Wednesday 29 October 2003
The centrosome is an indispensable component of the cell-cycle machinery of eukaryotic cells, and the perturbation of core centrosomal or centrosome-associated proteins is linked to cell-cycle misregulation and cancer. Named for its location near the cell centre, the centrosome, first described by Theodor Boveri in the early 1900s.
Initially considered simply as a microtubule organizing centre (MTOC), the centrosome is now known to have a key structural and/or functional role in many cellular processes and is found at the centre of diverse human pathologies
The long-recognized microtubule organizing capabilities (MTOC) of the centrosome are not limited to the accurate segregation of chromosomes, or the proper localization of the plane of cell division. The centrosome is a microtubule organizing centre (MTOC) in a broader sense, which is involved in the organization of intracellular transport and the spatial organization of not only proteins and processes, but also cellular organelles.
Most microtubule arrays in animal cells, including the bipolar spindle required for cell division, are organized by centrosomes. Thus, strict control of centrosome numbers is crucial for accurate chromosome segregation. Each centrosome comprises two centrioles, which need to be duplicated exactly once in every cell cycle.
Centrosome can be recognized under a light microscope as a densely staining structure that is adjacent to the eukaryotic nucleus, and comprises two centrioles that are surrounded by an amorphous, proteinaceous matrix termed the pericentriolar material.
The centrosome consists of two centrioles, each comprising nine microtubule triplets that form a barrel-shaped structure that is approximately 0.5 m long and 0.2 m in diameter. The centrioles are arranged perpendicularly to one another and are in close proximity, tethered by interconnecting fibres and surrounded by the pericentriolar material (PCM), which is a highly-ordered, dense matrix and is the site of cytoplasmic microtubule organization.
Proteins such as ninein and centriolin are involved in microtubule anchoring, whereas gamma-tubulin, pericentrins PCTN1 and PCTN2, polo and aurora kinases are thought to nucleate microtubules. Microtubule-severing proteins such as katanin are responsible for releasing microtubules into the cytoplasm. Pericentrin and ninein are transported towards the pericentriolar region through a microtubule-dependent mechanism.
Pericentriolar material 1 (PCM1) and its associated cargo (pericentrin, centrin and ninein) comprise the pericentriolar satellites and are recruited to the PCM in a dynein-dependent fashion through the activity of Bardet-Biedl syndrome 4 protein (BBS4) and its binding to p150Glued.
Other proteins, such as gamma-tubulin and centriolin, are transported to the PCM in a microtubule-independent manner.
The vertebrate centrosome is a highly organized organelle which serves, among other functions, as the cell microtubule organizing centre (MTOC). For this purpose, several proteins participate in the nucleation (gamma-tubulin, pericentrin, polo kinases, aurora kinases), anchoring (ninein, centriolin, dynactin) and release (katanin) of microtubules from the centrosome.
Cell cycle and mitosis
Historically, most centrosomal research has focused on the function of the centrosome as the MTOC and its pivotal role in regulating cell division in meiotic and mitotic cells. During interphase, microtubules are organized in astral arrays that radiate from the centrosome, and function as a scaffold to direct organelle and vesicle trafficking.
During mitosis, the centrosome mediates assembly and organization of the mitotic spindle that is required for correct chromosome segregation, although the centrosome is not essential for this function. Consistent with this role, centriole duplication is coordinated with the cell cycle.
Centrosome serves as a scaffold for anchoring an extensive number of regulatory proteins. Among these are cell-cycle regulators whose association with the centrosome is an essential step in cell-cycle control. The centrosome is required for several cell-cycle transitions, including G(1) to S-phase, G(2) to mitosis and metaphase to anaphase.
spatial organization of cellular organelles
The centrosome participates in regulating the spatial organization of cellular organelles such as the Golgi apparatus. Proteomic analysis of the centrosome identified a number of proteins that, when mutated, cause diverse human genetic phenotypes that have no overt link to cell-cycle defects, such as Alstrom syndrome and orofacioduigiral syndromes.
One molecular process that appears to be highly dependent on the organizing capabilities of the centrosome is the ubiquitin-proteasome degradation (UPD) pathway. This is not surprising, given the importance of UPD in regulating cell-cycle checkpoints in eukaryotes through the specific targeting of cell-cycle regulators.
