Cyclin Proteins

 Cyclin Proteins Background

A number of potentially fatal human diseases like cancer involve cell cycle defects. Cell cycle control is regulated by an evolutionarily conserved family of serine/threonine protein kinases called cyclin-dependent kinases (Cdks) and their regulatory subunits, the cyclins. Critical cell cycle events are both positively and negatively regulated by specific Cdks, whose activities oscillate throughout the cell cycle. Cdk activities are controlled by several different mechanisms, including binding of the positively activating cyclin subunits, inhibition by Cdk inhibitor proteins, phosphorylation by Cdk activating kinases (CAKs) or inhibitory kinases, and dephosphorylation by cell-cycle regulated phosphatases.

The founding members of the cyclin family, cyclins A and B, were first discovered as proteins that oscillated throughout the cell cycle, peaking in late G2 and M phase. These proteins were later shown to be required to activate Cdk1, (also known as Cdc2), which is required for entry into M phase in most eukaryotes. At the N terminus of these mitotic cyclins, there is a 9-amino acid destruction motif (RXALG[D/N/E/V]IXN) (D box), which targets the protein for ubiquitin-dependent degradation by the 26S proteasome during mitosis. Ubiquitination is mediated by an E3 ubiquitin ligase known as anaphase promoting complex (APC), which has several key targets during mitosis. For example, securin, the inhibitor of separase, needs to be degraded at the onset of anaphase to promote sister chromatid separation.

Other cyclins with sequence similarity to cyclins A and B were subsequently identified and shown to be required at other points during the cell cycle. The best characterized of these in metazoans include D-type cyclins, which partner with Cdk4 to control G1 phase events, and E-type cyclins, which partner with Cdk2 to control the transition from G1 to S phase. Many of the cellular signals that control entry into S phase function by promoting the stability or degradation of CycD or CycE. D-type cyclins are synthesized in response to growth factor stimulation and persist as long as the stimulation still exists. The protein levels do not show strong oscillation during cell cycle but only form a weak peak near G1-S. Upon serum starvation, they are rapidly degraded. The half-life of these proteins is only about 30 minutes. The levels of CycE, on the other hand, oscillate with the cell cycle, peaking in late G1. These G1 cyclins do not contain the Nterminal destruction signals found in mitotic cyclins but do contain PEST sequences (enriched for the amino acids Pro, Glu, Ser, Thr) at the C-terminus, which have been suggested to target proteins for rapid degradation. It was later shown that binding of Cdk2 protected free CycE from degradation by the ubiquitin-proteasome pathway. Phosphorylation of CycE by its cognate Cdk promotes its recognition by the protein degradation machinery. The Ser within the PEST sequence is at least one of the phosphorylation sites, which is consistent with the assumption that PEST is part of the destruction signals for G1 cyclins. This phosphorylation-mediated degradation mechanism provides a self-limiting control of protein level. The ubiquitin ligase responsible for CycE ubiquitination is SCF, which is composed of Skp1, Cul1 (Cdc53), Rbx1, and an F-box containing protein.

Several other members of the cyclin family do not show cell-cycle-dependent degradation or synthesis and some have been shown to play roles in cellular processes that are not directly related to cell cycle regulation. One group of cyclins, for example, regulates transcription by activating Cdks that can phosphorylate the carboxyterminal tail of the large subunit of RNA polymerase II. Several additional members of the cyclin family remain uncharacterized or poorly characterized.

In summary, a number of proteins in the cyclin family have been identified by virtue of their conserved cyclin box domain. Some of these proteins oscillate with the cell cycle like the founding members of the family, while others do not. Almost all members of the family are thought to partner with specific Cdks. Some cyclin/Cdk complexes regulate the cell cycle, while others regulate transcription or unknown processes.