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[[Centrosome]]s are the major [[microtubule organizing center]]<nowiki/>s (MTOC) in mammalian cells.<ref name="Meraldi">{{cite journal|last=Meraldi|first=P|author2=Nigg, E.A.|title=The centrosome cycle|journal=FEBS Letters|date=23 April 2002|volume=521|pages=9–13|doi=10.1016/S0014-5793(02)02865-X|pmid=12067716|issue=1–3}}</ref> Failure of centrosome regulation can cause mistakes in chromosome segregation and is associated with [[aneuploidy]]. A centrosome is composed of two orthogonal cylindrical proteins, called [[centriole]]s, which are surrounded by an electron and protein dense amorphous cloud of [[pericentriolar material]] (PCM).<ref name="Loncarek2009">{{cite journal|last=Loncarek|first=J.|author2=Khodjakov, A.|title=Ab ovo or de novo? Mechanisms of centriole duplication|journal=Mol Cells|date=February 2009|volume=27|issue=2|pages=135–142|doi=10.1007/s10059-009-0017-z|pmid=19277494|pmc=2691869}}</ref> The PCM is essential for nucleation and organization of microtubules.<ref name="Loncarek2009" /> The centrosome cycle is important to ensure that [[daughter cell]]s receive a centrosome after [[cell division]]. As the [[cell cycle]] progresses, the centrosome undergoes a series of morphological and functional changes. Initiation of the centrosome cycle occurs early in the cell cycle in order to have two centrosomes by the time [[mitosis]] occurs.
[[Centrosome]]s are the major [[microtubule organizing center]]<nowiki/>s (MTOC) in mammalian cells.<ref name="Meraldi">{{cite journal|last=Meraldi|first=P|author2=Nigg, E.A.|title=The centrosome cycle|journal=FEBS Letters|date=23 April 2002|volume=521|pages=9–13|doi=10.1016/S0014-5793(02)02865-X|pmid=12067716|issue=1–3}}</ref> Failure of centrosome regulation can cause mistakes in chromosome segregation and is associated with [[aneuploidy]]. A centrosome is composed of two orthogonal cylindrical proteins, called [[centriole]]s, which are surrounded by an electron and protein dense amorphous cloud of [[pericentriolar material]] (PCM).<ref name="Loncarek2009">{{cite journal|last=Loncarek|first=J.|author2=Khodjakov, A.|title=Ab ovo or de novo? Mechanisms of centriole duplication|journal=Mol Cells|date=February 2009|volume=27|issue=2|pages=135–142|doi=10.1007/s10059-009-0017-z|pmid=19277494|pmc=2691869}}</ref> The PCM is essential for nucleation and organization of microtubules.<ref name="Loncarek2009" /> The centrosome cycle is important to ensure that [[daughter cell]]s receive a centrosome after [[cell division]]. As the [[cell cycle]] progresses, the centrosome undergoes a series of morphological and functional changes. Initiation of the centrosome cycle occurs early in the cell cycle in order to have two centrosomes by the time [[mitosis]] occurs.


Since the centrosome organizes the microtubules of a cell, t has to do with the formation of the mitotic spindle, polarity and, therefore, cell shape, as well as all other processes having to do with the mitotic spindle. <ref name=":02">{{Cite journal|last=Meraldi|first=P|last2=Nigg|first2=E. A|date=2002-06-19|title=The centrosome cycle|url=http://www.sciencedirect.com/science/article/pii/S001457930202865X|journal=FEBS Letters|volume=521|issue=1|pages=9–13|doi=10.1016/S0014-5793(02)02865-X|issn=0014-5793}}</ref> The centriole is the inner core of the centrosome, and its conformation is typically somewhat like that of spokes on a wheel. It has a somewhat different conformation amount different organisms, but its overall structure is similar. Plants, on the other hand, do not typically have centrioles.<ref>{{Cite web|url=https://cshperspectives.cshlp.org/content/7/2/a015800.full|title=The Centrosome and its Duplications Cycle|last=Fu|first=Jingyan|date=2015|website=Cold Spring Harbor Perspectives in Biology|url-status=live|archive-url=|archive-date=|access-date=12/3/19}}</ref>


The centrosome cycle consists of four phases that are synchronized to the cell cycle. These include: centrosome duplication during the [[G1 phase]] and [[S Phase]], centrosome maturation in the [[G2 phase]], centrosome separation in the [[mitotic phase]], and centrosome disorientation in the late mitotic phase—G1 phase.
The centrosome cycle consists of four phases that are synchronized to the cell cycle. These include: centrosome duplication during the [[G1 phase]] and [[S Phase]], centrosome maturation in the [[G2 phase]], centrosome separation in the [[mitotic phase]], and centrosome disorientation in the late mitotic phase—G1 phase.


<br />
==Centriole synthesis==
==Centriole synthesis==
Centrioles are generated in new daughter cells through duplication of pre-existing [[centrioles]] in the mother cells. Each daughter cell inherits two centrioles (one centrosome) surrounded by pericentriolar material as a result of cell division. However, the two centrioles are of different ages. This is because one centriole originates from the mother cell while the other is replicated from the mother centriole during the cell cycle.
Centrioles are generated in new daughter cells through duplication of pre-existing [[centrioles]] in the mother cells. Each daughter cell inherits two centrioles (one centrosome) surrounded by pericentriolar material as a result of cell division. However, the two centrioles are of different ages. This is because one centriole originates from the mother cell while the other is replicated from the mother centriole during the cell cycle.
It is possible to distinguish between the two preexisting centrioles because the mother and daughter centriole differ in both shape and function.<ref>{{cite journal|last=Piel|first=M|author2=Nordberg, J|author3=Euteneuer, U|author4=Bornens, M|title=Centrosome-dependent exit of cytokinesis in animal cells|journal=Science|date=Feb 23, 2001|volume=291|issue=5508|pages=1550–3|pmid=11222861|doi=10.1126/science.1057330|bibcode=2001Sci...291.1550P}}</ref>
It is possible to distinguish between the two preexisting centrioles because the mother and daughter centriole differ in both shape and function.<ref>{{cite journal|last=Piel|first=M|author2=Nordberg, J|author3=Euteneuer, U|author4=Bornens, M|title=Centrosome-dependent exit of cytokinesis in animal cells|journal=Science|date=Feb 23, 2001|volume=291|issue=5508|pages=1550–3|pmid=11222861|doi=10.1126/science.1057330|bibcode=2001Sci...291.1550P}}</ref>
For example, the mother centriole can nucleate and organize microtubules, whereas the daughter centriole can only nucleate.
For example, the mother centriole can nucleate and organize microtubules, whereas the daughter centriole can only nucleate.



