Expanding landscape of CDKN1A (p21) functions: CDKN1A-mediated radioresistance of dermal Langerhans cells and its impact on the immune system

The CDKN1A (p21^WAF1/CIP1) protein is the founding member of the CIP/KIP family of cyclin-dependent kinase (CDK) inhibitors. It is a p53 transcriptional target that plays a pivotal role in the DNA damage surveillance network through activating cell cycle checkpoints, promoting DNA repair, downregulating apoptosis, and triggering a senescence-like growth arrested response (premature senescence). The anti-apoptotic property of CDKN1A is not only associated with its ability to halt cell-cycle progression and facilitate DNA repair, but also relies on its ability to inhibit the activity of proteins directly involved in the induction of apoptosis (e.g., the caspase cascade) and to control transcription, resulting in downregulation of pro-apoptotic genes and upregulation of genes with anti-apoptotic activities. In addition, we recently provided evidence suggesting that CDKN1A can positively regulate wild-type p53-induced phosphatase 1 (WIP1), an anti-apoptotic phosphatase that inhibits p53 and its upstream kinases (e.g., ATM; CHK2). Consistent with these properties of CDKN1A, treatment of p53 wildtype solid tumor-derived cells with ionizing radiation or chemotherapeutic agents results in sustained upregulation of CDKN1A, protection against apoptotic cell death, and growth arrest through premature senescence.