p21(Waf1/Cip1) protects against p53-mediated apoptosis of human melanoma cells

Oncogene. 1997 Feb 27;14(8):929-35. doi: 10.1038/sj.onc.1200897.

Abstract

The tumor suppressive effect of p53 is believed to be rooted in its two primary functions: the implementation of cellular growth arrest and the execution of apoptotic cell death. While p53-regulated expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) appears to be central for the implementation of G1 arrest, the participation of p21(Waf1/Cip1) in p53-triggered cell death remains controversial. In the present study, overexpression of p53 in human melanoma SK-MEL-110 cells through use of an adenoviral expression vector (AdCMV.p53) was found to result in apoptosis, while similar infection of primary vascular smooth muscle cells (VSMC) instead resulted in a moderate inhibition of growth. Expression of p21(Waf1/Cip1) was strongly elevated in VSMC, but showed little change in SK-MEL-110 cells, although expression of another p53-regulated gene (GADD45) was comparable in both AdCMV.p53-infected cell types. Evidence that p21(Waf1/Cip1) expression may be required for surviving p53-induced cell death was further supported by the finding that p53 overexpression was highly toxic for p21-deficient mouse embryonal fibroblasts (p21-/- MEFs). In both SK-MEL-110 and p21-/- MEFs, adenovirus-driven ectopic expression of p21(Waf1/Cip1) resulted in a substantial protection against p53-induced apoptosis, indicating that p21(Waf1/Cip1) rescued cells from a path of programmed cell death to one of enhanced survival.

MeSH terms

  • Animals
  • Apoptosis*
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / physiology*
  • Gene Expression
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Melanoma / pathology*
  • Mice
  • Mice, Knockout
  • Proteins / genetics
  • RNA, Messenger / genetics
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / physiology*

Substances

  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • GADD45 protein
  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • RNA, Messenger
  • Tumor Suppressor Protein p53