First, [[procentriole]]s begin to form near each preexisting centriole as the cell moves from the [[G1 phase]] to the S phase.<ref name="Chretien1997">{{cite journal|last=Chrétien|first=D|author2=Buendia, B|author3=Fuller, SD|author4=Karsenti, E|title=Reconstruction of the centrosome cycle from cryoelectron micrographs|journal=Journal of Structural Biology|date=November 1997|volume=120|issue=2|pages=117–33|pmid=9417977|doi=10.1006/jsbi.1997.3928}}</ref><ref>{{cite journal|last=Kuriyama|first=R|author2=Borisy, GG|title=Centriole cycle in Chinese hamster ovary cells as determined by whole-mount electron microscopy|journal=The Journal of Cell Biology|date=December 1981|volume=91|issue=3 Pt 1|pages=814–21|pmid=7328123|pmc=2112828|doi=10.1083/jcb.91.3.814}}</ref><ref>{{cite journal|last=Vorobjev|first=IA|author2=Chentsov, YuS|title=Centrioles in the cell cycle. I. Epithelial cells|journal=The Journal of Cell Biology|date=June 1982|volume=93|issue=3|pages=938–49|pmid=7119006|pmc=2112136|doi=10.1083/jcb.93.3.938}}</ref> During S and G2 phases of the cell cycle, the procentrioles elongate until they reach the length of the older mother and daughter centrioles. At this point, the daughter centriole which takes on characteristics of a mother centriole. Once they reach full length, the new centriole and its mother centriole form a [[diplosome]]. A diplosome is a rigid complex formed by an [[orthogonal]] mother and newly formed centriole (now a daughter centriole) that aids in the processes of mitosis. As mitosis occurs, the distance between mother and daughter centriole increases until, congruent with [[anaphase]], the diplosome breaks down and each centriole is surrounded by its own pericentriolar material.<ref name="Chretien1997" />
First, [[procentriole]]s begin to form near each preexisting centriole as the cell moves from the [[G1 phase]] to the S phase.<ref name="Chretien1997">{{cite journal|last=Chrétien|first=D|author2=Buendia, B|author3=Fuller, SD|author4=Karsenti, E|title=Reconstruction of the centrosome cycle from cryoelectron micrographs|journal=Journal of Structural Biology|date=November 1997|volume=120|issue=2|pages=117–33|pmid=9417977|doi=10.1006/jsbi.1997.3928}}</ref><ref>{{cite journal|last=Kuriyama|first=R|author2=Borisy, GG|title=Centriole cycle in Chinese hamster ovary cells as determined by whole-mount electron microscopy|journal=The Journal of Cell Biology|date=December 1981|volume=91|issue=3 Pt 1|pages=814–21|pmid=7328123|pmc=2112828|doi=10.1083/jcb.91.3.814}}</ref><ref>{{cite journal|last=Vorobjev|first=IA|author2=Chentsov, YuS|title=Centrioles in the cell cycle. I. Epithelial cells|journal=The Journal of Cell Biology|date=June 1982|volume=93|issue=3|pages=938–49|pmid=7119006|pmc=2112136|doi=10.1083/jcb.93.3.938}}</ref> During S and G2 phases of the cell cycle, the procentrioles elongate until they reach the length of the older mother and daughter centrioles. At this point, the daughter centriole which takes on characteristics of a mother centriole. Once they reach full length, the new centriole and its mother centriole form a [[diplosome]]. A diplosome is a rigid complex formed by an [[orthogonal]] mother and newly formed centriole (now a daughter centriole) that aids in the processes of mitosis. As mitosis occurs, the distance between mother and daughter centriole increases until, congruent with [[anaphase]], the diplosome breaks down and each centriole is surrounded by its own pericentriolar material.<ref name="Chretien1997" />


<br />
==Centrosome duplication==
==Centrosome duplication==
'''Cell cycle regulation of centrosome duplication'''
'''Cell cycle regulation of centrosome duplication'''

Centrosomes are only supposed to replicate once in each cell cycle and are therefore highly regulated.<ref name=":2">{{Cite journal|last=Fujita|first=Hiroki|last2=Yoshino|first2=Yuki|last3=Chiba|first3=Natsuko|date=2016-03|title=Regulation of the centrosome cycle|url=https://www.ncbi.nlm.nih.gov/pubmed/27308597|journal=Molecular & Cellular Oncology|volume=3|issue=2|pages=e1075643|doi=10.1080/23723556.2015.1075643|issn=2372-3556|pmc=4905396|pmid=27308597}}</ref> The centrosome cycle has been found to be regulated by multiple things, including reversible phosphorylation and [[proteolysis]]. <ref name=":04">{{Cite journal|last=Meraldi|first=P|last2=Nigg|first2=E. A|date=2002-06-19|title=The centrosome cycle|url=http://www.sciencedirect.com/science/article/pii/S001457930202865X|journal=FEBS Letters|volume=521|issue=1|pages=9–13|doi=10.1016/S0014-5793(02)02865-X|issn=0014-5793}}</ref> It also undergoes specific processes in each step of cell division due to the heavy regulation, which is why the process is so efficient.<ref name=":2" />



