G2 phase
Encyclopedia
G2 phase is the 3rd and final subphase of Interphase
in the cell cycle
directly preceding Mitosis
. It follows the successful completion of S phase
, during which the cell’s DNA
is replicated. G2 phase ends with the onset of prophase
, the first phase of mitosis in which the cell’s chromatin
condenses into chromosome
s and the nuclear envelope
begins to break down.
synthesis during which the cell readies itself for mitosis. Curiously, G2 phase is not a necessary part of the cell cycle, as some cell types (particularly young Xenopus
embryos and some cancer
s ) proceed directly from DNA replication
to mitosis. Though much is known about the genetic network which regulates G2 phase and subsequent entry into mitosis, there is still much to be discovered concerning its significance and regulation, particularly in regards to cancer. One hypothesis is that the growth in G2 phase is regulated as a method of cell size control. Fission yeast (S. Pombe
) has been previously shown to employ such a mechanism, via Cdr2
-mediated spatial regulation of Wee1
activity. Though Wee1 is a fairly conserved negative regulator of mitotic entry, no general mechanism of cell size control in G2 has yet been elucidated.
Biochemically, the end of G2 phase occurs when a threshold level of active cyclin B1
/CDK1
complex, also known as Maturation promoting factor
(MPF) has been reached. The activity of this complex is tightly regulated during G2. In particular, the G2 checkpoint arrests cells in G2 in response to DNA damage through inhibitory regulation of CDK1.
cells, the G2/M DNA damage checkpoint
consists of an arrest of the cell in G2 just before mitotic entry in response to genotoxic stress (such as UV radiation, oxidative stress, DNA intercalating agents, etc.) in both a p53
-dependent and p53-independent manner. DNA damage signals cause activation of the transcription factor
p53. CDK1 is directly inhibited by three transcriptional targets of p53: p21
, Gadd45
, and 14-3-3σ. Inactive Cyclin B1/CDK1 is sequestered in the nucleus by p21, while active Cyclin B1/CDK1 complexes are sequestered in the cytoplasm by 14-3-3σ. Gadd45 disrupts the binding of Cyclin B1 and CDK1 through direct interaction with CDK1. P53 also transcriptionally represses CDK1.
P53-independent G2 arrest is mainly affected through the actions of Chk1 kinase
. DNA damage is sensed by ATM and ATR (Rad3 and Mec1 in yeast), which then signal to Chk1 and Chk2. Chk1 then mediates the degradation of cdc25A
, an activator of CDK1. ATR/ATM also activate p53, indicating that these pathways may act synergistically in regulating G2 arrest.
Both p53-dependent and p53-independent cell cycle arrest are not specific to G2; these same proteins function upstream in DNA damage checkpoints in G1
and S phase as well. In yeast, which has no p53 homolog
, G2 arrest functions through the p53-independent pathway.
, biochemical switches in the cell cycle
Mitotic entry is determined by a threshold level of active cyclin B1/CDK1 complex. In vertebrates, there are five cyclin B isoforms (B1
, B2
, B3, B4, and B5), but specific role of each of these isoforms in regulating mitotic entry is still unclear. It is known that cyclin B1 can compensate for loss of both cyclin B2 (and vice versa in Drosophila
). Cyclin B1/CDK1 activity is regulated both spatially and temporally during G2 phase to ensure proper entry into mitosis.
Cyclin B1 transcription begins at the end of S phase after DNA replication. Its promoter contains consensus binding sequences
for a number of transcription factors, including p53
, p21
, Ets
, Ap-1
, NF-Y, c-Myc
, TFE3
, and USF. Cyclin B1 accumulates in the cytoplasm throughout G2, where it binds to and activates CDK1’s kinase activity. CDK1 activity is modulated primarily through regulation of its inhibitory phosphorylation sites at Thr14 and Tyr15. Wee1 and Myt1
phosphorylate these two residues, with Wee1 acting on the Tyr15 site and Myt1 acting predominantly on the Thr14 site. However, Myt1 has a separate inhibitory effect on CDK1; it can also sequester CDK1 in the cytoplasm
via interaction with Myt1’s C-terminal domain
. CDK1 is dephosphorylated primarily through the actions of Cdc25, which can dephosphorylate both the Thr14 and Tyr15 residues of CDK1. There are three isoforms of Cdc25 (A
, B
, and C
) in mammalian cells, all of which have been shown to have roles in regulation of G2 phase.
