Cyclin
Encyclopedia
Cyclins are a family of proteins
that control the progression of cells through the cell cycle
by activating cyclin-dependent kinase
(Cdk) enzyme
s.
. Cyclins themselves have no enzymatic activity but have binding sites for some substrates and target the Cdks to specific subcellular locations.
They were discovered by R. Timothy Hunt in 1982 while studying the cell cycle of sea urchins.
Cyclins, when bound with the dependent kinase
s, such as the p34
(cdc2
) or cdk1 proteins, form the maturation-promoting factor. MPFs activate other proteins through phosphorylation
. These phosphorylated proteins, in turn, are responsible for specific events during cycle division such as microtubule
formation and chromatin remodeling
. Cyclins can be divided into four classes based on their behavior in the cell cycle of vertebrate somatic cells and yeast cells: G1/S cyclins, S cyclins, M cyclins, G1 cyclins. This division is useful when talking about most cell cycles, but it is not universal as some cyclins have different functions or timing in different cell types.
G1/S Cyclins rise in late G1 and fall in early S phase. The Cdk- G1/S cyclin complex begins to induce the initial processes of DNA replication, primarily by arresting systems that prevent S phase Cdk activity in G1. The cyclins also promote other activities to progress the cell cycle, like centrosome duplication in vertebrates or spindle pole body in yeast. The rise in presence of G1/S cyclins is paralleled by a rise in S cyclins.
S cyclins bind to Cdk and the complex directly induces DNA replication. The levels of S cyclins remain high, not only throughout S phase, but through G2 and early mitosis as well to promote early events in mitosis.
M cyclin concentrations rise as the cell begins to enter mitosis and the concentrations peak at metaphase. Cell changes in the cell cycle like the assembly of mitotic spindles and alignment of sister-chromatids along the spindles are induced by M cyclin- Cdk complexes. The destruction of M cyclins during metaphase and anaphase, after the Spindle Assembly Checkpoint is satisfied, causes the exit of mitosis and cytokinesis .
G1 cyclins do not behave like the other cyclins, in that the concentrations increase gradually (with no oscillation), throughout the cell cycle based on cell growth and the external growth-regulatory signals. The presence of G cyclins coordinate cell growth with the entry to a new cell cycle.
of similar all-α fold, the first located at the N-terminus and the second at the C-terminus. All cyclins are believed to contain a similar tertiary structure of two compact domains of 5 α helices. The first of which is the conserved cyclin box, outside of which cyclins are divergent. For example, the amino-terminal regions of S and M cyclins contain short destruction-box motifs that target these proteins for proteolysis in mitosis.
CABLES2, CNTD1, CNTD2
, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine
for their discovery of cyclin and cyclin-dependent kinase.
Protein family
A protein family is a group of evolutionarily-related proteins, and is often nearly synonymous with gene family. The term protein family should not be confused with family as it is used in taxonomy....
that control the progression of cells through 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...
by activating cyclin-dependent kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
(Cdk) enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s.
Function
Cyclins were originally named because their concentration varies in a cyclical fashion during the cell cycle. (Note that the cyclins are now classified according to their conserved cyclin box structure, and not all these cyclins alter in level through the cell cycle .) The oscillations of the cyclins, namely fluctuations in cyclin gene expression and destruction by proteolysis, induce oscillations in Cdk activity to drive the cell cycle. A cyclin forms a complex with Cdk, which begins to activate the Cdk, but the complete activation requires phosphorylation, as well. Complex formation results in activation of the Cdk active siteActive site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
. Cyclins themselves have no enzymatic activity but have binding sites for some substrates and target the Cdks to specific subcellular locations.
They were discovered by R. Timothy Hunt in 1982 while studying the cell cycle of sea urchins.
Cyclins, when bound with the dependent 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...
s, such as the p34
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....
(cdc2
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....
) or cdk1 proteins, form the maturation-promoting factor. MPFs activate other proteins through phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
. These phosphorylated proteins, in turn, are responsible for specific events during cycle division such as microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
formation and chromatin remodeling
Chromatin Structure Remodeling (RSC) Complex
RSC is a 17-subunit complex with the capacity to remodel the structure of chromatin. It exhibits a DNA-dependent ATPase activity stimulated by both free and nucleosomal DNA and a capacity to perturb nucleosome structures...