Centrosome duplication is heavily regulated by cell cycle controls. This link between the cell cycle and the centrosome cycle is mediated by [[cyclin-dependent kinase 2]] (Cdk2). Cdk2 is a protein kinase (an enzyme) known to regulate the cell cycle.<ref name=":0">{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/1017|title=CDK2 cyclin dependent kinase 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2019-12-01}}</ref> There has been ample evidence <ref>{{cite journal|last=Hinchcliffe|first=EH|author2=Li, C|author3=Thompson, EA|author4=Maller, JL|author5=Sluder, G|title=Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts|journal=Science|date=Feb 5, 1999|volume=283|issue=5403|pages=851–4|pmid=9933170|doi=10.1126/science.283.5403.851|bibcode=1999Sci...283..851H}}</ref><ref>{{cite journal|last=Matsumoto|first=Y|author2=Hayashi, K|author3=Nishida, E|title=Cyclin-dependent kinase 2 (Cdk2) is required for centrosome duplication in mammalian cells|journal=Current Biology|date=Apr 22, 1999|volume=9|issue=8|pages=429–32|pmid=10226033|doi=10.1016/S0960-9822(99)80191-2}}</ref><ref name="Meraldi1999">{{cite journal|last=Meraldi|first=P|author2=Lukas, J|author3=Fry, AM|author4=Bartek, J|author5=Nigg, EA|title=Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A|journal=Nature Cell Biology|date=June 1999|volume=1|issue=2|pages=88–93|pmid=10559879|doi=10.1038/10054}}</ref><ref>{{cite journal|last=Lacey|first=KR |author2=Jackson, PK |author3=Stearns, T|title=Cyclin-dependent kinase control of centrosome duplication|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Mar 16, 1999|volume=96|issue=6|pages=2817–22|pmid=10077594|pmc=15852|doi=10.1073/pnas.96.6.2817|bibcode=1999PNAS...96.2817L }}</ref> that Cdk2 is necessary for both [[DNA replication]] and centrosome duplication, which are both key events in S phase. It has also been shown <ref name="Meraldi1999" /><ref>{{cite journal|last=Hinchcliffe|first=EH|author2=Sluder, G.|title=Centrosome duplication: Three kinases come up a winner!|journal=Curr Biol|year=2001b|volume=11|pages=R698–R701|doi=10.1016/S0960-9822(01)00412-2|issue=17}}</ref><ref>{{cite journal|last=Matsumoto|first=Y|author2=Maller, JL|title=A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry|journal=Science|date=Oct 29, 2004|volume=306|issue=5697|pages=885–8|pmid=15514162|doi=10.1126/science.1103544|bibcode=2004Sci...306..885M}}</ref> that Cdk2 complexes with both [[cyclin A]] and [[cyclin E]] and this complex is critical for centrosome duplication.<ref name=":0" /> Three Cdk2 substrates have been proposed to be responsible for regulation of centriole duplication: [[nucleophosmin]] (NPM/B23), [[CP110]], and MPS1.<ref name="Loncarek2009" /> Nucleophosmin is only found in unreplicated centrosomes and its [[phosphorylation]] by Cdk2/cyclin E removes NPM from the centrosomes, initiating procentriole formation.<ref>{{cite journal|last=Okuda|first=M |author2=Horn, HF |author3=Tarapore, P |author4=Tokuyama, Y |author5=Smulian, AG |author6=Chan, PK |author7=Knudsen, ES |author8=Hofmann, IA |author9=Snyder, JD |author10=Bove, KE |author11=Fukasawa, K|title=Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication|journal=Cell|date=Sep 29, 2000|volume=103|issue=1|pages=127–40|pmid=11051553|doi=10.1016/S0092-8674(00)00093-3}}</ref><ref>{{cite journal|last=Tokuyama|first=Y |author2=Horn, HF |author3=Kawamura, K |author4=Tarapore, P |author5=Fukasawa, K|title=Specific phosphorylation of nucleophosmin on Thr(199) by cyclin-dependent kinase 2-cyclin E and its role in centrosome duplication|journal=The Journal of Biological Chemistry|date=Jun 15, 2001|volume=276|issue=24|pages=21529–37|pmid=11278991|doi=10.1074/jbc.M100014200}}</ref> CP110 is an important centrosomal protein that is phosphorylated by both mitotic and interphase Cdk/cyclin complexes and is thought to influence centrosome duplication in the S phase. [19] MPS1 is a protein kinase that is essential to the spindle assembly checkpoint,<ref>{{cite journal|last=Stucke|first=VM |author2=Silljé, HH |author3=Arnaud, L |author4=Nigg, EA|title=Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication|journal=The EMBO Journal|date=Apr 2, 2002|volume=21|issue=7|pages=1723–32|pmid=11927556|doi=10.1093/emboj/21.7.1723|pmc=125937}}</ref> and it is thought to possibly remodel an [[SASS6|SAS6]]-cored intermediate between severed mother and daughter centrioles into a pair of cartwheel protein complexes onto which procentrioles assemble.<ref>{{cite journal|last=Pike|first=Amanda N|author2=Fisk, Harold N|title=Centriole assembly and the role of Mps1: defensible or dispensable?|journal=Cell Division|date=April 14, 2011|pages=6–14|pmid=21492451|doi=10.1186/1747-1028-6-9|pmc=3094359|volume=6}}</ref>