CDK1, in turn, phosphorylates and modulates the activity of Wee1 and the Cdc25 isoforms A and C. Specifically, CDK1 phosphorylation inhibits Wee1 kinase activity, activates Cdc25C phosphatase
activity, and stabilizes Cdc25A. Thus, CDK1 forms a positive feedback
loop with Cdc25 and a double negative feedback loop with Wee1 (essentially a net positive feedback loop). These loops encode a hysteretic
bistable switch in CDK1 activity relative to Cyclin B1 levels. It is thought that this hysteretic behavior ensures that cells commit to mitosis even if cyclin B1 levels falter.
In mammals, cyclin B1/CDK1 translocation to the nucleus is activated by phosphorylation of five serine
sites on cyclin B1’s cytoplasmic retention site (CRS): S116, S26, S128, S133, and S147. In ‘’Xenopus Laevis’’, Cyclin B1 contains four analogous CRS serine phosphorylation sites (S94, S96, S101, and S113) indicating that this mechanism is highly conserved. Nuclear export is also inactivated by phosphorylation of Cyclin B1’s Nuclear export signal
(NES). The regulators of these phosphorylation sites are still largely unknown but several factors have been identified, including extracellular signal-regulated kinases
(ERKs), PLK1
, and CDK1 itself. Upon reaching some threshold level of phosphorylation, translocation of cyclin B1/CDK1 to the nucleus is extremely rapid. Once in the nucleus, Cyclin B1/CDK1 phosphorylates many targets in preparation for mitosis, including Histone H1
, nuclear lamins, centrosomal proteins
, and Microtubule Associated Proteins (MAPs)
.
Recently, evidence has emerged suggesting a more important role for cyclin A2
/CDK complexes in regulating entry into mitosis. Cyclin A2/CDK2 activity begins in early S phase and increases during G2. Cdc25B has been shown to dephosphorylate Tyr15 on CDK2 in early-to-mid G2 in a manner similar to the aforementioned CDK1 mechanism. Downregulation of cyclin A2 in U2OS cells increases Wee1 activity and lowers Plk1 and Cdc25C activity. However, cyclin A2/CDK complexes do not function strictly as activators of cyclin B1/CDK1 in G2, as CDK2 has been shown to be required for activation of the p53-independent G2 checkpoint activity, perhaps through a stabilizing phosphorylation on Cdc6
. CDK2-/- cells also have aberrantly high levels of Cdc25A. Cyclin A2/CDK1 has also been shown to mediate proteosomal destruction of Cdc25B. These pathways are often deregulated in cancer.
Interphase
Interphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...
in 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...
directly preceding 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...
. It follows the successful completion of S phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
, during which the cell’s DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
is replicated. G2 phase ends with the onset of prophase
Prophase
Prophase, from the ancient Greek πρό and φάσις , is a stage of mitosis in which the chromatin condenses into a highly ordered structure called a chromosome in which the chromatin becomes visible. This process, called chromatin condensation, is mediated by the condensin complex...
, the first phase of mitosis in which the cell’s chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
condenses into chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s and the nuclear envelope
Nuclear envelope
A nuclear envelope is a double lipid bilayer that encloses the genetic material in eukaryotic cells. The nuclear envelope also serves as the physical barrier, separating the contents of the nucleus from the cytosol...
begins to break down.
