Cyclins and the Cell Cycle
Cyclins are cofactors that bind, activate and impart substrate specificity to cyclin-dependent kinases (CDKs) allowing cell cycle progression. D-type cyclins are essential for the activation of CDK4 and CDK6, and are expressed in response to the occurrence of mitogens.
The cyclin D-CDK4/6 active complex phosphorylates targets that permit the transition from G1 to S phase (Malumbres & Barbacid, 2009).
Cyclins D1, D2 and D3
There are three D-type cyclins - cyclins D1, D2 and D3, all of which have a very similar protein structure.
All of the D-type cyclins have the following domains:
- a domain called the ‘cyclin box’, through which CDK binding occurs
- an N-terminal retinoblastoma tumor suppressor protein (RB) binding domain
- a C-terminal region PEST domain containing an important threonine residue responsible for phosphorylation-mediated regulation of cyclin proteolysis
There is another isoform of human cyclin D1 called cyclin D1b, which does not have part of the C-terminal end, and is formed as a result of alternative splicing (Musgrove et al., 2011).
Targets of the Cyclin D-CDK4/6 Complex
Upon activation, cyclin D-CDK4/6 complexes phosphorylate their numerous target substrates, including RB and RB-like proteins. The result is that E2F transcription factors are derepressed, and this in turn causes the induction of genes that are mandatory for the cell’s entry into the S phase of the cell cycle.
Other substrates targeted by the cyclin D-CDK4/6 complex include migration proteins, mitochondrial proteins involved with the function of these organelles, proteins concerned with the response to DNA damage, and proteins involved with centrosome duplication.
Non-catalytic D-type Cyclin Functions
D-type cyclins are not only catalysts but also play other roles, such as regulating transcriptional processes, modifying chromatin structure, migration of cells, the response of cells to DNA damage, cell interactions with nuclear hormone receptors and the sequestration of CDK inhibitors, which is vital for progression of the cell cycle (Musgrove et al., 2011).
When individual D-type cyclins are subjected to knockout, in mouse experiments, the result is the mild expression of several different phenotypic forms. This may indicate that each of the D-type cyclins are required to play distinctive parts in some types of cells, even while they have redundant actions in most cell types (Choi & Anders, 2014).
D-type Cyclins and Cancer
Abnormalities in cell cycle regulation are characteristic of malignant cell growths. There is much evidence to suggest that in many human cancers the cyclin D-CDK4/6 complex has lost regulatory control, and for this reason several molecules which inhibit CDK4/6 are now under clinical trials (Choi & Anders, 2014).
Most published research has focused on the role played by cyclin D1 in cancer, but it is also known that cyclin D3 is necessary for the pathogenesis of Notch-1-induced T-cell acute lymphoblastic leukemia (Malumbres, 2012).
Cyclin D1 and Cancer
Cyclin D1 is found to be expressed at an excessively high level in many human malignancies, including most cases of breast cancer. This means that the cyclin D1 gene is upregulated, perhaps by changes at the gene locus, altered or abnormal transcriptional signaling, or by the prevention of normal cyclin D1 proteolysis.
The effect of such upregulation is that the cyclin D1-CDK4/6 gene remains in an activated state for a long time, which allows cancer cells to enter the cell cycle persistently, instead of becoming senescent and then entering apoptosis (Choi & Anders, 2014).
An important mouse experiment by Yu et al. (2001) demonstrated that the development of tumors induced by the breast cancer oncogene ERBB2 could be prevented by removing the cyclin D1 gene from the animal’s genome.
In another set of experiments with mice, those animals in whom tumors had already been established then underwent knockout of cyclin D1. The results showed that cyclin D1 was closely involved in maintaining tumor growth by preventing tumor cells from undergoing apoptosis or senescence (Choi et al., 2012). Later mouse studies indicated that cyclin D1 ablation in itself was not enough to prevent the development of tumors in response to ERBB2 induction, because it is compensated for by the upregulation of cyclin D3 (Zhang et al., 2014).
More studies will be necessary to clarify how different D-type cyclins act in the various types of cancer.
- Choi, Y. J., & Anders, L. (2014). Signaling through cyclin D-dependent kinases. Oncogene, 33 (15), 1890–903.
- Choi, Y. J., Li, X., Hydbring, P., Sanda, T., Stefano, J., Christie, A. L., Signoretti, S., Look, a T., Kung, A. L., von Boehmer, H., & Sicinski, P. (2012). The requirement for cyclin D function in tumor maintenance. Cancer Cell, 22 (4), 438–51.
- Malumbres, M. (2012). Cell cycle-based therapies move forward. Cancer Cell, 22 (4), 419–20.
- Malumbres, M., & Barbacid, M. (2009). Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer, 9 (3), 153–66.
- Musgrove, E. a, Caldon, C. E., Barraclough, J., Stone, A., & Sutherland, R. L. (2011). Cyclin D as a therapeutic target in cancer. Nat. Rev. Cancer, 11 (8), 558–72.
- Yu, Q., Geng, Y., & Sicinski, P. (2001). Specific protection against breast cancers by cyclin D1 ablation. Nature, 411 (6841), 1017–21.
- Zhang, Q., Sakamoto, K., & Wagner, K.-U. (2014). D-type Cyclins are important downstream effectors of cytokine signaling that regulate the proliferation of normal and neoplastic mammary epithelial cells. Mol. Cell. Endocrinol., 382 (1), 583–92.
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