Transcriptional repression of c-Jun's E3 ubiquitin ligases contributes to c-Jun induction by UV

UV radiation is a major environmental carcinogen. The oncoprotein c-Jun that is required for development of skin cancer is stabilized by UV radiation. The mechanism leading to its stabilization after exposure to UV is not known. The lack of knowledge was particularly sharpened, after the discovery that JNK, the most potent positive regulator of c-Jun, activates Itch, an E3-ligase of c-Jun and JunB. In this study we demonstrate that the expression of all three E3 ubiquitin ligases of c-Jun is down-regulated by UV. The levels of Itch/AIP4 and Fbw7 alpha transcripts are reduced following UV exposure in every cell line examined. Repression of hCOP1 and its associated protein hDET1, which is required for c-Jun degradation, is cell type dependent. Expression of Fbw7 alpha is down-regulated by UVC or UVB, independently of the p53, MAPK and the PKC pathways but the repression is inhibited in the absence of active Fbw7 proteins suggesting that a target protein of Fbw7 is involved in Fbw7 expression/repression. The repression does not require protein synthesis and UV does not change Fbw7 mRNA stability. The characteristics of Fbw7a repression perfectly match with those of c-Jun induction. Unlike UV, ionizing radiation does not repress Fbw7 alpha and does not induce c-Jun. In addition, the repression kinetics correlates tightly with the kinetics of c-Jun induction by UV Moreover, abrogation of Fbw7 UV-responsiveness abolishes c-Jun induction by UV and knockdown of Fbw7 results in elevated basal expression of c-Jun but reduced UV-dependent induction thus, proving the essential role of this repression in c-Jun induction by UV. (C) 2008 Elsevier Inc. All rights reserved.