Overview
G2 phase is a period of rapid cell growth and proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
synthesis during which the cell readies itself for mitosis. Curiously, G2 phase is not a necessary part of the cell cycle, as some cell types (particularly young Xenopus
Xenopus
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
embryos and some cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s ) proceed directly from 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...
to mitosis. Though much is known about the genetic network which regulates G2 phase and subsequent entry into mitosis, there is still much to be discovered concerning its significance and regulation, particularly in regards to cancer. One hypothesis is that the growth in G2 phase is regulated as a method of cell size control. Fission yeast (S. Pombe
Schizosaccharomyces pombe
Schizosaccharomyces pombe, also called "fission yeast", is a species of yeast. It is used as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measure 3 to 4 micrometres in diameter and 7 to 14 micrometres in length...
) has been previously shown to employ such a mechanism, via Cdr2
CDR2
CDR2 can refer to* Complementarity determining region 2 on antibodies* Cerebellar degeneration-related protein 2, a protein expressed by ovarian cancer cells...
-mediated spatial regulation of Wee1
Wee1
Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe . It has a molecular mass of 96 kDa and it is a key regulator of cell cycle progression....
activity. Though Wee1 is a fairly conserved negative regulator of mitotic entry, no general mechanism of cell size control in G2 has yet been elucidated.
Biochemically, the end of G2 phase occurs when a threshold level of active cyclin B1
Cyclin B1
G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the CCNB1 gene.- Function :Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with to form the maturation-promoting factor...
/CDK1
Cdk1
Cyclin dependent kinase 1 also known as Cdk1 or cell division control protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S....
complex, also known as Maturation promoting factor
Maturation promoting factor
Maturation-promoting factor is a heterodimeric protein composed of cyclin B and cyclin-dependent kinase that stimulates the mitotic and meiotic cell cycles...
(MPF) has been reached. The activity of this complex is tightly regulated during G2. In particular, the G2 checkpoint arrests cells in G2 in response to DNA damage through inhibitory regulation of CDK1.
G2/M Checkpoint
In vertebrateVertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
cells, the G2/M DNA damage checkpoint
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
consists of an arrest of the cell in G2 just before mitotic entry in response to genotoxic stress (such as UV radiation, oxidative stress, DNA intercalating agents, etc.) in both a p53
P53
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...
-dependent and p53-independent manner. DNA damage signals cause activation of the transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
p53. CDK1 is directly inhibited by three transcriptional targets of p53: p21
P21
p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...
, Gadd45
Gadd45
The Growth Arrest and DNA Damage or gadd45 genes, including , and , are implicated as stress sensors that modulate the response of mammalian cells to genotoxic/physiological stress, and modulate tumor formation...
, and 14-3-3σ. Inactive Cyclin B1/CDK1 is sequestered in the nucleus by p21, while active Cyclin B1/CDK1 complexes are sequestered in the cytoplasm by 14-3-3σ. Gadd45 disrupts the binding of Cyclin B1 and CDK1 through direct interaction with CDK1. P53 also transcriptionally represses CDK1.
P53-independent G2 arrest is mainly affected through the actions of Chk1 kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
. DNA damage is sensed by ATM and ATR (Rad3 and Mec1 in yeast), which then signal to Chk1 and Chk2. Chk1 then mediates the degradation of cdc25A
CDC25A
Cell division cycle 25 homolog A , also known as CDC25A, is a mammalian gene.-Interactions:CDC25A has been shown to interact with ASK1, Epidermal growth factor receptor, C-Raf, CHEK1, Cyclin E1, PIM1 and YWHAB.-Further reading:...
, an activator of CDK1. ATR/ATM also activate p53, indicating that these pathways may act synergistically in regulating G2 arrest.
Both p53-dependent and p53-independent cell cycle arrest are not specific to G2; these same proteins function upstream in DNA damage checkpoints in G1
G1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
and S phase as well. In yeast, which has no p53 homolog
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
, G2 arrest functions through the p53-independent pathway.
End of G2/Entry into Mitosis
See also: maturation promoting factorMaturation promoting factor
Maturation-promoting factor is a heterodimeric protein composed of cyclin B and cyclin-dependent kinase that stimulates the mitotic and meiotic cell cycles...