Centrosome duplication is heavily regulated by cell cycle controls. This link between the cell cycle and the centrosome cycle is mediated by [[cyclin-dependent kinase 2]] (Cdk2). Cdk2 is a protein kinase (an enzyme) known to regulate the cell cycle.<ref name=":0">{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/1017|title=CDK2 cyclin dependent kinase 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2019-12-01}}</ref> There has been ample evidence <ref>{{cite journal|last=Hinchcliffe|first=EH|author2=Li, C|author3=Thompson, EA|author4=Maller, JL|author5=Sluder, G|title=Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts|journal=Science|date=Feb 5, 1999|volume=283|issue=5403|pages=851–4|pmid=9933170|doi=10.1126/science.283.5403.851|bibcode=1999Sci...283..851H}}</ref><ref>{{cite journal|last=Matsumoto|first=Y|author2=Hayashi, K|author3=Nishida, E|title=Cyclin-dependent kinase 2 (Cdk2) is required for centrosome duplication in mammalian cells|journal=Current Biology|date=Apr 22, 1999|volume=9|issue=8|pages=429–32|pmid=10226033|doi=10.1016/S0960-9822(99)80191-2}}</ref><ref name="Meraldi1999">{{cite journal|last=Meraldi|first=P|author2=Lukas, J|author3=Fry, AM|author4=Bartek, J|author5=Nigg, EA|title=Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A|journal=Nature Cell Biology|date=June 1999|volume=1|issue=2|pages=88–93|pmid=10559879|doi=10.1038/10054}}</ref><ref>{{cite journal|last=Lacey|first=KR |author2=Jackson, PK |author3=Stearns, T|title=Cyclin-dependent kinase control of centrosome duplication|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Mar 16, 1999|volume=96|issue=6|pages=2817–22|pmid=10077594|pmc=15852|doi=10.1073/pnas.96.6.2817|bibcode=1999PNAS...96.2817L }}</ref> that Cdk2 is necessary for both [[DNA replication]] and centrosome duplication, which are both key events in S phase. It has also been shown <ref name="Meraldi1999" /><ref>{{cite journal|last=Hinchcliffe|first=EH|author2=Sluder, G.|title=Centrosome duplication: Three kinases come up a winner!|journal=Curr Biol|year=2001b|volume=11|pages=R698–R701|doi=10.1016/S0960-9822(01)00412-2|issue=17}}</ref><ref>{{cite journal|last=Matsumoto|first=Y|author2=Maller, JL|title=A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry|journal=Science|date=Oct 29, 2004|volume=306|issue=5697|pages=885–8|pmid=15514162|doi=10.1126/science.1103544|bibcode=2004Sci...306..885M}}</ref> that Cdk2 complexes with both [[cyclin A]] and [[cyclin E]] and this complex is critical for centrosome duplication.<ref name=":0" /> Three Cdk2 substrates have been proposed to be responsible for regulation of centriole duplication: [[nucleophosmin]] (NPM/B23), [[CP110]], and MPS1.<ref name="Loncarek2009" /> Nucleophosmin is only found in unreplicated centrosomes and its [[phosphorylation]] by Cdk2/cyclin E removes NPM from the centrosomes, initiating procentriole formation.<ref>{{cite journal|last=Okuda|first=M |author2=Horn, HF |author3=Tarapore, P |author4=Tokuyama, Y |author5=Smulian, AG |author6=Chan, PK |author7=Knudsen, ES |author8=Hofmann, IA |author9=Snyder, JD |author10=Bove, KE |author11=Fukasawa, K|title=Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication|journal=Cell|date=Sep 29, 2000|volume=103|issue=1|pages=127–40|pmid=11051553|doi=10.1016/S0092-8674(00)00093-3}}</ref><ref>{{cite journal|last=Tokuyama|first=Y |author2=Horn, HF |author3=Kawamura, K |author4=Tarapore, P |author5=Fukasawa, K|title=Specific phosphorylation of nucleophosmin on Thr(199) by cyclin-dependent kinase 2-cyclin E and its role in centrosome duplication|journal=The Journal of Biological Chemistry|date=Jun 15, 2001|volume=276|issue=24|pages=21529–37|pmid=11278991|doi=10.1074/jbc.M100014200}}</ref> CP110 is an important centrosomal protein that is phosphorylated by both mitotic and interphase Cdk/cyclin complexes and is thought to influence centrosome duplication in the S phase. [19] MPS1 is a protein kinase that is essential to the spindle assembly checkpoint,<ref>{{cite journal|last=Stucke|first=VM |author2=Silljé, HH |author3=Arnaud, L |author4=Nigg, EA|title=Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication|journal=The EMBO Journal|date=Apr 2, 2002|volume=21|issue=7|pages=1723–32|pmid=11927556|doi=10.1093/emboj/21.7.1723|pmc=125937}}</ref> and it is thought to possibly remodel an [[SASS6|SAS6]]-cored intermediate between severed mother and daughter centrioles into a pair of cartwheel protein complexes onto which procentrioles assemble.<ref>{{cite journal|last=Pike|first=Amanda N|author2=Fisk, Harold N|title=Centriole assembly and the role of Mps1: defensible or dispensable?|journal=Cell Division|date=April 14, 2011|pages=6–14|pmid=21492451|doi=10.1186/1747-1028-6-9|pmc=3094359|volume=6}}</ref>


