What are Cyclins and CDKs?
Cyclins and Cyclin-dependent kinases (CDKs) are critical regulators of the cell cycle. Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating CDK enzymes. CDKs are a group of serine/threonine kinases that, once activated by cyclins, phosphorylate various target proteins to drive cell cycle transitions.
How do Cyclins and CDKs regulate the Cell Cycle?
The cell cycle is divided into phases: G1, S, G2, and M. Different cyclins and CDKs are responsible for transitioning the cell through these phases. For instance, Cyclin D pairs with CDK4/6 to progress through the G1 phase, while Cyclin E/CDK2 pushes the cell from G1 into the S phase. Cyclin A/CDK2 and Cyclin B/CDK1 are active in the S and G2/M phases, respectively. The precise control of these stages is crucial for normal cell proliferation.
How are Cyclins and CDKs linked to Cancer?
Cancer often involves the dysregulation of the cell cycle, leading to uncontrolled cell proliferation. Overexpression or hyperactivation of cyclins and CDKs can result in the bypassing of critical cell cycle checkpoints, contributing to oncogenesis. For example, overexpression of Cyclin D1 and Cyclin E has been linked to various cancers, including breast and lung cancer.
Genetic mutations: Mutations in genes encoding cyclins or CDKs can result in their constitutive activation or overexpression. For instance, mutations in the
CCND1 gene can lead to increased levels of Cyclin D1.
Epigenetic changes: Promoter methylation or histone modifications can alter the expression levels of cyclins and CDKs.
Loss of regulatory proteins: Proteins such as
p21 and
p27 are CDK inhibitors. Their loss or downregulation can lead to unchecked CDK activity.
Oncogenic signaling pathways: Activation of pathways like
PI3K/AKT can upregulate cyclin expression.
Resistance: Tumors can develop resistance to CDK inhibitors through various mechanisms, including compensatory activation of other pathways.
Toxicity: As CDKs are also important for normal cell function, their inhibition can lead to adverse effects.
Biomarker development: Identifying reliable biomarkers to predict patient response to CDK inhibitors is crucial.
Future research is focused on overcoming these challenges through combination therapies, improving the specificity of CDK inhibitors, and identifying novel regulatory mechanisms of cyclins and CDKs.
