CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs?
The Cyclin-dependent kinase (CDK) Activating Kinase (CAK) is responsible for the activating phosphorylation of CDK1, CDK2, CDK4 and CDK6 and regulation of the cell cycle. The kinase is composed of three subunits: CDK7, Cyclin H and MAT1 (ménage a trois). Together with six other subunits, CAK is also part of the general transcription factor TFIIH where it is involved in promoter clearance and progression of transcription from the preinitiation to the initiation stage. CAK is required for cell cycle progression, which suggests that CDK7 could be a target for cancer therapy. However its role in transcription and its ubiquitous presence raise sensible concerns about possible toxicity of its inhibitors. The recently determined structure of CDK7 allows the design of inhibitors with differential specificity for the different CDKs. We review the role of CAK in different biological processes and evaluate the biological evidence for CDK7 as a possible pharmacological target.
Lolli
Graziano
G
Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, Oxford, UK. graziano@biop.ox.ac.uk
Johnson
Louise N
LN
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D018844:Cyclin-Dependent Kinases / Q000378:metabolism / Q000502:physiology*; D000070819:Discoidin Domain Receptor 1; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009369:Neoplasms / Q000628:therapy*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D000970:Antineoplastic Agents; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human