects of cellular differentiation, and that several human genetic diseases can be linked to centrosome malfunction. The characterization of proteins required for the function of the centrosome as a microtubule organizing center (MTOC) might reveal how structural and functional centrosome aberrations affect genomic stability and cancer development as well as developmental processes. I will study a key component of the centrosome and other MTOCs, the gamma-tubulin complex, and identify and characterize additional centrosome proteins involved in microtubule organization. I propose to: 1) analyze the mitosis-specific function and regulation of gamma-tubulin and associated proteins, 2) reconstitute the centrosomal attachment and function of the gamma-tubulin complex in a purified system in vitro, and 3) test proteins of the centrosome proteome for localization to a non-centrosomal microtubule organizing center, to identify and characterize those centrosome proteins specifically involved in microtubule organization.'
Introduzione (Teaser)
Understanding the molecular basis of microtubule polymerisation and organisation is uncovering potential targets for anti-mitotic cancer drugs.
Descrizione progetto (Article)
Accurate chromosome segregation strongly depends upon correct microtubule organisation in mitosis by centrosomal and acentrosomal microtubule organising centres (MTOCs). Malfunctions in the formation and regulation of MTOCs are strongly associated with cancer development. Consequently, centrosomes and proteins involved are putative targets for anti-mitotic cancer drugs. Despite these observations, the molecular details of the function of MTOCs are still poorly understood.
The EU project 'Microtubule organizing centres and microtubule nucleation in mitosis' (MTOC Function) is focusing on the study of the key component of MTOCs, the cytoplasmic tubulin ring complex (TuRC). The primary goal is to better understand how MTOCs are formed and regulated, and how they contribute to proper microtubule organisation. The answer to these questions will enlighten the molecular basis of defects that lead to the cancer phenotype.
MTOC Function researchers utilised a multidisciplinary approach combining molecular biology, biochemistry and mass spectrometry-based proteomics. Protein mapping and comparative analysis of whole protein mixtures from non-synchronised and mitotic human cells were performed. These analyses characterised the composition and the interacting proteins of TuRC.
Novel, core and transient subunits of TuRCs were identified associated with specific cell phases, such as the GCP8/MOZART2 (interphase and mitosis), and the augmin complex (mitosis). Further targeted studies on these proteins shed more light on their function in the organisation and regulation of the microtubule network.
The results are being used to develop a proposed model in which the formation of mitotic centrosomes is regulated by multiple protein phosphorylation events by mitotic kinase polo-like kinase 1 (Plk1).
In addition, preliminary results as well as published data, showed an interplay of centrosomal and acentrosomal microtubule nucleation, which is currently under deeper investigation.
Project work has established the basic tools and knowledge for detailed analyses of the roles of proteins involved in microtubule organisation, in both interphase and mitosis. Such investigation will provide valuable insights into the molecular basis of the cancer phenotype and possibly several other human diseases (e.g. Parkinson's and Alzheimer's).