Cell Division Cycle Regulation | Role of Cyclins

Cyclins are a family of proteins that bind with the regulatory subunit of CDK and make them active. Cyclin was originally named so because their concentration varies in a cyclic fashion during the cell division cycle.

Key Features of Cyclins

Types of Cyclins

Classification of cyclin is based upon the structure of the conserved cyclin box. The fluctuation in cyclin concentration during the cell cycle is because of the destruction of cyclin by the ubiquitin-proteasome system. Cyclin has no catalytic activity. Different cyclins are required at different stages of the cell cycle.

CYCLIN D : The Gatekeeper of the Cell Cycle

Cyclin D synthesis is initiated during G1 phase. It drives the transition from G1 phase to S phase. When growth factors and mitogens (for a unicellular organism) are present, the cells start the expression of cyclin D. The growth factors work through RTK pathways and stimulate the Ras, Raf, and ERK which leads to the activation of Myc. Myc increases the rate of transcription of cyclin D. Cyclin D initiates the cell cycle and interacts with both CDK4 and CDK6.

The Cln3 is a yeast homologue of cyclin D. It interacts with Cdc28 (cell division control protein) during G1. In proliferating cells, the continuous signalling by a growth factor causes the accumulation of the cyclin D-CDK4/6 complex. This accumulation is of great importance for cell cycle progression.

Cyclin D-CDK4/6 complex partially phosphorylates retinoblastoma tumour suppressor protein (Rb). This phosphorylation of Rb is important for S phase progression. The phosphorylation of RB causes dissociation of RB from E2f. E2f is a transcription factor for Cyclin E. Cyclin E is important for S phase progression.

Cyclin E: Key Regulator of G1/S Transition

The transition from G1 to S phase requires binding between Cyclin E to G1 phase CDK2. Cyclin E/CDK2 phosphorylates retinoblastoma protein (Rb) to promote G1 progression. Hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase

In addition to Rb, Cyclin E/CDK2 targets other regulators:

• p27^Kip1 and p21^Cip1, which are CDK inhibitors, are phosphorylated by Cyclin E/CDK2 during the G1 and S phases, respectively. This phosphorylation marks them for ubiquitin-mediated degradation, thereby enhancing CDK activity and reinforcing cell cycle progression.

• Smad3, a downstream effector of the TGF-β signaling pathway (a known inhibitor of the cell cycle), is also phosphorylated by Cyclin E/CDK2. This phosphorylation inhibits Smad3’s transcriptional activity, effectively antagonizing TGF-β-mediated growth arrest.

• Other substrates include CBP/p300 (transcriptional coactivators) and E2F-5. Cyclin E/CDK2-mediated phosphorylation of these proteins stimulates transcriptional programs required for efficient cell cycle progression.

Cyclin A

Cyclin A plays a role in the regulation of two different stages of cell cycle. It can associate with both CDK2 and CDK1. The association of cyclin A with CDK2 is required for the passage of the cells into S phase while the association with CDK1 is required for entry into M phase. In S phase of cell division cycle, Cyclin A-CDK2 complex is present.

Cyclin B

Cyclin B is a mitotic cyclin. The complex of CDK and cyclin B is called maturation promoting factor or mitosis promoting factor (MPF). Cyclin B is necessary for the progression of the cells into and out of M phase of the cell cycle. Cyclin B synthesis starts in S phase but it is exported out of nucleus doe to the presence of a nucleus exporting sequence. Cyclin B-CDK1 complex activation causes breakdown of nuclear envelope and initiation of prophase and deactivation of this complex leads the cell to exit mitois. During late anaphase, cyclin B concentration falls abruptly due to the degradation by UPS (CDK1 is constitutively present).

Cyclin A and cyclin B have destruction box and cyclin D and E contains a PEST [P: Proline, E: glutamic acid, S: serine, T: threonine] sequence required for efficient ubiquitin-mediated cyclin proteolysis at the end of G1 phase of the cell cycle. Ubiquitin-mediated proteolysis of cyclin is catalysed by a ubiquitin ligase enzyme. Skp1-Cullin-F-box (SCF) and anaphase-promoting complex (APC) is responsible for the ubiquitylation and destruction of cyclins.

Cyclin Types and Their Cell Cycle Roles

Cyclins in Yeast vs. Humans