Centrosome cycle
Encyclopedia
Centrosome
s are the major microtubule organizing center
(MTOC) in mammalian cells. 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 dense and protein dense amorphous cloud of pericentriolar matrix
(PCM). The PCM is essential for nucleation and organization of microtubules. 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, so that by the time mitosis
occurs there are two centrosomes.
The centrosome cycle consists of four phases that are synchronized to cell cycle; these include: centrosome duplication (G1/S), centrosome maturation (G2), centrosome separation (M), and centrosome disorientation (M/G1). Centrioles are generated in new daughter cells through duplication of preexisting centrioles in the mother cells. Each daughter cell inherits two centrioles (one centrosome) surrounded by PCM as a results of cell division. However, the two centrioles are of different ages. One centriole originated from the mother cell and the other was replicated from the mother centriole during the daughter cell cycle. A procentriole (what will eventually become a daughter centriole) begins to form near each existing mother centriole during the advancement from G1 to S phase in the cell cycle. It is possible to distinguish between these two centrioles, because the mother and daughter centriole differ morphologically and functionally. For example, the mother centriole can nucleate and organize microtubules, whereas the daughter centriole can only nucleate. During S and G2 phase of the cell cycle, the daughter centrioles are elongating until the reach the length of the mother centriole. When a daughter cell has reached full length, the mother and daughter form a diplosome
. A diplosome is a rigid complex formed by an orthogonal mother and 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 breakdown and each centriole is surrounded by its own PCM.
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). There has been ample evidence that Cdk2 is necessary for both DNA replication
and centrosome duplication, which are both key events in S phase. It has also been shown that Cdk2 complexes with both cyclin A
and cyclin E
and this complex is critical for centrosome duplication. Three Cdk2 substrates have been proposed to be responsible for regulation of centriole duplication. These include: nucleophosmin (NPM/B23), CP110
, and Msp1. Nucleophosmin is only found in unreplicated centrosomes and it’s phosphorylation
by Cdk2/cyclin E removes NPM from the centrosomes, initiating procentriole formation. 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 S phase. [19] MSP-1 is a protein kinase that is essential to the spindle assembly checkpoint.
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]
, the terminal phase of cell division.
, 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 the increase number of centrosomes influences tumor progression.
Centrosome
In cell biology, the centrosome is an organelle that serves as the main microtubule organizing center of the animal cell as well as a regulator of cell-cycle progression. It was discovered by Edouard Van Beneden in 1883...
s are the major microtubule organizing center
Microtubule organizing center
The microtubule-organizing center is a structure found in eukaryotic cells from which microtubules emerge. MTOCs have two main functions: the organization of eukaryotic flagella and cilia and the organization of the mitotic and meiotic spindle apparatus, which separate the chromosomes during cell...
(MTOC) in mammalian cells. Failure of centrosome regulation can cause mistakes in chromosome segregation and is associated with aneuploidy
Aneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
. A centrosome is composed of two orthogonal cylindrical proteins, called centriole
Centriole
A Centriole is a barrel-shaped cell structure found in most animal eukaryotic cells, though it is absent in higher plants and most fungi. The walls of each centriole are usually composed of nine triplets of microtubules...
s, which are surrounded by an electron dense and protein dense amorphous cloud of pericentriolar matrix
Pericentriolar material
Pericentriolar material is an amorphous mass of protein which makes up the part of the centrosome that surrounds the two centrioles. The PCM contains proteins responsible for microtubule nucleation and anchoring including γ-tubulin, pericentrin and ninein....
(PCM). The PCM is essential for nucleation and organization of microtubules. The centrosome cycle is important to ensure that daughter cells receive a centrosome after cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
. As the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
progresses, the centrosome undergoes a series of morphological and functional changes. Initiation of the centrosome cycle occurs early in the cell cycle, so that by the time mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
occurs there are two centrosomes.