<br />
==Centrosome maturation==
==Centrosome maturation==


Centrosome maturation is defined as the increase or accumulation of γ-tubulin ring complexes and other PCM proteins at the centrosome.<ref name="Meraldi" /> This increase in γ -tubulin gives the mature centrosome greater ability to nucleate microtubules. Phosphorylation plays a key regulatory role in centrosome maturation, and it is thought that [[Polo-like kinase]]s (Plks) and [[Aurora kinase]]s are responsible for this phosphorylation. [21] The phosphorylation of downstream targets of Plks and Aurora A lead to the recruitment of γ –tubulin and other proteins that form PCM around the centrioles. [23]
Centrosome maturation is defined as the increase or accumulation of γ-tubulin ring complexes and other PCM proteins at the centrosome.<ref name="Meraldi" /> This increase in γ -tubulin gives the mature centrosome greater ability to nucleate microtubules. Phosphorylation plays a key regulatory role in centrosome maturation, and it is thought that [[Polo-like kinase]]s (Plks) and [[Aurora kinase]]s are responsible for this phosphorylation. [21] The phosphorylation of downstream targets of Plks and Aurora A lead to the recruitment of γ –tubulin and other proteins that form PCM around the centrioles. [23]


<br />
==Centrosome separation==
==Centrosome separation==


In early mitosis, several motor proteins drive the separation of centrosomes. With the onset of prophase, the motor protein dynein provides the majority of the force required to pull the two centrosomes apart. The separation event actually occurs at the G2/M transition and happens in two steps. In the first step, the connection between the two parental centrioles is destroyed. In the second step, the centrosomes are separated via microtubule motor proteins.<ref name="Meraldi" />
In early mitosis, several motor proteins drive the separation of centrosomes. With the onset of prophase, the motor protein dynein provides the majority of the force required to pull the two centrosomes apart. The separation event actually occurs at the G2/M transition and happens in two steps. In the first step, the connection between the two parental centrioles is destroyed. In the second step, the centrosomes are separated via microtubule motor proteins.<ref name="Meraldi" />


<br />
==Centrosome disorientation==
==Centrosome disorientation==


Centrosome disorientation refers to the loss of orthogonality between the mother and daughter centrioles.<ref name="Meraldi" /> Once disorientation occurs, the mature centriole begins to move toward the cleave furrow. It has been proposed that this movement is a key step in [[abscission]], the terminal phase of cell division.<ref>{{cite journal|last=Rusan|first=Nasser M.|author2=Rogers, Gregory C.|title=Centrosome Function: Sometimes Less Is More|journal=Traffic|date=1 May 2009|volume=10|issue=5|pages=472–481|doi=10.1111/j.1600-0854.2009.00880.x|pmid=19192251}}</ref>
Centrosome disorientation refers to the loss of orthogonality between the mother and daughter centrioles.<ref name="Meraldi" /> Once disorientation occurs, the mature centriole begins to move toward the cleave furrow. It has been proposed that this movement is a key step in [[abscission]], the terminal phase of cell division.<ref>{{cite journal|last=Rusan|first=Nasser M.|author2=Rogers, Gregory C.|title=Centrosome Function: Sometimes Less Is More|journal=Traffic|date=1 May 2009|volume=10|issue=5|pages=472–481|doi=10.1111/j.1600-0854.2009.00880.x|pmid=19192251}}</ref>

<br />


==Centrosome reduction==
==Centrosome reduction==
Centrosome reduction is the gradual loss of centrosomal components that takes place after [[mitosis]] and during [[Cellular differentiation|differentiation]].<ref> Atypical centrioles during sexual reproduction Tomer Avidor-Reiss*, Atul Khire, Emily L. Fishman and Kyoung H. Jo Curr Biol. 2015 Nov 16;25(22):2956-63. doi: 10.1016/j.cub.2015.09.045. Epub 2015 Oct 17. http://journal.frontiersin.org/article/10.3389/fcell.2015.00021/full</ref> In cycling cells, after [[mitosis]] the centrosome has lost most of its [[pericentriolar material]] (PCM) and its microtubule nucleation capacity. In [[sperm]], [[centriole]] structure is also changed in addition to the loss of PCM and its microtubule nucleation capacity.<ref>Asterless Reduction during Spermiogenesis Is Regulated by Plk4 and Is Essential for Zygote Development in Drosophila. Khire A1, Vizuet AA1, Davila E1, Avidor-Reiss T2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654664/</ref>
Centrosome reduction is the gradual loss of centrosomal components that takes place after [[mitosis]] and during [[Cellular differentiation|differentiation]].<ref> Atypical centrioles during sexual reproduction Tomer Avidor-Reiss*, Atul Khire, Emily L. Fishman and Kyoung H. Jo Curr Biol. 2015 Nov 16;25(22):2956-63. doi: 10.1016/j.cub.2015.09.045. Epub 2015 Oct 17. http://journal.frontiersin.org/article/10.3389/fcell.2015.00021/full</ref> In cycling cells, after [[mitosis]] the centrosome has lost most of its [[pericentriolar material]] (PCM) and its microtubule nucleation capacity. In [[sperm]], [[centriole]] structure is also changed in addition to the loss of PCM and its microtubule nucleation capacity.<ref>Asterless Reduction during Spermiogenesis Is Regulated by Plk4 and Is Essential for Zygote Development in Drosophila. Khire A1, Vizuet AA1, Davila E1, Avidor-Reiss T2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654664/</ref>

<br />


==Dysregulation of the centrosome cycle==
==Dysregulation of the centrosome cycle==
Line 38: Line 54:
Improper progression through the centrosome cycle can lead to incorrect numbers of centrosomes and aneuploidy, which could eventually lead to cancer. The role of centrosomes in tumor progression is unclear. The mis-expression of genes such as [[p53]], [[BRCA1]], [[Mdm2]], Aurora-A and [[survivin]] causes an increase in the amount of centrosomes present in a cell. However, it is not well understood how these genes influence the centrosome or how an increase in centrosomes influences tumor progression.<ref>{{cite journal|last=Cunha-Ferreira|first=Inês |author2=Bento, Inês |author3=Bettencourt-Dias, Mónica|title=From Zero to Many: Control of Centriole Number in Development and Disease|journal=Traffic|date=1 May 2009|volume=10|issue=5|pages=482–498|doi=10.1111/j.1600-0854.2009.00905.x|pmid=19416494}} https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654664/</ref>
Improper progression through the centrosome cycle can lead to incorrect numbers of centrosomes and aneuploidy, which could eventually lead to cancer. The role of centrosomes in tumor progression is unclear. The mis-expression of genes such as [[p53]], [[BRCA1]], [[Mdm2]], Aurora-A and [[survivin]] causes an increase in the amount of centrosomes present in a cell. However, it is not well understood how these genes influence the centrosome or how an increase in centrosomes influences tumor progression.<ref>{{cite journal|last=Cunha-Ferreira|first=Inês |author2=Bento, Inês |author3=Bettencourt-Dias, Mónica|title=From Zero to Many: Control of Centriole Number in Development and Disease|journal=Traffic|date=1 May 2009|volume=10|issue=5|pages=482–498|doi=10.1111/j.1600-0854.2009.00905.x|pmid=19416494}} https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654664/</ref>


