Cyclin-dependent kinase inhibitor 1A–Cyclin-dependent kinase 1 axis (p21–CDK1 axis)

The p21–CDK1 cell cycle regulatory axis is a critical signaling pathway that coordinates the transition of cells from the G2 phase into mitosis. It is primarily defined by the inhibitory interaction between the cyclin-dependent kinase inhibitor 1A (p21, encoded by CDKN1A) and cyclin-dependent kinase 1 (CDK1), the master kinase driving mitotic entry. In response to DNA damage, the tumor suppressor p53 induces p21 expression, which then binds to and inactivates CDK1/Cyclin B complexes, effectively halting the cell cycle to prevent the segregation of damaged DNA. This axis is frequently dysregulated in various cancers, often due to p53 mutations or the epigenetic silencing of p21, which allows for unchecked proliferation and resistance to therapy. Therapeutic strategies targeting this axis include the use of CDK1 inhibitors to induce mitotic catastrophe or the induction of p21 via HDAC inhibitors to restore cell cycle checkpoints and promote senescence. Recent research has also identified the STING pathway as a non-canonical regulator of this axis, highlighting its importance in maintaining epithelial genome integrity and its potential as a biomarker for treatment response.

Other names

p21-CDK1 pathwayp21-Cdc2 axisCDKN1A-CDK1 axisp53-p21-CDK1 axisWAF1-CDK1 axisCIP1-CDK1 axis

The axis is modulated by pharmacologically inducing p21 expression to inhibit CDK1-mediated mitotic entry or by directly inhibiting CDK1 activity to trigger cell cycle arrest, senescence, or mitotic catastrophe in cancer cells.