Differential regulation of the p21/WAF-1 and mdm2 genes after high-dose UV irradiation: p53-dependent and p53-independent regulation of the mdm2 gene

Mol Med. 1997 Jul;3(7):441-51.


Background: DNA damage in mammalian cells stabilizes the p53 protein which then functions as a cell cycle checkpoint by leading to growth arrest or apoptosis. p53 is a transcription factor and positively regulates the expression of the p21/WAF-1 gene and the mdm2 gene. After high-dose UV irradiation, p53 increases the expression of the p21/WAF-1 gene immediately (2 to 5 hours after irradiation) while the induction of the mdm2 gene is delayed (8 to 12 hours after irradiation). Experiments presented here explore this differential expression of two different p53-regulated genes.

Materials and methods: IP-Western (protein) and Northern (mRNA) blot experiments are used to follow mdm2 and p21/WAF-1 expression in primary rat or mouse cells after a low-dose (4 J/m2) or a high-dose (20 J/M2) of UV irradiation. Northern blot and nuclear run-on experiments are employed to study mRNA stability as well as transcription rates of selected genes.

Results: After high-dose UV irradiation, p53 is rapidly stabilized and the expression of p21/WAF1 is immediately increased. By contrast, both protein and mRNA levels of mdm2 first decrease in a p53-independent manner, and later increase in a p53-dependent manner. The initial decline of mdm2 expression following high-dose UV irradiation is UV-dosage dependent and regulated at the level of transcription.

Conclusion: p53 regulates two genes, p21/WAF1 (blocks cell cycle progression) and mdm2 (reverses p53 activity), that mediate opposite actions. This process is regulated in a temporal fashion after high-dose UV irradiation, so that cell cycle progression can be halted while DNA repair continues prior to reversal of p53-mediated arrest by mdm2.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics*
  • Cyclins / metabolism
  • Cyclins / radiation effects*
  • Dose-Response Relationship, Radiation
  • Down-Regulation / genetics
  • Down-Regulation / radiation effects
  • Fibroblasts / metabolism
  • Fibroblasts / radiation effects
  • Gene Expression Regulation / radiation effects*
  • Mice
  • Nuclear Proteins*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / radiation effects
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogenes / radiation effects*
  • RNA, Messenger / radiation effects
  • Rats
  • Transcription, Genetic / radiation effects
  • Tumor Suppressor Protein p53 / physiology*
  • Tumor Suppressor Protein p53 / radiation effects
  • Ultraviolet Rays*


  • Cdkn1a protein, mouse
  • Cdkn1a protein, rat
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • Mdm2 protein, mouse
  • Mdm2 protein, rat
  • Proto-Oncogene Proteins c-mdm2