<br />

== The Centrosome Cycle and Disease ==
Issues with the centrosome can have detrimental effects on the cell, which can lead to diseases in the organisms hosting the cells. Cancer is a heavily studied disease that has been found to have a relation to the cell's centrosome. <ref name=":03">{{Cite journal|last=Meraldi|first=P|last2=Nigg|first2=E. A|date=2002-06-19|title=The centrosome cycle|url=http://www.sciencedirect.com/science/article/pii/S001457930202865X|journal=FEBS Letters|volume=521|issue=1|pages=9–13|doi=10.1016/S0014-5793(02)02865-X|issn=0014-5793}}</ref> Dwarfism, microcephaly, and ciliopathies have also recently been genetically linked to centrosome proteins. <ref>{{Cite journal|last=Nigg|first=Erich A.|last2=Čajánek|first2=Lukáš|last3=Arquint|first3=Christian|date=2014-08-01|title=The centrosome duplication cycle in health and disease|url=https://www.ncbi.nlm.nih.gov/pubmed/24951839|journal=FEBS letters|volume=588|issue=15|pages=2366–2372|doi=10.1016/j.febslet.2014.06.030|issn=1873-3468|pmid=24951839}}</ref>


Centrosomes are believed to be related to cancer due to the fact that they contain tumor suppressor proteins and oncogenes. These proteins have been found to cause detrimental alterations in the centrosome of various tumor cells. <ref name=":1">{{Cite journal|last=Rivera-Rivera|first=Yainyrette|last2=Saavedra|first2=Harold I|date=2016-12-13|title=Centrosome – a promising anti-cancer target|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167523/|journal=Biologics : Targets & Therapy|volume=10|pages=167–176|doi=10.2147/BTT.S87396|issn=1177-5475|pmc=5167523|pmid=28008224}}</ref> There are two main categories of the centrosome alteration: structural and functional. The structural changes can lead to different shapes, sizes, numbers, positions, or composition, while the functional changes can lead to issues with the microtubules and mitotic spindles, therefore becoming detrimental in cell division.<ref name=":1" /> Researchers are hopeful that the targeting of carious centrosomal proteins may be a possible treatment to or prevention of cancer. <ref name=":1" />
<br />
==References==
==References==
{{reflist|2}}
{{reflist|2}}

Revision as of 15:15, 5 December 2019

Diagram of the centrosome cycle.[1]

Centrosomes are the major microtubule organizing centers (MTOC) in mammalian cells.[2] Failure of centrosome regulation can cause mistakes in chromosome segregation and is associated with aneuploidy. A centrosome is composed of two orthogonal cylindrical proteins, called centrioles, which are surrounded by an electron and protein dense amorphous cloud of pericentriolar material (PCM).[3] The PCM is essential for nucleation and organization of microtubules.[3] The centrosome cycle is important to ensure that daughter cells receive a centrosome after cell division. As the cell cycle progresses, the centrosome undergoes a series of morphological and functional changes. Initiation of the centrosome cycle occurs early in the cell cycle in order to have two centrosomes by the time mitosis occurs.


Since the centrosome organizes the microtubules of a cell, t has to do with the formation of the mitotic spindle, polarity and, therefore, cell shape, as well as all other processes having to do with the mitotic spindle. [4] The centriole is the inner core of the centrosome, and its conformation is typically somewhat like that of spokes on a wheel. It has a somewhat different conformation amount different organisms, but its overall structure is similar. Plants, on the other hand, do not typically have centrioles.[5]

The centrosome cycle consists of four phases that are synchronized to the cell cycle. These include: centrosome duplication during the G1 phase and S Phase, centrosome maturation in the G2 phase, centrosome separation in the mitotic phase, and centrosome disorientation in the late mitotic phase—G1 phase.


Centriole synthesis

Centrioles are generated in new daughter cells through duplication of pre-existing centrioles in the mother cells. Each daughter cell inherits two centrioles (one centrosome) surrounded by pericentriolar material as a result of cell division. However, the two centrioles are of different ages. This is because one centriole originates from the mother cell while the other is replicated from the mother centriole during the cell cycle. It is possible to distinguish between the two preexisting centrioles because the mother and daughter centriole differ in both shape and function.[6] For example, the mother centriole can nucleate and organize microtubules, whereas the daughter centriole can only nucleate.


First, procentrioles begin to form near each preexisting centriole as the cell moves from the G1 phase to the S phase.[7][8][9] During S and G2 phases of the cell cycle, the procentrioles elongate until they reach the length of the older mother and daughter centrioles. At this point, the daughter centriole which takes on characteristics of a mother centriole. Once they reach full length, the new centriole and its mother centriole form a diplosome. A diplosome is a rigid complex formed by an orthogonal mother and newly formed centriole (now a daughter centriole) that aids in the processes of mitosis. As mitosis occurs, the distance between mother and daughter centriole increases until, congruent with anaphase, the diplosome breaks down and each centriole is surrounded by its own pericentriolar material.[7]


Centrosome duplication

Cell cycle regulation of centrosome duplication

Centrosomes are only supposed to replicate once in each cell cycle and are therefore highly regulated.[10] The centrosome cycle has been found to be regulated by multiple things, including reversible phosphorylation and proteolysis. [11] It also undergoes specific processes in each step of cell division due to the heavy regulation, which is why the process is so efficient.[10]


