Coactivation of AP-1 activity and TGF- 1 gene expression in the stress response of normal skin cells to ionizing radiation
M Martin1,3,
M-C Vozenin1,
N Gault1,
F Crechet1,
CM Pfarr2 & J-L Lefaix1
1Laboratoire de Radiobiologie et d’Etude du Génome, CEA, DVS, 91191, Gif sur Yvette, France
2Unité des Virus Oncogènes, CNRS, Institut Pasteur, 75724, Paris, cedex 15, France and Department of Cell Biology and Biochemistry, Texas Tech University School of Medicine, 3601 4th Street, Lubbock, Texas 79424, USA
3Author for correspondence
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Activation of the AP-1 transcription factor and TGF-1 growth factor by ionizing radiation was studied both in vivo in pig skin, and in vitro in human fibroblasts and keratinocytes. Three and 6 h after irradiation, the Fos and Jun proteins and their binding activity to an AP-1 consensus sequence were strongly induced by high doses of  -rays. c-Fos, c-Jun and JunB proteins were found to be present in gel-shift complexes by probing with specific antibodies. Both keratinocytes and fibroblasts exhibited heightened AP-1 activity following irradiation. As we previously found that TGF-1 is involved in the development of skin lesions induced by radiation, TGF-1 gene expression was also examined. Two and 6 h after irradiation, the levels of TGF-1 transcripts were increased in skin. By immunostaining, TGF-1 protein levels were found to be increased in fibroblasts, keratinocytes and endothelial cells. As the TGF-1 promoter contains AP-1 binding sites, the relation between AP-1 activity and TGF-1 induction was addressed. The -365 TGF-1 promoter fragment, which contains a high affinity AP-1 site, exhibited increased binding to Jun and Fos proteins following irradiation. These results suggest that stress-inducible TGF-1 expression is mediated by the activation of AP-1 transcription factor. |