, biochemical switches in the cell cycle
Biochemical switches in the cell cycle
A series of biochemical switches control transitions between and within the various phases of the cell cycle. The cell cycle is a series of complex, ordered, sequential events that control how a single cell divides into two cells, and involves several different phases...
Mitotic entry is determined by a threshold level of active cyclin B1/CDK1 complex. In vertebrates, there are five cyclin B isoforms (B1
Cyclin B1
G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the CCNB1 gene.- Function :Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with to form the maturation-promoting factor...
, B2
Cyclin B2
G2/mitotic-specific cyclin-B2 is a protein that in humans is encoded by the CCNB2 gene.-Interactions:Cyclin B2 has been shown to interact with TGF beta receptor 2.-Further reading:...
, B3, B4, and B5), but specific role of each of these isoforms in regulating mitotic entry is still unclear. It is known that cyclin B1 can compensate for loss of both cyclin B2 (and vice versa in Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
). Cyclin B1/CDK1 activity is regulated both spatially and temporally during G2 phase to ensure proper entry into mitosis.
Cyclin B1 transcription begins at the end of S phase after DNA replication. Its promoter contains consensus binding sequences
Consensus sequence
In molecular biology and bioinformatics, consensus sequence refers to the most common nucleotide or amino acid at a particular position after multiple sequences are aligned. A consensus sequence is a way of representing the results of a multiple sequence alignment, where related sequences are...
for a number of transcription factors, including p53
P53
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...
, p21
P21
p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...
, Ets
ETS
ETS is an abbreviation of:* Expiration, term of service, US Army* Euro Truck Simulator video game* The Elements of Typographic Style, a book on typography* Enterprise test software, software used by electronics manufacturers for product testing...
, Ap-1
AP-1 (transcription factor)
In the field of molecular biology, the activator protein 1 is a transcription factor which is a heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors,...
, NF-Y, c-Myc
Myc
Myc is a regulator gene that codes for a transcription factor. In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences and recruiting histone acetyltransferases...
, TFE3
TFE3
Transcription factor E3 is a protein that in humans is encoded by the TFE3 gene.-Interactions:TFE3 has been shown to interact with E2F3, Mothers against decapentaplegic homolog 3 and Microphthalmia-associated transcription factor.-Further reading:...
, and USF. Cyclin B1 accumulates in the cytoplasm throughout G2, where it binds to and activates CDK1’s kinase activity. CDK1 activity is modulated primarily through regulation of its inhibitory phosphorylation sites at Thr14 and Tyr15. Wee1 and Myt1
MYT1
Myelin transcription factor 1 is a protein that in humans is encoded by the MYT1 gene.- External links :...
phosphorylate these two residues, with Wee1 acting on the Tyr15 site and Myt1 acting predominantly on the Thr14 site. However, Myt1 has a separate inhibitory effect on CDK1; it can also sequester CDK1 in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
via interaction with Myt1’s C-terminal domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
. CDK1 is dephosphorylated primarily through the actions of Cdc25, which can dephosphorylate both the Thr14 and Tyr15 residues of CDK1. There are three isoforms of Cdc25 (A
CDC25A
Cell division cycle 25 homolog A , also known as CDC25A, is a mammalian gene.-Interactions:CDC25A has been shown to interact with ASK1, Epidermal growth factor receptor, C-Raf, CHEK1, Cyclin E1, PIM1 and YWHAB.-Further reading:...
, B
CDC25B
M-phase inducer phosphatase 2 is an enzyme that in humans is encoded by the CDC25B gene.-Interactions:CDC25B has been shown to interact with MAPK14, Casein kinase 2, alpha 1, CHEK1, MELK, Estrogen receptor alpha, YWHAB, YWHAZ, YWHAH and YWHAE....
, and C
CDC25C
M-phase inducer phosphatase 3 is an enzyme that in humans is encoded by the CDC25C gene.-Interactions:CDC25C has been shown to interact with MAPK14, CHEK1, PCNA, PIN1, PLK3 and NEDD4.-Further reading:...
) in mammalian cells, all of which have been shown to have roles in regulation of G2 phase.
