Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

Abstract

Sustained Hedgehog (HH) signaling is implicated in basal cell carcinoma of the skin and other types of cancer. Here we show that GLI1 and GLI2, the main transcriptional activators of the HH pathway, directly regulate expression of the activator protein 1 (AP-1) family member JUN, a transcription factor controlling keratinocyte proliferation and skin homeostasis. Activation of the JUN promoter by GLI is dependent on a GLI-binding site and the AP-1 sites known to be involved in self-activation of JUN. Transcription of JUN is greatly enhanced in the presence of GLI and requires activated JUN protein.GLI2act is a more potent activator than GLI1 in these experiments and physical interaction with phosphorylated JUN was only detected for GLI2act. The synergistic effect of GLI and JUN extends to the activation of further GLI target genes as shown by shRNA-mediated knockdown of JUN in human keratinocytes. Some of these cooperatively activated genes are involved in cell-cycle progression, which is consistent with a significant reduction of the proliferative potential of GLI in the absence of JUN. These results suggest a novel connection between HH/GLI pathway activity and JUN, which may contribute to the oncogenic activity of HH/GLI signaling in skin.

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Koga et al, 2008;Kasperczyk et al, 2009). Expression of Gli1 is reported to be regulated by TGFb, Ras, JUN, SCL/TAL1 and EWS-FLI1 oncoprotein (Ji et al, 2007;Kasai et al, 2008;Zwerner et al, 2008;Beauchamp et al, 2009;Laner-Plamberger et al, 2009;NolanStevaux et al, 2009). The interaction between PKC and hedgehog signaling varies depending on PKC isoforms and cell types.…”

Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal

“…In addition to Gli1, Itch is involved in the regulation of c-Jun and other targets . Recently, a cooperation between c-Jun and Gli1 has been described in human keratinocytes, in which Hh enhances the expression of c-Jun, thus synergizing with it for cell cycle progression (Laner-Plamberger et al, 2009). To rule out the possibility that c-Jun regulates MB growth by targeting AP-1, we tested whether a cross-talk between Gli1 and c-Jun also exists in MB cells.…”

Inhibition of Gli1 results in altered c-Jun activation, inhibition of cisplatin-induced upregulation of ERCC1, XPD and XRCC1, and inhibition of platinum–DNA adduct repair

“…12 Further, Gli2 can upregulate c-jun through that same specific binding site. When Gli2 and c-jun bind to their respective sites concurrently, there is synergistic upregulation of c-jun.…”

“…Laner-Plamberger et al 12 reported their findings of the molecular interface between Gli and c-jun in immortalized keratinocytes. They report that c-jun has five potential Gli binding sites in the promoter of the c-jun gene.…”

“…8,11 Laner-Plamberger et al 12 reported on the relationship between Gli and c-jun. In this report, we investigate the possible relationship between Gli, c-jun, ERCC1 and cellular resistance to cisplatin.…”