Regulation of cyclin-Cdk activity in mammalian cells

Abstract

Cell cycle progression is driven by the coordinated regulation of the activities of cyclin-dependent kinases (Cdks). Of the several mechanisms known to regulate Cdk activity in response to external signals, regulation of cyclin gene expression, post-translational modification of Cdks by phosphorylation-dephosphorylation cascades, and the interaction of cyclin/Cdk complexes with protein inhibitors have been thoroughly studied. During recent years, much attention has also been given to mechanisms that regulate protein degradation by the ubiquitin/proteasome pathway, as well as to the regulation of subcellular localization of the proteins that comprise the intrinsic cell cycle clock. The purpose of the present review is to summarize the most important aspects of the various mechanisms implicated in cell cycle regulation.

The phosphoinositide 3-kinase/Akt pathway regulates cell cycle progression of HL60 human leukemia cells through cytoplasmic relocalization of the cyclin-dependent kinase inhibitor p27Kip1 and control of cyclin D1 expression

“…26 The first one is at the G1/S phase transition for initiation and completion of DNA replication in S phase. 30,31 The second checkpoint is at the G2/M phase transition and controls mitosis and cell division. 32 When Figure 6 The expression, threonine phosphorylation, and localization of p27 Kip1 are regulated through the PI3K/Akt pathway.…”

p53 downregulates expression of the G1/S cell cycle phosphatase Cdc25A

“…Proper control of Cyclin/Cdk activity ensures that the initiation of cell cycle events occurs only after a successful completion of the previous cycle. Cyclin/Cdk activity is regulated on several different levels, such as transcription of their genes, proteolysis, subcellular localization and binding of specific inhibitors (Obaya and Sedivy, 2002;Vermeulen et al, 2003).…”

“…Initially, Cyclin/Cdk complexes are kept in an inactive state by phosphorylation. The Myt1 and Wee1 kinases mediate the inactivation of Cdk1 and Cdk2 by phosphorylation of two sites in their ATP binding loop (Obaya and Sedivy, 2002). Conversely, Cdc25 dual-specificity phosphatases catalyse cell cycle progression by dephosphorylating the same residues, thereby activating Cdks (Nilsson and Hoffmann, 2000).…”

Signal Transduction and Actin in the Regulation of G1-Phase Progression

“…In these complexes, the cyclins are the activating subunits that interact with specific CDKs to regulate their activity and substrate specificity, whereas the CDKs are serine/threonine kinases that require binding of a specific cyclin in order to be ready to become activated. In addition to binding a cyclin, CDK activity is also dependent on the phosphorylation of threonine and tyrosine residues-some of which are stimulatory, whereas others are inhibitory 9,10 -and on the interaction with specific inhibitory proteins-the CDK inhibitory proteins. [11][12][13] Two families of CKIs have been identified on the basis of their structures and affinities for cyclin-CDK complexes.…”