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CDKs, or cyclin-dependent kinases, are heteromeric serine/threonine kinases that control progression through the cell cycle, transcription, and neuronal function and development. The activity of CDKs is dependent on their regulatory subunits, the cyclins. There are 20 known CDKs in humans, which are split into groups based on their evolutionary and functional relationships, and are regulated by 29 cyclins. The cell cycle is largely controlled by CDK1, CDK4 and CDK5 subfamilies, while other CDKs play roles in transcription and are not regulated in a cell cycle-dependent manner.
Cyclins are a heterogeneous family of proteins that have a common 100 amino acid sequence called the cyclin box. Their only cellular role is to activate CDKs, and their expression fluctuates throughout the cell cycle, dependent on the cell cycle phase they are involved in. There are several subfamilies of cyclins, and several 'orphan' cyclins for which no CDK binding partner has been identified.
CDKs are constitutively expressed and range in size from 250 amino acid residues, consisting of just the catalytic serine/threonine kinase domain, to over 1500 amino acid residues with N- and C-terminal extensions of variable length. All CDKs have a two-lobed structure, with β-sheets in the N-terminal and α-helices in the C-terminal, and an active site between the lobes. An area in the C-terminal lobe, named the T-loop, contains phosphorylation sensitive residues. In inactive, cyclin-free CDKs the T-loop blocks the catalytic cleft preventing enzymatic activity. The majority of CDKs are located in the nucleus, however some family members are cytosolic, including CDK5 and CDK14 of the CDK5 subfamily.
CDKs and cyclins control progression through the cell cycle, following extracellular mitogenic stimuli. CDKs are activated by binding to a cyclin; each CDK has minimal kinase activity when unbound. The exact structural changes that occur upon cyclin binding vary for different CDKs. Cyclin A binding to CDK2 occurs at both the N- and C-lobes of CDK2, whereas interactions between CDK4 and cyclin D are limited to the N-lobe.
Increased expression of cyclin D is the first step in CDK control of the cell cycle. Cyclin D binds to CDK4 or CDK6, and this complex phosphorylates and inactivates retinoblastoma protein (Rb). This releases Rb-mediated inhibition of transcription and results in liberation of the transcription factors E2F and DP1, which then induces transcription of genes including cyclins A and E, DNA polymerase and thymidine kinase. CDK4-cyclin E complexes then form, initiating G1/S transition regulating centrosome duplication. Once DNA has been replicated in S phase, CDK1 is activated by binding to cyclin A or B, which promotes centrosome maturation and separation, chromosome condensation and mitotic exit following breakdown of the nuclear envelope.
Although CDK1 and CDK4 subfamilies control the cell cycle, there is a level of redundancy between the roles of individual family members. For example, when CDK4 or CDK6 are absent, CDK2 can bind cyclin D and carry out the same role in G1 phase of the cell cycle. However, these compensatory roles don't occur in all cell types; CDK4-null mice are viable and have no changes in global cell proliferation, but they show decreased proliferation of pancreatic β-cells and pituitary endocrine cells.
As well as cyclin binding, CDK activity is regulated via three mechanisms:
The CDK-Cyclin-Rb pathway is almost universally dysregulated in cancer cells, and most transcriptional CDKs have also been linked to cancer cell growth and proliferation. Both pan-CDK and selective inhibitors, the majority of which are ATP-competitive at the catalytic binding site, have been investigated for their therapeutic application in cancer. Outside of oncology, abnormalities in CDK activity and regulation have been identified in cardiovascular disorders, viral infection, neurogenerative disorders like Alzheimer's disease and Parkinson's disease, as well as ischemic and traumatic stroke.
Flavopiridol (Cat. No. 3094) was the first CDK inhibitor to enter clinical trials and is a pan-CDK inhibitor that displays potency and selectivity for CDKs 1, 2, 4, 6, 7 and 9. In vitro, Flavopiridol blocks the cell cycle at G2, which can be caused by direct inhibition of CDK1, or indirect inhibition via CDK7. It has been investigated in multiple clinical trials for different disorders, particularly solid tumors and hematological malignacies. More recently, selective inhibitors of different CDK subfamilies have been under investigation and have entered clinical trials.
In cancer, the effect of CDK inhibitors can be influenced by the oncogene that is driving tumorgenesis. For example, Purvalanol A (Cat. No. 1580) has therapeutic effect in cancers driven by MYC, but no other oncogenes. Similarly, some selective CDK4 inhibitors are highly efficient in HER2-positive breast cancer cells but have no effect on MYC-driven breast cancer.
Additionally, advances in drug discovery chemistry have enabled the development of tools for targeted protein degradation of CDKs. These heterobifunctional small molecules, known as Degraders, harness the ubiquitin-proteasome system to induced selective degradation of target proteins for investigation of protein function and signaling pathways.
Tocris offers the following scientific literature for Cyclin-Dependent Kinases (CDKs) to showcase our products. We invite you to request* your copy today!
*Please note that Tocris will only send literature to established scientific business / institute addresses.
In normal cells, each stage of the cell cycle is tightly regulated, however in cancer cells many genes and proteins that are involved in the regulation of the cell cycle are mutated or over expressed. Adapted from the 2015 Cancer Product Guide, Edition 3, this poster summarizes the stages of the cell cycle and DNA repair. It also highlights strategies for enhancing replicative stress in cancer cells to force mitotic catastrophe and cell death.
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