• CHOLESTATIC LIVER DISEASES
• CELL CYCLE CONTROL
• HEPATOCELLULAR CARCINOMA

p21^Waf1/Cip1 was originally identified as a crucial p53-regulated factor that controls cyclin-dependent kinase 1/2 (CDK1/CDK2) activities and sequesters proliferating cell nuclear antigen. The physical interaction with CDKs prevents binding and phosphorylation of retinoblastoma proteins which is required for the release of E2F transcription factors important for S-phase progression. Consequently, p21^Waf1/Cip1 was classified as a tumour suppressor that interferes with cell cycle progression and DNA synthesis.1 ,2 Meanwhile, it has been realised that p21^Waf1/Cip1 has a plethora of alternative functions in apoptosis, differentiation, migration, DNA repair, gene regulation, stem cell renewal and oncogenesis.1 ,2 Most of these functions are regulated in a dual and p53-independent manner. Cell proliferation is not exclusively inhibited but can also be promoted by p21^Waf1/Cip1 when it is present at certain threshold concentrations. During apoptosis, the cytostatic effect of p21^Waf1/Cip1 can protect cells from genotoxic insults (which require cell cycle progression for induction of cell death) or through mechanisms that are based on cytoplasmic interference with caspase activation, suppression of E2F1- or Myc-induced pro-apoptotic gene expression and inhibition of pro-apoptotic stress kinases. Alternatively, p21^Waf1/Cip1 can induce apoptosis through p53-dependent or -independent regulation of Bax and death receptors.1 ,2

p21^Waf1/Cip1 is not readily mutated in human cancers and expression is downregulated …