Centrosome duplication is heavily regulated by cell cycle controls. This link between the cell cycle and the centrosome cycle is mediated by cyclin-dependent kinase 2 (Cdk2). Cdk2 is a protein kinase (an enzyme) known to regulate the cell cycle.[12] There has been ample evidence [13][14][15][16] that Cdk2 is necessary for both DNA replication and centrosome duplication, which are both key events in S phase. It has also been shown [15][17][18] that Cdk2 complexes with both cyclin A and cyclin E and this complex is critical for centrosome duplication.[12] Three Cdk2 substrates have been proposed to be responsible for regulation of centriole duplication: nucleophosmin (NPM/B23), CP110, and MPS1.[3] Nucleophosmin is only found in unreplicated centrosomes and its phosphorylation by Cdk2/cyclin E removes NPM from the centrosomes, initiating procentriole formation.[19][20] CP110 is an important centrosomal protein that is phosphorylated by both mitotic and interphase Cdk/cyclin complexes and is thought to influence centrosome duplication in the S phase. [19] MPS1 is a protein kinase that is essential to the spindle assembly checkpoint,[21] and it is thought to possibly remodel an SAS6-cored intermediate between severed mother and daughter centrioles into a pair of cartwheel protein complexes onto which procentrioles assemble.[22]


Centrosome maturation

Centrosome maturation is defined as the increase or accumulation of γ-tubulin ring complexes and other PCM proteins at the centrosome.[2] This increase in γ -tubulin gives the mature centrosome greater ability to nucleate microtubules. Phosphorylation plays a key regulatory role in centrosome maturation, and it is thought that Polo-like kinases (Plks) and Aurora kinases are responsible for this phosphorylation. [21] The phosphorylation of downstream targets of Plks and Aurora A lead to the recruitment of γ –tubulin and other proteins that form PCM around the centrioles. [23]


Centrosome separation

In early mitosis, several motor proteins drive the separation of centrosomes. With the onset of prophase, the motor protein dynein provides the majority of the force required to pull the two centrosomes apart. The separation event actually occurs at the G2/M transition and happens in two steps. In the first step, the connection between the two parental centrioles is destroyed. In the second step, the centrosomes are separated via microtubule motor proteins.[2]


Centrosome disorientation

Centrosome disorientation refers to the loss of orthogonality between the mother and daughter centrioles.[2] Once disorientation occurs, the mature centriole begins to move toward the cleave furrow. It has been proposed that this movement is a key step in abscission, the terminal phase of cell division.[23]


Centrosome reduction

Centrosome reduction is the gradual loss of centrosomal components that takes place after mitosis and during differentiation.[24] In cycling cells, after mitosis the centrosome has lost most of its pericentriolar material (PCM) and its microtubule nucleation capacity. In sperm, centriole structure is also changed in addition to the loss of PCM and its microtubule nucleation capacity.[25]


Dysregulation of the centrosome cycle

Improper progression through the centrosome cycle can lead to incorrect numbers of centrosomes and aneuploidy, which could eventually lead to cancer. The role of centrosomes in tumor progression is unclear. The mis-expression of genes such as p53, BRCA1, Mdm2, Aurora-A and survivin causes an increase in the amount of centrosomes present in a cell. However, it is not well understood how these genes influence the centrosome or how an increase in centrosomes influences tumor progression.[26]


The Centrosome Cycle and Disease

Issues with the centrosome can have detrimental effects on the cell, which can lead to diseases in the organisms hosting the cells. Cancer is a heavily studied disease that has been found to have a relation to the cell's centrosome. [27] Dwarfism, microcephaly, and ciliopathies have also recently been genetically linked to centrosome proteins. [28]


Centrosomes are believed to be related to cancer due to the fact that they contain tumor suppressor proteins and oncogenes. These proteins have been found to cause detrimental alterations in the centrosome of various tumor cells. [29] There are two main categories of the centrosome alteration: structural and functional. The structural changes can lead to different shapes, sizes, numbers, positions, or composition, while the functional changes can lead to issues with the microtubules and mitotic spindles, therefore becoming detrimental in cell division.[29] Researchers are hopeful that the targeting of carious centrosomal proteins may be a possible treatment to or prevention of cancer. [29]

