The contribution of calpains in the down-regulation of Mdm2 and p53 proteolysis in reconstructed human epidermis in response to solar irradiation.
The p53 protein accumulates in human skin cells in vitro and in vivo when UV-irradiated. The transient stability of p53 requires a decrease in the activity of the ubiquitin ligase murine double minute 2 (Mdm2). Solar light irradiation (52.5, 105 and 405 mJ/cm2) of reconstructed human epidermis caused cutaneous damage. Specifically, UV-B induced the formation of sunburn cells and at first, an increase in the accumulation of p53 protein. Unexpectedly, 24 h after irradiation, a specific proteolytic cleavage of p53 resulted in the formation of a 40 kDa fragment. Both the accumulation of p53 and the proteolytic cleavage increased, commensurate with the UV dose. In contrast to p53, the level of expression of Mdm2 decreased drastically with the UV dose. It is important to note that calpastatin (20 microM), a specific inhibitor of calpains, decreased the formation of sunburn cells, inhibited the cleavage of p53 and induced an accumulation of Mdm2. The apoptotic process is strongly repressed. This demonstrates for the first time that calpains can participate in the down-regulation of Mdm2 in the epidermis very rapidly after UV irradiation, and that they contribute to a specific cleavage of p53 protein. All of these processes may be involved in the apoptotic response of the skin to UV stimulation.
Gélis
Christelle
C
Laboratoire des IMRCP, UMR 5623 au CNRS, Université Paul Sabatier, 31062 Toulouse Cedex 04, France.
Mavon
Alain
A
Vicendo
Patricia
P
D002154:Calpain / Q000378:metabolism*; D004817:Epidermis / Q000201:enzymology / Q000502:physiology* / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D013472:Sunlight; D014466:Ultraviolet Rays
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002154:Calpain