CDK1, in turn, phosphorylates and modulates the activity of Wee1 and the Cdc25 isoforms A and C. Specifically, CDK1 phosphorylation inhibits Wee1 kinase activity, activates Cdc25C phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
activity, and stabilizes Cdc25A. Thus, CDK1 forms a positive feedback
Positive feedback
Positive feedback is a process in which the effects of a small disturbance on a system include an increase in the magnitude of the perturbation. That is, A produces more of B which in turn produces more of A. In contrast, a system that responds to a perturbation in a way that reduces its effect is...
loop with Cdc25 and a double negative feedback loop with Wee1 (essentially a net positive feedback loop). These loops encode a hysteretic
Hysteresis
Hysteresis is the dependence of a system not just on its current environment but also on its past. This dependence arises because the system can be in more than one internal state. To predict its future evolution, either its internal state or its history must be known. If a given input alternately...
bistable switch in CDK1 activity relative to Cyclin B1 levels. It is thought that this hysteretic behavior ensures that cells commit to mitosis even if cyclin B1 levels falter.
In mammals, cyclin B1/CDK1 translocation to the nucleus is activated by phosphorylation of five serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
sites on cyclin B1’s cytoplasmic retention site (CRS): S116, S26, S128, S133, and S147. In ‘’Xenopus Laevis’’, Cyclin B1 contains four analogous CRS serine phosphorylation sites (S94, S96, S101, and S113) indicating that this mechanism is highly conserved. Nuclear export is also inactivated by phosphorylation of Cyclin B1’s Nuclear export signal
Nuclear export signal
A nuclear export signal is a short amino acid sequence of 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite effect of a nuclear localization signal, which targets a...
(NES). The regulators of these phosphorylation sites are still largely unknown but several factors have been identified, including extracellular signal-regulated kinases
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
(ERKs), PLK1
PLK1
Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 or serine/threonine-protein kinase 13 , is an enzyme that in humans is encoded by the PLK1 gene.- Structure :...
, and CDK1 itself. Upon reaching some threshold level of phosphorylation, translocation of cyclin B1/CDK1 to the nucleus is extremely rapid. Once in the nucleus, Cyclin B1/CDK1 phosphorylates many targets in preparation for mitosis, including Histone H1
Histone H1
Histone H1 is one of the five main histone protein families which are components of chromatin in eukaryotic cells. Though highly conserved, it is nevertheless the most variable histone in sequence across species.- Structure :...
, nuclear lamins, centrosomal proteins
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...
, and Microtubule Associated Proteins (MAPs)
Microtubule-associated protein
In cell biology, microtubule-associated proteins are proteins that interact with the microtubules of the cellular cytoskeleton.-Function:...
.
Recently, evidence has emerged suggesting a more important role for cyclin A2
Cyclin A2
Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene.-Interactions:Cyclin A2 has been shown to interact with ITGB3BP, Retinoblastoma-like protein 1, E2F1, CDC6, SKP2 and Flap structure-specific endonuclease 1.-References:...
/CDK complexes in regulating entry into mitosis. Cyclin A2/CDK2 activity begins in early S phase and increases during G2. Cdc25B has been shown to dephosphorylate Tyr15 on CDK2 in early-to-mid G2 in a manner similar to the aforementioned CDK1 mechanism. Downregulation of cyclin A2 in U2OS cells increases Wee1 activity and lowers Plk1 and Cdc25C activity. However, cyclin A2/CDK complexes do not function strictly as activators of cyclin B1/CDK1 in G2, as CDK2 has been shown to be required for activation of the p53-independent G2 checkpoint activity, perhaps through a stabilizing phosphorylation on Cdc6
Cdc6
Cdc6, or Cell Division Cycle 6, is a protein in eukaryotic cells that is studied in the budding yeast Saccharomyces cerevisiae. It is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle that coordinate...
. CDK2-/- cells also have aberrantly high levels of Cdc25A. Cyclin A2/CDK1 has also been shown to mediate proteosomal destruction of Cdc25B. These pathways are often deregulated in cancer.