In general, all stages of the cell cycle are chronologically separated in humans and are triggered by cyclin-Cdk complexes which are periodically expressed and partially redundant in function.

The abundance of cyclins is generally regulated by protein synthesis and degradation through APC/C- and CRL-dependent pathways.

The yeast homologue of cyclin D, referred to as CLN3, interacts with Cdc28 (cell division control protein) during G1.

The second five-helix bundle is composed of the same arrangement of helices, but the primary sequence of the two subdomains is distinct.

Rb is an important regulator of genes responsible for progression through the cell cycle, in particular through G1/S phase.

This happens in response to sensors of external growth-regulatory signals and cell growth, and Rb is phosphorylated as a result.

The cyclin D-Cdk4,6, complex, through phosphorylation and inactivation of metabolic enzymes, also influences cell survival.

When the final 37 amino acid residues are truncated, it had previously been shown that Rb phosphorylation levels are reduced and G1 arrest is induced.

[14] Kinetic assays have shown that with the same truncation, the reduction of Rb phosphorylation by cyclin D1-Cdk4,6 is 20 fold and Michaelis-Menten constant (Km) is significantly increased.

Deletion of this helix or disruption of it via proline residue substitutions also show a significant reduction in Rb phosphorylation.

[25] Inhibition of cyclin D via inactivation or degradation leads to cell cycle exit and differentiation.

Inactivation of cyclin D is triggered by several cyclin-dependent kinase inhibitor protein (CKIs) like the INK4 family (e.g. p14, p15, p16, p18).

Another way in which DNA damage targets Cdks is p53-dependent induction of p21, which inhibits cyclin E-Cdk2 complex.

Cyclins in yeast are controlled by expression, inhibition via CKIs like Far1, and degradation by ubiquitin-mediated proteolysis.

[29] Given that many human cancers happen in response to errors in cell cycle regulation and in growth factor dependent intracellular pathways, involvement of cyclin D in cell cycle control and growth factor signaling makes it a possible oncogene.

Gene amplification is responsible for overproduction of cyclin D protein in bladder cancer and esophageal carcinoma, among others.

[5] In cases of sarcomas, colorectal cancers and melanomas, cyclin D overproduction is noted, however, without the amplification of the chromosomal region that encodes it (chromosome 11q13, putative oncogene PRAD1, which has been identified as a translocation event in case of mantle cell lymphoma[43]).

Likewise, overexpression of cyclin D protein due to gene translocation is observed in human breast cancer.

In its active form, Rb prevents crossing of the G1 checkpoint by blocking transcription of genes responsible for advances in cell cycle.

Thus, blocking transcription of INK4 gene would increase cyclin D/Cdk4 activity, which would in turn result in abnormal inactivation of Rb.

On the other hand, in case of cyclin D in cancer cells (or loss of p16INK4) wild-type Rb is retained.

Due to the importance of p16INK/cyclin D/Cdk4 or 6/Rb pathway in growth factor signaling, mutations in any of the players involved can give rise to cancer.

[5] Studies with mutants suggest that cyclins are positive regulators of cell cycle entry.