Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases

Abstract

The role of cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs), as core components of the machinery that drives cell cycle progression is well established. Increasing evidence indicates that mammalian cyclins and CDKs also carry out important roles in other cellular processes such as transcription, DNA damage repair, the control of cell death, differentiation, the immune response and metabolism. Some of these non-canonical functions are performed by cyclins or by CDKs, independent of their respective cell cycle partners, suggesting a substantial divergence in the function of these proteins during evolution.

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

“…CDK6 cooperates with the NF-κB subunit p65 to induce the expression of inflammatory genes [Handschick et al 2014]. Cyclin D-CDK4/6 complexes are also involved in glucose metabolism [Lee et al 2014] and in the processes of apoptosis and cell differentiation [Hydbring et al 2016]. The relevance of all these effects in different tumor types and their implication for the activity of CDK4/6 inhibitors must be better clarified.…”

“…Cyclins and CDKs can also regulate transcription factors and exert other functions independently from cyclin-CDK complexes' kinase activity [Hydbring et al 2016], and therefore not subject to inhibition by current CDK4/6 inhibitors. Among these are: a direct role of cyclin D1 in gene transcription [Bienvenu et al 2010]; its involvement in DNA damage repair [Jirawatnotai et al 2011]; its repression of specificity protein 1-mediated transcription [Shao and Robbins, 1995]; inhibition of cyclin D-interacting myb-like protein (DMP1, affecting, via p19 ARF and MDM2, the expression of p53) [Hirai and Sherr, 1996]; induction of vascular endothelial growth factor (VEGF) expression [Yasui et al 2006]; its activating action on the estrogen receptor (ER) [Zwijsen et al 1997], and inhibitory action on the androgen receptor [Reutens et al 2001].…”

“…Cyclins and CDKs have several functions beyond their canonical role in cell cycle [Hydbring et al 2016;Musgrove et al 2011]. Cyclin D-CDK complexes phosphorylate several transcription factors, and regulate their function independently of their action on the pocket proteins.…”

Interchangeable Roles for E2F Transcriptional Repression by the Retinoblastoma Protein and p27KIP1–Cyclin-Dependent Kinase Regulation in Cell Cycle Control and Tumor Suppression

“…The RB protein antagonizes S-phase entry by repressing E2F-regulated genes necessary for DNA replication (4). Working in opposition to pRB are CDKs (5), in particular cyclin Dand E-associated kinases, that phosphorylate and inactivate upstream regulators of cell cycle entry, including pRB and p27 KIP1 , as well as stimulate the activation of downstream effectors of DNA replication (6,7). While this suggests CDKs control pRB, a key target gene that is repressed by pRB-E2F is CCNE1, which encodes cyclin E, and this creates a regulatory loop whereby cyclin E/CDK2 becomes maximally active at almost the same time pRB is maximally phosphorylated and finally releases all E2Fs (4).…”

Characterization of a pumpkin mRNA encoding a Cyclin-Dependent Protein Kinase (CDK) potentially involved in phloem development

“…CDKs are key regulators of cell cycle progression in all eukaryotes, and in plants link phytohormone signaling and environmental cues to the cell cycle via phosphorylation of transcription factors that promote cell cycle progression (Joubès et al, 2001;Komaki and Sugimoto, 2012). There are several types of CDKs, which include non-canonical ones, whose main roles appear to regulate transcription elongation and splicing of genes that are not directly involved in cell cycle progression, as well as in modification of chromatin (Tanny et al, 2014;Hydbring et al, 2016). Indeed, a closer inspection of the sequence, as well as phylogenetic analysis supported the grouping of this protein with type C CDKs.…”