c-Jun Regulates Eyelid Closure and Skin Tumor Development through EGFR Signaling

Abstract

To investigate the function of c-Jun during skin development and skin tumor formation, we conditionally inactivated c-jun in the epidermis. Mice lacking c-jun in keratinocytes (c-jun(Deltaep)) develop normal skin but express reduced levels of EGFR in the eyelids, leading to open eyes at birth, as observed in EGFR null mice. Primary keratinocytes from c-jun(Deltaep) mice proliferate poorly, show increased differentiation, and form prominent cortical actin bundles, most likely because of decreased expression of EGFR and its ligand HB-EGF. In the absence of c-Jun, tumor-prone K5-SOS-F transgenic mice develop smaller papillomas, with reduced expression of EGFR in basal keratinocytes. Thus, using three experimental systems, we show that EGFR and HB-EGF are regulated by c-Jun, which controls eyelid development, keratinocyte proliferation, and skin tumor formation.

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

“…Although JunB is classically known to antagonize some biological functions of c-Jun such as cell proliferation, 27 both also share redundancy on certain target genes, which include Egfr and Proliferin. 44,45 On the other hand, FosB has been shown to bind in a complex with c-Jun, which was associated with FasL induction and cell death, indicating that c-Jun/FosB dimer has a pro-apoptotic function. 46 Consistently, our data indicate that similar to c-Jun, expression of JunB and FosB could also induce the suppression of paox, increase the level of Az and lead to the subsequent degradation of DNp73.…”

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

“…Papillomas form in mice overexpressing the activated son of sevenless (SOS) gene under the keratin 5 promoter leading to Jun activation through the Ras pathway . In contrast, only small tumors formed in the absence of Jun (Zenz et al, 2003) and tumor formation was also impaired in mice expressing mutant Jun proteins that cannot be phosphorylated and activated by JNK (Behrens et al, 1999.…”

“…Jun is essential in embryonic development (Johnson et al, 1993), though knocking out Jun in keratinocytes results in normal skin architecture. Cultured primary Jun À/À keratinocytes, however, show reduced proliferation (Zenz et al, 2003). An important contribution of JUN to cellular proliferation is the transcriptional activation of cyclin D1 (CCND1) in keratinocytes and other positive regulators of cell-cycle progression as well as inhibition of negative regulators (reviewed in Zenz and Wagner, 2006).…”

c-Jun, at the crossroad of the signaling network

“…Besides MAP3K1, embryonic eyelid closure depends on signals derived from WNT, Sonic hedgehog, BMP/Activin, FGF and EGF (Luetteke et al, 1993;Mine et al, 2005;Gage et al, 2008;Huang et al, 2009). In addition, eyelid closure requires the participation of a number of intracellular signaling kinases, such as JNK, ROCK and CDH1, and nuclear transcription factors, such as c-Jun, Fra-2, FOXL2, SMAD and GRHL3 (McHenry et al, 1998;Li et al, 2003;Zenz et al, 2003;Zhang et al, 2003;Uda et al, 2004;Thumkeo et al, 2005;Takatori et al, 2008;Yu et al, 2008;Naoe et al, 2010). While how these factors are organized into a morphogenetic network for eyelid closure has not been well understood, molecular analyses of these mice have begun to unveil that some of the factors are organized into concerted signal transduction cascades.…”