References

  1. ^ "Figure 1". Aurora-A: the maker and breaker of spindle poles. Journal of Cell Science. Archived from the original on 11 May 2012. Retrieved 11 December 2012.
  2. ^ a b c d Meraldi, P; Nigg, E.A. (23 April 2002). "The centrosome cycle". FEBS Letters. 521 (1–3): 9–13. doi:10.1016/S0014-5793(02)02865-X. PMID 12067716.
  3. ^ a b c Loncarek, J.; Khodjakov, A. (February 2009). "Ab ovo or de novo? Mechanisms of centriole duplication". Mol Cells. 27 (2): 135–142. doi:10.1007/s10059-009-0017-z. PMC 2691869. PMID 19277494.
  4. ^ Meraldi, P; Nigg, E. A (19 June 2002). "The centrosome cycle". FEBS Letters. 521 (1): 9–13. doi:10.1016/S0014-5793(02)02865-X. ISSN 0014-5793.
  5. ^ Fu, Jingyan (2015). "The Centrosome and its Duplications Cycle". Cold Spring Harbor Perspectives in Biology. Retrieved 12/3/19. {{cite web}}: Check date values in: |access-date= (help)CS1 maint: url-status (link)
  6. ^ Piel, M; Nordberg, J; Euteneuer, U; Bornens, M (23 February 2001). "Centrosome-dependent exit of cytokinesis in animal cells". Science. 291 (5508): 1550–3. Bibcode:2001Sci...291.1550P. doi:10.1126/science.1057330. PMID 11222861.
  7. ^ a b Chrétien, D; Buendia, B; Fuller, SD; Karsenti, E (November 1997). "Reconstruction of the centrosome cycle from cryoelectron micrographs". Journal of Structural Biology. 120 (2): 117–33. doi:10.1006/jsbi.1997.3928. PMID 9417977.
  8. ^ Kuriyama, R; Borisy, GG (December 1981). "Centriole cycle in Chinese hamster ovary cells as determined by whole-mount electron microscopy". The Journal of Cell Biology. 91 (3 Pt 1): 814–21. doi:10.1083/jcb.91.3.814. PMC 2112828. PMID 7328123.
  9. ^ Vorobjev, IA; Chentsov, YuS (June 1982). "Centrioles in the cell cycle. I. Epithelial cells". The Journal of Cell Biology. 93 (3): 938–49. doi:10.1083/jcb.93.3.938. PMC 2112136. PMID 7119006.
  10. ^ a b Fujita, Hiroki; Yoshino, Yuki; Chiba, Natsuko (2016-03). "Regulation of the centrosome cycle". Molecular & Cellular Oncology. 3 (2): e1075643. doi:10.1080/23723556.2015.1075643. ISSN 2372-3556. PMC 4905396. PMID 27308597. {{cite journal}}: Check date values in: |date= (help)
  11. ^ Meraldi, P; Nigg, E. A (19 June 2002). "The centrosome cycle". FEBS Letters. 521 (1): 9–13. doi:10.1016/S0014-5793(02)02865-X. ISSN 0014-5793.
  12. ^ a b "CDK2 cyclin dependent kinase 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 1 December 2019.
  13. ^ Hinchcliffe, EH; Li, C; Thompson, EA; Maller, JL; Sluder, G (5 February 1999). "Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts". Science. 283 (5403): 851–4. Bibcode:1999Sci...283..851H. doi:10.1126/science.283.5403.851. PMID 9933170.
  14. ^ Matsumoto, Y; Hayashi, K; Nishida, E (22 April 1999). "Cyclin-dependent kinase 2 (Cdk2) is required for centrosome duplication in mammalian cells". Current Biology. 9 (8): 429–32. doi:10.1016/S0960-9822(99)80191-2. PMID 10226033.
  15. ^ a b Meraldi, P; Lukas, J; Fry, AM; Bartek, J; Nigg, EA (June 1999). "Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A". Nature Cell Biology. 1 (2): 88–93. doi:10.1038/10054. PMID 10559879.
  16. ^ Lacey, KR; Jackson, PK; Stearns, T (16 March 1999). "Cyclin-dependent kinase control of centrosome duplication". Proceedings of the National Academy of Sciences of the United States of America. 96 (6): 2817–22. Bibcode:1999PNAS...96.2817L. doi:10.1073/pnas.96.6.2817. PMC 15852. PMID 10077594.
  17. ^ Hinchcliffe, EH; Sluder, G. (2001b). "Centrosome duplication: Three kinases come up a winner!". Curr Biol. 11 (17): R698–R701. doi:10.1016/S0960-9822(01)00412-2.
  18. ^ Matsumoto, Y; Maller, JL (29 October 2004). "A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry". Science. 306 (5697): 885–8. Bibcode:2004Sci...306..885M. doi:10.1126/science.1103544. PMID 15514162.
  19. ^ Okuda, M; Horn, HF; Tarapore, P; Tokuyama, Y; Smulian, AG; Chan, PK; Knudsen, ES; Hofmann, IA; Snyder, JD; Bove, KE; Fukasawa, K (29 September 2000). "Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication". Cell. 103 (1): 127–40. doi:10.1016/S0092-8674(00)00093-3. PMID 11051553.
  20. ^ Tokuyama, Y; Horn, HF; Kawamura, K; Tarapore, P; Fukasawa, K (15 June 2001). "Specific phosphorylation of nucleophosmin on Thr(199) by cyclin-dependent kinase 2-cyclin E and its role in centrosome duplication". The Journal of Biological Chemistry. 276 (24): 21529–37. doi:10.1074/jbc.M100014200. PMID 11278991.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ Stucke, VM; Silljé, HH; Arnaud, L; Nigg, EA (2 April 2002). "Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication". The EMBO Journal. 21 (7): 1723–32. doi:10.1093/emboj/21.7.1723. PMC 125937. PMID 11927556.
  22. ^ Pike, Amanda N; Fisk, Harold N (14 April 2011). "Centriole assembly and the role of Mps1: defensible or dispensable?". Cell Division. 6: 6–14. doi:10.1186/1747-1028-6-9. PMC 3094359. PMID 21492451.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  23. ^ Rusan, Nasser M.; Rogers, Gregory C. (1 May 2009). "Centrosome Function: Sometimes Less Is More". Traffic. 10 (5): 472–481. doi:10.1111/j.1600-0854.2009.00880.x. PMID 19192251.
  24. ^ Atypical centrioles during sexual reproduction Tomer Avidor-Reiss*, Atul Khire, Emily L. Fishman and Kyoung H. Jo Curr Biol. 2015 Nov 16;25(22):2956-63. doi: 10.1016/j.cub.2015.09.045. Epub 2015 Oct 17. http://journal.frontiersin.org/article/10.3389/fcell.2015.00021/full
  25. ^ Asterless Reduction during Spermiogenesis Is Regulated by Plk4 and Is Essential for Zygote Development in Drosophila. Khire A1, Vizuet AA1, Davila E1, Avidor-Reiss T2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654664/
  26. ^ Cunha-Ferreira, Inês; Bento, Inês; Bettencourt-Dias, Mónica (1 May 2009). "From Zero to Many: Control of Centriole Number in Development and Disease". Traffic. 10 (5): 482–498. doi:10.1111/j.1600-0854.2009.00905.x. PMID 19416494. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654664/
  27. ^ Meraldi, P; Nigg, E. A (19 June 2002). "The centrosome cycle". FEBS Letters. 521 (1): 9–13. doi:10.1016/S0014-5793(02)02865-X. ISSN 0014-5793.
  28. ^ Nigg, Erich A.; Čajánek, Lukáš; Arquint, Christian (1 August 2014). "The centrosome duplication cycle in health and disease". FEBS letters. 588 (15): 2366–2372. doi:10.1016/j.febslet.2014.06.030. ISSN 1873-3468. PMID 24951839.
  29. ^ a b c Rivera-Rivera, Yainyrette; Saavedra, Harold I (13 December 2016). "Centrosome – a promising anti-cancer target". Biologics : Targets & Therapy. 10: 167–176. doi:10.2147/BTT.S87396. ISSN 1177-5475. PMC 5167523. PMID 28008224.{{cite journal}}: CS1 maint: unflagged free DOI (link)

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