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p21Waf1/Cip1 revisited: oncogenic function in hepatocellular carcinoma
  1. Daniel Goldenberg1,
  2. Robert Eferl2
  1. 1 Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel
  2. 2 Department for Internal Medicine I, Medical University Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria
  1. Correspondence to Dr Robert Eferl, Department for Internal Medicine I, Medical University Vienna & Comprehensive Cancer Center (CCC), Institute for Cancer Research, Borschkegasse 8a, Vienna A-1090, Austria; robert.eferl{at}

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p21Waf1/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, p21Waf1/Cip1 was classified as a tumour suppressor that interferes with cell cycle progression and DNA synthesis.1 ,2 Meanwhile, it has been realised that p21Waf1/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 p21Waf1/Cip1 when it is present at certain threshold concentrations. During apoptosis, the cytostatic effect of p21Waf1/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, p21Waf1/Cip1 can induce apoptosis through p53-dependent or -independent regulation of Bax and death receptors.1 ,2

p21Waf1/Cip1 is not readily mutated in human cancers and expression is downregulated …

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  • Contributors Drafting the work or revising it critically for important intellectual content.

  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

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