Cyclin
Cyclins are proteins that control the progression of a cell through the cell cycle by activating cyclin-dependent kinases (CDK).[1]
Etymology
Cyclins were originally discovered by
In an interview for "The Life Scientific" (aired on 13/12/2011) hosted by
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.[5]) The oscillations of the cyclins, namely fluctuations in cyclin gene expression and destruction by the ubiquitin mediated proteasome pathway, induce oscillations in Cdk activity to drive the cell cycle. A cyclin forms a complex with Cdk, which begins to activate but the complete activation requires phosphorylation, as well. Complex formation results in activation of the Cdk active site. Cyclins themselves have no enzymatic activity but have binding sites for some substrates and target the Cdks to specific subcellular locations.[5]
Cyclins, when bound with the dependent
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, such as 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.
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.
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.[6] Expression of cyclins detected immunocytochemically in individual cells in relation to cellular DNA content (cell cycle phase),[7] or in relation to initiation and termination of DNA replication during S-phase, can be measured by flow cytometry.[8]
Domain structure
Cyclins are generally very different from each other in primary structure, or amino acid sequence. However, all members of the cyclin family are similar in 100 amino acids that make up the cyclin box. Cyclins contain two
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.[12][13] A study in C. elegans revealed the specific roles of mitotic cyclins.[14][15] Notably, recent studies have shown that cyclin A creates a cellular environment that promotes microtubule detachment from kinetochores in prometaphase to ensure efficient error correction and faithful chromosome segregation. Cells must separate their chromosomes precisely, an event that relies on the bi-oriented attachment of chromosomes to spindle microtubules through specialized structures called kinetochores. In the early phases of division, there are numerous errors in how kinetochores bind to spindle microtubules. The unstable attachments promote the correction of errors by causing a constant detachment, realignment and reattachment of microtubules from kinetochores in the cells as they try to find the correct attachment. Protein cyclin A governs this process by keeping the process going until the errors are eliminated. In normal cells, persistent cyclin A expression prevents the stabilization of microtubules bound to kinetochores even in cells with aligned chromosomes. As levels of cyclin A decline, microtubule attachments become stable, allowing the chromosomes to be divided correctly as cell division proceeds. In contrast, in cyclin A-deficient cells, microtubule attachments are prematurely stabilized. Consequently, these cells may fail to correct errors, leading to higher rates of chromosome mis-segregation.[16]
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,
- G2/M cyclins – essential for the control of the cell cycle at the G2/M transition (mitosis). G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase).
- CDK1– regulates progression from G2 to M phase.
Subtypes
The specific cyclin subtypes along with their corresponding CDK (in brackets) are:
| 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? ( Cdc2 )
|
Puc1, Cig1? (Cdc2) | Cig2, Cig1? (Cdc2) | Cdc13 (Cdc2) |
| 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
|
Cdk6 )
|
Cdk2 )
|
Cdk1 )
|
Cdk1 )
|
| family | members |
|---|---|
| A | CCNA1, CCNA2 |
| B | CCNB1, CCNB2, CCNB3 |
| C | CCNC
|
| D | CCND1, CCND2, CCND3 |
| E | CCNE1, CCNE2 |
| F | CCNF |
| G | CCNG1, CCNG2 |
| H | CCNH |
| I | CCNI, CCNI2 |
| J | CCNJ, CCNJL |
| K | CCNK |
| L | CCNL1, CCNL2 |
| O | CCNO |
| P | CCNP |
| T | CCNT1, CCNT2 |
| Y | CCNY, CCNYL1, CCNYL2, CCNYL3 |
Other proteins containing this domain
In addition, the following human protein contains a cyclin domain:
History
References
- S2CID 19528945.
- S2CID 32305758.
- ^ "Tim Hunt - Biographical". NobelPrize.org.
- ^ a b "The Life Scientific". BBC Radio 4. BBC. Retrieved 13 December 2011.
- ^ ISBN 978-0-19-920610-0.
- S2CID 21441201.
- PMID 8875049.
- PMID 26059433.
- S2CID 5118433.
- PMID 8591034.
- PMID 11377199.
- PMID 15840442.
- ISBN 978-0-470-04217-5.
- PMID 19829076.
- PMID 20016257.
- S2CID 34397179.
- ^ "The Nobel Prize in Physiology or Medicine 2001". The Nobel Foundation. Retrieved 2009-03-15.
Further reading
- Krieger M, Scott MP, Matsudaira PT, Lodish HF, Darnell JE, Zipursky L, Kaiser C, Berk A (2004). Molecular cell biology (Fifth ed.). New York: W.H. Freeman and CO. ISBN 0-7167-4366-3.
External links
- Eukaryotic Linear Motif resource motif class LIG_CYCLIN_1