. Cyclins can be divided into four classes based on their behavior in the cell cycle of vertebrate somatic cells and yeast cells: G1/S cyclins, S cyclins, M cyclins, G1 cyclins. This division is useful when talking about most cell cycles, but it is not universal as some cyclins have different functions or timing in different cell types.
G1/S Cyclins rise in late G1 and fall in early S phase. The Cdk- G1/S cyclin complex begins to induce the initial processes of DNA replication, primarily by arresting systems that prevent S phase Cdk activity in G1. The cyclins also promote other activities to progress the cell cycle, like centrosome duplication in vertebrates or spindle pole body in yeast. The rise in presence of G1/S cyclins is paralleled by a rise in S cyclins.
S cyclins bind to Cdk and the complex directly induces DNA replication. The levels of S cyclins remain high, not only throughout S phase, but through G2 and early mitosis as well to promote early events in mitosis.
M cyclin concentrations rise as the cell begins to enter mitosis and the concentrations peak at metaphase. Cell changes in the cell cycle like the assembly of mitotic spindles and alignment of sister-chromatids along the spindles are induced by M cyclin- Cdk complexes. The destruction of M cyclins during metaphase and anaphase, after the Spindle Assembly Checkpoint is satisfied, causes the exit of mitosis and cytokinesis .
G1 cyclins do not behave like the other cyclins, in that the concentrations increase gradually (with no oscillation), throughout the cell cycle based on cell growth and the external growth-regulatory signals. The presence of G cyclins coordinate cell growth with the entry to a new cell cycle.
Domain structure
Cyclins are generally very different from each other in primary structure, or amino acid sequence. The similarity between members of the cyclin family are similar in the 100 amino acids that make up the cyclin box. Cyclins contain two domainsProtein 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...
of similar all-α fold, the first located at the N-terminus and the second at the C-terminus. All cyclins are believed to contain a similar tertiary structure of two compact domains of 5 α helices. The first of which is the conserved cyclin box, outside of which cyclins are divergent. For example, the amino-terminal regions of S and M cyclins contain short destruction-box motifs that target these proteins for proteolysis in mitosis.
Types
There are several different cyclins that are active in different parts of the cell cycle and that cause the Cdk to phosphorylate different substrates. There are also several "orphan" cyclins for which no Cdk partner has been identified. For example, cyclin F is an orphan cyclin that is essential for G2/M transition.Main groups
There are two main groups of cyclins:- G1/S cyclins – essential for the control of the cell cycle at the G1/S transition,
- Cyclin ACyclin ACyclin 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:*...
/ CDK2Cyclin-dependent kinase 2Cyclin-dependent kinase 2 also known as cell division protein kinase 2 is an enzyme that in humans is encoded by the CDK2 gene.-Function:...
– active in S phase. - Cyclin DCyclin DCyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition...
/ CDK4Cyclin-dependent kinase 4Cyclin-dependent kinase 4 is part of the cyclin-dependent kinase family.It is regulated by Cyclin D.-Interactions:Cyclin-dependent kinase 4 has been shown to interact with SERTAD1, CDC37, CEBPA, PCNA, Cyclin D3, Cyclin D1, CDKN2C, MyoD, P16, CDKN2B, Drebrin-like and CDKN1B.-External links:...
, Cyclin D / CDK6Cyclin-dependent kinase 6Cell division protein kinase 6 is an enzyme that in humans is encoded by the CDK6 gene.It is regulated by Cyclin D.-Interactions:Cyclin-dependent kinase 6 has been shown to interact with CDKN2C, P16, PPM1B, Cyclin D3, Cyclin D1 and PPP2CA....
, and Cyclin ECyclin ECyclin 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....
/ CDK2 – regulates transition from G1 to S phase.
- Cyclin A
- G2/M cyclins – essential for the control of the cell cycle at the G2/M transition (mitosisMitosisMitosis 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...
). G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phaseMetaphaseMetaphase, from the ancient Greek μετά and φάσις , is a stage of mitosis in the eukaryotic cell cycle in which condensed & highly coiled chromosomes, carrying genetic information, align in the middle of the cell before being separated into each of the two daughter cells...
).- Cyclin BCyclin BCyclin B is a member of the cyclin family.Cyclin B is a mitotic cyclin. The amount of cyclin B and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of cyclin B...
/ CDK1Cdk1Cyclin 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....
– regulates progression from G2 to M phase.
