Cyclins and CDKs in Liver Diseases

Abstract

The transition of one cell cycle stage to another is tightly controlled by a number of cellular proteins. The key controlling proteins are the cyclin-dependent kinases (CDKs), which are regulated by cyclins and CDK inhibitors. The current chapter will focus on the regulation of cyclins and CDKs in liver diseases. Cyclin protein levels rise and fall during the cell cycle and thereby periodically activate CDKs, whereas the CDK protein levels remain stable during the cell cycle. CDKs belong to a family of serine/threonine protein kinases that are activated at specific time points of the cell cycle. CDK activity is regulated by phosphorylation on conserved threonine and tyrosine residues, in addition to cyclin binding. The phosphorylation induces conformational changes and enhances the binding of cyclins [39]. Nine CDKs have been identified to date, and five of these are found to be active during the cell cycle: CDK4, CDK6 and CDK2 during G1 phase; CDK2 during S phase; CDK1 during G2 and M phases; CDK7 in all cell cycle phases. Similarly, different cyclins are required at different phases of the cell cycle. Sixteen cyclins have been identified, and similar to CDKs, not all of them are related to the cell cycle (Fig. 27.1). Cyclin D binds to CDK4 and CDK6, and the cyclin D/CDK complexes are essential for entry in G1 phase. Cyclin E binds to CDK2, and regulates progression from G1 to S phase. Cyclin A binds with CDK2, and the complex is crucial for the progression of DNA synthesis during S phase. The cyclin A/CDK1 complex promotes cell cycle progression from late G2 to M phase. The cyclin B/CDK1 complex further regulates the M phases. The cyclin H/CDK7 complex is involved in all cell cycle phases. 27.2 Cyclins and CDKs in Liver Regeneration