All tags Cancer D-type cyclins

D-type cyclins

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 necessary for the activation of CDK4 and CDK6, and are expressed in response to the presence of mitogens.

The cyclin D-CDK4/6 active complex phosphorylates targets that permit the transition from G1 to S phase (Malumbres & Barbacid, 2009).

Cyclin D1, D2 and D3

There are three D-type cyclins: cyclin D1, cyclin D2 and cyclin D3, which are closely related in protein domain structure.

All contain a ‘cyclin box’ domain, which mediates CDK binding; an N-terminal retinoblastoma tumor suppressor protein (RB) binding domain; and a C-terminal region PEST domain, which includes a vital threonine residue that allows regulation of cyclin proteolysis through phosphorylation. A second human cyclin D1 isoform, cyclin D1b, lacks a portion of the C-terminus and arises from 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. This leads to the derepression of E2F transcription factors, which then induce expression of genes required for entry into S phase. Other target substrates include proteins involved in migration, mitochondrial function, the DNA damage response and centrosome duplication.

Non-catalytic roles of D-type cyclins

D-type cyclins also have non-catalytic roles in transcriptional regulation, chromatin modification, migration, the DNA damage response, interactions with nuclear hormone receptors and, importantly for cell cycle progression, sequestration of CDK inhibitors (Musgrove et al., 2011).

Knockout of individual D-type cyclins in mouse models results in diverse but mild phenotypes, which suggests that, while they have redundant roles in most cells, individual D- type cyclins are required for specific roles in some cell types (Choi & Anders, 2014).

D-type cyclins and cancer

Aberrant cell cycle regulation is a primary characteristic of cancer. A large body of evidence now links deregulation of cyclin D-CDK4/6 with many human cancers and there are several inhibitors of CDK4/6 in clinical trials (Choi & Anders, 2014).

Although the involvement of cyclin D1 in cancer has been the subject of most investigations, it has been demonstrated that cyclin D3 is required for the development of Notch1-induced T cell acute lymphoblastic leukemia (Malumbres, 2012).

Cyclin D1 and cancer

Overexpression of cyclin D1 has been reported in a large proportion of human cancers, and is found in the majority of breast cancer cases. Upregulation of cyclin D1 may occur as a result of gene locus alterations, aberrant transcriptional signalling or disruption of cyclin D1 proteolysis.

This leads to prolonged cyclin D1-CDK4/6 activation, giving cancer cells the power to enter the cell cycle continuously and to avoid senescence and apoptosis (Choi & Anders, 2014).

In a key experiment, Yu et al. (2001) showed that removal of the cyclin D1 gene from the mouse genome prevented ERBB2 (a breast cancer oncogene) induced tumorigenesis.

Furthermore, knockout of cyclin D1 in mouse models with established tumours demonstrated a role for cyclin D1 in tumor maintenance by preventing apoptosis or senescence of cancer cells (Choi et al., 2012). However, further mouse model studies indicated that ablation of cyclin D1 alone is insufficient to prevent ERBB2-induced tumorigenesis due to a compensatory upregulation of cyclin D3 (Zhang et al., 2014).

Thus, further investigation is needed to clarify the relative roles of the D-type cyclins in different cancer types.

References

  • 1. Choi, Y. J., & Anders, L. (2014). Signaling through cyclin D-dependent kinases. Oncogene, 33 (15), 1890–903.
  • 2. 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.
  • 3. Malumbres, M. (2012). Cell cycle-based therapies move forward. Cancer Cell, 22 (4), 419–20.
  • 4. Malumbres, M., & Barbacid, M. (2009). Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer, 9 (3), 153–66.
  • 5. 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.
  • 6. Yu, Q., Geng, Y., & Sicinski, P. (2001). Specific protection against breast cancers by cyclin D1 ablation. Nature, 411 (6841), 1017–21.
  • 7. 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.