The centrosome cycle consists of four phases that are synchronized to cell cycle; these include: centrosome duplication (G1/S), centrosome maturation (G2), centrosome separation (M), and centrosome disorientation (M/G1). Centrioles are generated in new daughter cells through duplication of preexisting centrioles in the mother cells. Each daughter cell inherits two centrioles (one centrosome) surrounded by PCM as a results of cell division. However, the two centrioles are of different ages. One centriole originated from the mother cell and the other was replicated from the mother centriole during the daughter cell cycle. A procentriole (what will eventually become a daughter centriole) begins to form near each existing mother centriole during the advancement from G1 to S phase in the cell cycle. It is possible to distinguish between these two centrioles, because the mother and daughter centriole differ morphologically and functionally. For example, the mother centriole can nucleate and organize microtubules, whereas the daughter centriole can only nucleate. During S and G2 phase of the cell cycle, the daughter centrioles are elongating until the reach the length of the mother centriole. When a daughter cell has reached full length, the mother and daughter form a diplosome
Diplosome
In cell biology, a diplosome is a pair of centrioles arranged perpendicularly, located near the nucleus. It is present in all eukaryotic cells except for higher plants. It plays an important role in mitosis. The rigid arrangement of centrioles in a diplosome is generally established after the...
. A diplosome is a rigid complex formed by an orthogonal mother and daughter centriole that aids in the processes of mitosis. As mitosis occurs, the distance between mother and daughter centriole increases until, congruent with anaphase
Anaphase
Anaphase, from the ancient Greek ἀνά and φάσις , is the stage of mitosis or meiosis when chromosomes move to opposite poles of the cell....
, the diplosome breakdown and each centriole is surrounded by its own PCM.
Centrosome Duplication
Cell Cycle Regulation of Centrosome DuplicationCentrosome 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
Cyclin-dependent kinase 2
Cyclin-dependent kinase 2 also known as cell division protein kinase 2 is an enzyme that in humans is encoded by the CDK2 gene.-Function:...
(Cdk2). There has been ample evidence that Cdk2 is necessary for both DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
and centrosome duplication, which are both key events in S phase. It has also been shown that Cdk2 complexes with both cyclin A
Cyclin A
Cyclin A is a member of the cyclin family.Cyclin A binds to S phase Cdk2 and is required for the cell to progress through the S phase. Cyclin A/ Cdk2 is inhibited by the complex p21CIP.-External links:*...
and cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....
and this complex is critical for centrosome duplication. Three Cdk2 substrates have been proposed to be responsible for regulation of centriole duplication. These include: nucleophosmin (NPM/B23), CP110
CP110
Centriolar coiled coil protein 110kDa, also known as CCP110 and previously called CP110, is a human gene. It is a cell cycle-dependent CDK substrate and regulates centrosome duplication. CCP110 suppresses a cilia assembly program....
, and Msp1. Nucleophosmin is only found in unreplicated centrosomes and it’s phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
by Cdk2/cyclin E removes NPM from the centrosomes, initiating procentriole formation. 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 S phase. [19] MSP-1 is a protein kinase that is essential to the spindle assembly checkpoint.
Centrosome Maturation
Centrosome maturation is defined as the increase or accumulation of γ-tubulin ring complexes and other PCM proteins at the centrosome. This increase in γ -tubulin allows the mature centrosome to have a greater ability to nucleate microtubules. Phosphorylation is a key regulatory role in centrosome maturation and it is thought that Polo-like kinases (Plks) and Aurora kinaseAurora Kinase
Aurora kinases are serine/threonine kinases that are essential for cell proliferation. The enzyme helps the dividing cell dispense its genetic materials to its daughter cells. More specifically, Aurora kinases play a crucial role in cellular division by controlling chromatid segregation...
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 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. First, the connection between the two parental centrioles is destroyed. Second, the centrosomes are separated via microtubules motor proteins.Centrosome Disorientation
Centrosome disorientation refers to the loss of orthogonality between the mother and daughter centrioles. Once disorientation occurs, the mature centriole begins to move toward the cleave furrow and it was purposed that this movement is a key step in abscissionAbscission
Abscission is a term used in several areas of biology. In plant sciences it most commonly refers to the process by which a plant drops one or more of its parts, such as a leaf, fruit, flower or seed...
, the terminal phase of cell division.
Disregulation 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 misexpression of genes such as, p53P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
, Mdm2
Mdm2
Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
, Aurora-A and survivin
Survivin
Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene....
, 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 the increase number of centrosomes influences tumor progression.