- Cyclin B
Subtypes
Specific cyclin subtypes include:| Species | G1 | G1/S | S | M |
|---|---|---|---|---|
| S. cerevisiae | Cln3 (Cdk1) | Cln 1,2 (Cdk1) | Clb 5,6 (Cdk1) | Clb 1,2,3,4 (Cdk 1) |
| S. pombe | Puc1? (Cdk1) | Puc1, Cig1? (Cdk1) | Cig2, Cig1? (Cdk1) | Cdc13 (Cdk1) |
| D. melanogaster | cyclin D (Cdk4) | cyclin E (Cdk2) | cyclin E, A (Cdk2,1) | cyclin A, B, B3 (Cdk1) |
| X. laevis | either not known or not present | cyclin E (Cdk2) | cyclin E, A (Cdk2,1) | cyclin A, B, B3 (Cdk1) |
| H. sapiens | cyclin D Cyclin D Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition... 1,2,3 (Cdk4,6) |
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.... (Cdk2) |
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:*... (Cdk2,1) |
cyclin B Cyclin B Cyclin B is a member of the cyclin family.Cyclin B is a mitotic cyclin. The amount of cyclin B and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of cyclin B... (Cdk1) |
| family | members |
|---|---|
| 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:*... |
CCNA1, CCNA2 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:... |
| B Cyclin B Cyclin B is a member of the cyclin family.Cyclin B is a mitotic cyclin. The amount of cyclin B and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of cyclin B... |
CCNB1 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... , CCNB2 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:... , CCNB3 |
| C | CCNC |
| D Cyclin D Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition... |
CCND1 Cyclin D1 G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:... , CCND2 Cyclin D2 G1/S-specific cyclin-D2 is a protein that in humans is encoded by the CCND2 gene.-Further reading:... , CCND3 |
| 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.... |
CCNE1 Cyclin E1 G1/S-specific cyclin-E1 is a protein that in humans is encoded by the CCNE1 gene.-Interactions:Cyclin E1 has been shown to interact with Retinoblastoma-like protein 2, Cdk1, CDC25A, Cyclin-dependent kinase 2, SMARCA4, CDKN1B, HERC5, CUL3 and P21.... , CCNE2 |
| F | CCNF CCNF G2/mitotic-specific cyclin-F is a protein that in humans is encoded by the CCNF gene.-Further reading:... |
| G | CCNG1 CCNG1 Cyclin-G1 is a protein that in humans is encoded by the CCNG1 gene.-Interactions:CCNG1 has been shown to interact with P16, Mdm2, PPP2R4 and P53.-Further reading:... , CCNG2 CCNG2 Cyclin-G2 is a protein that in humans is encoded by the CCNG2 gene.-Further reading:... |
| H | CCNH Cyclin H Cyclin-H is a protein that in humans is encoded by the CCNH gene.-Interactions:Cyclin H has been shown to interact with P53, Cyclin-dependent kinase 7 and MNAT1.-Further reading:... |
| I | CCNI CCNI (gene) Cyclin-I is a protein that in humans is encoded by the CCNI gene.-Further reading:... , CCNI2 |
| J | CCNJ, CCNJL |
| K | CCNK Cyclin K Cyclin-K is a protein that in humans is encoded by the CCNK gene.-Further reading:... |
| L | CCNL1 CCNL1 Cyclin-L1 is a protein that in humans is encoded by the CCNL1 gene.-Further reading:... , CCNL2 CCNL2 Cyclin-L2 is a protein that in humans is encoded by the CCNL2 gene.-Further reading:... |
| O | CCNO Cyclin O Cyclin-O is a protein that in humans is encoded by the CCNO gene.-Interactions:Cyclin O has been shown to interact with RPA2 and PCNA.-Further reading:... |
| T | CCNT1, CCNT2 |
| Y | CCNY, CCNYL1, CCNYL2, CCNYL3 |
Other proteins containing this domain
In addition, the following human proteins contain a cyclin domain:CABLES2, CNTD1, CNTD2
History
Leland H. HartwellLeland H. Hartwell
Leland Harrison Hartwell is former president and director of the Fred Hutchinson Cancer Research Center in Seattle, Washington. He shared the 2001 Nobel Prize in Physiology or Medicine with Paul Nurse and R...
, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
for their discovery of cyclin and cyclin-dependent kinase.