Cyclins and Their Catalytic Partners (CDKs) In The Cell Cycle

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(Last Updated On: April 23, 2017)
cell cycle abnormalities in patients with gastrointestinal cancers

Cell-Cycle abnormalities in patients with gastrointestinal cancers. Image: Mikhail et al. 2015

The proliferation of the gastrointestinal cancer is not only linked to the activation of the different types of oncogenes such as Ras proteins and dysfunction of the tumor suppressor genes but also linked to the DNA repair pathway and cell cycle deregulation.

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The cell cycle is a highly regulated biological process that is composed of different regulatory, catalytic and inhibitory proteins. These proteins direct the normal cell proliferation and cell differentiation. There are different stages of the cell division; mitosis, the preparatory stage of the cell cycle to make the cell ready for division and interphase with subphases G1, S, and G2

Phases and subphases of the cell cycle are controlled through the cyclic expression of the regulatory proteins such as cyclin, their catalytic partners; cyclin-dependent protein kinases and cyclin-dependent protein kinase inhibitors (CDKis).

There are nine types of CDKs and five of them are most important for the cell cycle regulation. CDK4 and CDK6 are associated with cyclin D (D1, D2 and D3) to regulate the progression of the cell cycle in the G1 phase while Cyclin E-CDK2 complex regulates the late G1 phase and also induce the DNA synthesis in the early S phase. Cyclin A-CDK1 complex along with the Cyclin H-CDK7 promotes the entry of the cell into the M phase. At last, Cyclin B-CDK1 complex mediates the mitotic entry.

In normal condition, cells with a lack of proper growth conditions are arrested into a resting phase or G phase, which is also a part of the G1 phase. When mitotic signal stimulates the G0 phase, cells progress towards the G1 checkpoint.  The G1 checkpoint is called as a restriction (R) point which is regulated by the tumor suppressor protein retinoblastoma-1 (Rb1). Retinoblastoma-1 binds to the transcription factor E2F and prevents the E2F regulated gene expression.

Retinoblastoma-1 is a substrate for the cyclin D-CDK4/6 complex where this complex phosphorylates the Rb1 thereby inactivating it. The inactivated Rb1 and the cyclin D-CDK4/6 promote the progression of the early G1 phase towards the R point. Once the cells pass through the R point, they are committed to the entry into the S phase.

The inactivated retinoblastoma-1 also prevents the inhibitory effect of the transcription factor E2F and thereby allows the expression of the E2F regulated genes. E2F regulated expression includes the genes mediating DNA replication, nucleotide biosynthesis, and enzymes of the DNA repair system such as DNA polymerase-α, thymidylate synthase, thymidine kinase, ribonucleotide reductase, etc.

Therefore, to maintain the proper G1 regulation, Cyclin D-CDK4/5 complex is antagonized by the INK4. INK4 is a member of the CDK inhibitory proteins (CDKis) and are of different types such as p16INK4a, p15INK4b, p18INK4c and p19INK4d. They are specific for the catalytic subunits of the CDK 4 and CDK6.

The CDK-interacting proteins or Kinase inhibitor proteins (CIP/KIP) are another family of the CDK inhibitors and include p21Cip1, p27Kip1 and p57Kip. They are potent inhibitors of the cyclin A and E and their catalytic partners, CDK1 and CDK2 respectively.

Cyclin E-CDK2 complex promotes the progress of the late G1 phase and induces the DNA synthesis in the S phase by phosphorylating the p27Kip1. CDK2 also forms a complex with cyclin A that promotes the proper DNA replication in the S phase while in the late G1 phase and early M phase. The cyclin A-CDK1 complex along with the cyclin H-CDK7 complex (also called as a CDK-activating kinase) promotes the cell entry into the M-phase.

At last, cyclin B-CDK1 complex controls the cell progress through the G2 phase into the M phase while to continue the cell cycle from M phase, cyclin B needs to be degraded mediated by the ubiquitination.

In conclusion, defective cyclin and CDK function are the main cause of the dysfunctional cell cycle that occurs in most of the cancer cells and, therefore, targeting the CDK is a potential strategy to develop the cancer therapeutics.

Reference: The American Journal of Pathology (Cyclin-Dependent Kinase Inhibitors and the Treatment of Gastrointestinal Cancers)

Article doi: 10.1016/j.ajpath.2015.01.008

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