However, in addition to mediating cyclin degradation as part of the cell-cycle regulatory mechanism, UPD is also crucial for regulating other cellular processes that include, but are not limited to, cellular differentiation and development, the stress response, the morphogenesis of neuronal networks, neurotransmission and apoptosis.
mportantly, although proteasome activity can be found throughout the cytosol, proteasomes are invariably concentrated at the mammalian centrosome, an observation that has led to the description of the centrosome as a proteolytic centre.
Although found in different subcellular locations, proteasomal components such as ubiquitin, the 20S and 19S subunits of the proteasome, as well as the E3 enzyme parkin, are concentrated in the centrosomal region and co-localize with the known centrosomal marker gamma-tubulin.
Furthermore, these various proteasomal components co-purify with -tubulin in the centrosomal fractions after sucrose-gradient ultracentrifugation27. Furthermore, when intracellular levels of misfolded proteins are high (that is, upon proteasome inhibition with drugs such as lactacystin, or the overexpression of misfolded mutant proteins), the centrosome-associated proteasome network expands, recruiting additional proteolytic machinery from the cytosol in a microtubule-independent manner; all the above evidence indicates that the centrosome has a crucial role in the organization and subcellular localization of proteasomes.
Centrosomal dysfunction is involved in several human diseases that are caused by cell-cycle misregulation, protein-clearance defects, cell-migration perturbations and impaired microtubule-based intracellular transport.
Abnormalities in centrosome number, size and morphology have been observed in nearly all human tumour types, including breast, colon, liver, bone marrow, cervical and prostate.
Loss of p53 or retinoblastoma tumour-suppressor protein (Rb) results in centrosome amplification in mammals, as does deficiency of the breast cancer gene BRCA1 and the overexpression of aurora-A in transiently transfected cultured cells, and other mitotic kinases that are implicated in cancer progression.
Centrosome amplification might arise from cytokinesis defects or misregulation of the duplication process and can result in chromsomal instability.
Infection with ’high-risk’ human papillomavirus (HPV) types, such as HPV16 and HPV18, is associated with more than 90% of cervical cancer cases. The E6 and E7 oncoproteins of HPV16 induce mitotic defects by uncoupling centrosome duplication from the cell cycle, whereas the E6 and E7 proteins of low-risk HPV6 do not induce chromosomal abnormalities and are not typically associated with malignancy.
Centrosome has a role in a number of functions. The centrosome and basal body are required for reproduction, and their perturbation is likely to affect fertility.
The association of the lissencephaly 1 protein (LIS1) with dynactins (DCTNs) is required for nuclear motility and genomic union in the mammalian fertilized oocyte, and the sperm basal body facilitates organization of the maternal components of the egg after fertilization.
Centrins have a role in centriole duplication and in sperm centriole activation and deactivation during sexual reproduction131, and ubiquitin-dependent proteolysis is important in mammalian spermatogenesis, fertilization and sperm quality control.
As such, it is reasonable to anticipate that some cases of male infertility will be attributed to centrosomal dysfunction.
The centrosome is likely to be implicated in autoimmunity.
Several proteins in the mitotic spindle apparatus, including the core centrosomal protein NUMA1 (nuclear mitotic apparatus protein), are the targets of autoimmune sera from patients and centrosomal proteins such as pericentriolar material 1 (PCM1) were first identified using autoimmune serum.
Perhaps most interesting, mutations in nucleoside phosphorylase (NP ), a centriolar and basal body protein, result in severe combined immunodeficiency.
Centrosomal proteins are involved in the organization of the Golgi apparatus through interactions with Golgi-resident proteins, such as trans-golgi network protein 2 (TGN38) and Golgi autoantigen a l (GOLGA1 or golgin-famili A1 among GOLGAs).
Although no diseases related to mislocalization of the Golgi are known to date, it is possible that this will emerge as another mechanism of disease.
Plk4 (also called Sak), a member of the Polo kinase family, has been identified as a novel positive regulator of centriole formation.
Chromosome instability, which is equated to mitotic defects and consequential chromosome segregation errors, provides a formidable basis for the acquisition of further malignant phenotypes during tumour progression.
Centrosomes have a crucial role in the formation of bipolar mitotic spindles, which are essential for accurate chromosome segregation.
Mutations of certain oncogenic and tumour-suppressor proteins directly induce chromosome instability by disrupting the normal function and numeral integrity of centrosomes.
- ubiquitin-proteasome-mediated protein degradation
- neuronal migration
- axonal targeting
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