AP-2α: a regulator of EGF receptor signaling and proliferation in skin epidermis

Wang, Xuan; Bolotin, Diana; Chu, David H.; Polak, Lisa; Williams, Trevor; Fuchs, Elaine

doi:10.1083/jcb.200510002

Cited by 78 publications

(89 citation statements)

References 56 publications

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“…ERK activation is necessary for induction of the binding activities of AP-2 in T cells (53). Also, increased ERK signal has been reported in the absence of AP-2␣ in mouse epidermis (54). In addition, we found that blockade of AP-2 by AP-2 antisense approaches had no effect on ERK activ- for an additional 24 h and then subjecting them to Western blot analysis for COX-2, AP-2␣, and actin protein levels.…”

Section: Discussionmentioning

confidence: 60%

Extracellular Matrix Fibronectin Increases Prostaglandin E2 Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways

Han

Ritzenthaler

Wingerd

et al. 2007

Journal of Biological Chemistry

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We have previously demonstrated that fibronectin (Fn) stimulates the proliferation of non-small cell lung carcinoma (NSCLC) cell growth through the induction of cyclooxygenase-2 (COX-2) and prostaglandin E 2 secretion. Here, we demonstrate that NSCLC cells express mRNA and protein for the prostaglandin E 2 receptor EP4 and that Fn enhances its stimulatory effect by inducing the expression of EP4, but not of EP1, EP2, and EP3 receptor subtypes. The effect of Fn on EP4 was inhibited by an antibody against ␣5␤1 integrin and by inhibitors of phosphoinositide 3-kinase (wortmannin) and extracellular signal-regulated kinase (PD98095), but not by inhibitors of protein kinase C (calphostin C), of protein kinase A (H-89), or of mammalian target of rapamycin (rapamycin). A COX-2 small interfering RNA was also inhibitory. Fn significantly increased AP-2 binding activity in the promoter of the EP4 gene, and AP-2 antisense oligonucleotides blocked Fn-induced EP4 expression. Using full-length and mutated EP4 promoter constructs, we found that Fn stimulation of EP4 gene expression was inhibited when one AP-2 site (؊1000 bp) was mutated. Fn induced nuclear AP-2␣ protein expression through multiple signaling pathways. Our results indicate that Fn-induced NSCLC cell proliferation is mediated through EP4. Furthermore, they show that Fn induces EP4 expression through the activation of ␣5␤1-dependent signals that include induction of extracellular signalregulated kinase and phosphoinositide 3-kinase pathways as well as expression of COX-2. These events lead to activation of the transcription factor AP-2␣, which interacts with specific regions in the EP4 gene promoter, leading to transcription of the EP4 gene.Extracellular matrix proteins are considered to play roles in the migration and differentiation of various cells, including carcinoma cells. Fibronectin (Fn), 2 a matrix glycoprotein highly expressed in tobacco-related lung diseases, has been shown to stimulate carcinoma cell growth, including lung carcinoma (1-3). We previously reported that Fn stimulated human lung carcinoma cell growth through induction of cyclooxygenase-2 (COX-2) signaling and subsequent production of prostaglandin E 2 (PGE 2 ) (4). High PGE 2 levels are considered important in carcinoma growth and progression, and inhibition of PGE 2 synthesis blocks growth of carcinoma cells (5). The effect of PGE 2 has been attributed to its known capacity to bind to its receptors, designated EP1, EP2, EP3, and EP4 (6). These receptors have been implicated in carcinoma cell growth and progression (5,7,8,9). PGE 2 , acting via EP4, contributes to tumor growth and progression of gallbladder and colorectal carcinoma (7,8). A recent study of EP4 knock-out mice suggested a role for EP4 receptor in colon carcinoma (7). PGE 2 and its signaling through the EP4 receptor have been shown to mediate non-small cell lung carcinoma (NSCLC) invasiveness (10). Taken together, these observations suggest that manipulation of prostaglandin metabolism downstream from COX-2 produces more profou...

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Section: Discussionmentioning

confidence: 60%

Extracellular Matrix Fibronectin Increases Prostaglandin E2 Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways

Han

Ritzenthaler

Wingerd

et al. 2007

Journal of Biological Chemistry

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“…The consequences of epidermal ablation of Lrig1 (26), Mig-6 (37), or the transcription factor AP2␣ (38) are all consistent with proliferation of the interfollicular SC compartment in response to EGFR ligand stimulation. Expression of Lrig1 ensures that SC are less responsive to growth-factor stimulation than their more differentiated progeny.…”

Section: Discussionmentioning

confidence: 83%

Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence

Jensen

Watt²

2006

Proc. Natl. Acad. Sci. U.S.A.

295

310

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“…However, it is interesting that the Notch pathway is linked to early follicle development (Favier et al, 2000) and that EGFR has been recently identified as a key negative regulator of notch1 gene expression in primary human keratinocytes (Kolev et al, 2008). It is also noteworthy that AP2α , which is a negative regulator of the EGF receptor (Wang et al, 2006), also becomes strongly expressed in the emerging HF placode (Panteleyev et al, 2003). Guo et al (Guo et al, 1993) suggest that 'elevated growth response might block the mesenchymal-epithelial signalling necessary for HF morphogenesis'.…”

Section: Research Articlementioning

confidence: 99%

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

et al. 2009

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A key initial event in hair follicle morphogenesis is the localised thickening of the skin epithelium to form a placode, partitioning future hair follicle epithelium from interfollicular epidermis. Although many developmental signalling pathways are implicated in follicle morphogenesis, the role of epidermal growth factor (EGF) and keratinocyte growth factor (KGF, also known as FGF7) receptors are not defined. EGF receptor (EGFR) ligands have previously been shown to inhibit developing hair follicles; however, the underlying mechanisms have not been characterised. Here we show that receptors for EGF and KGF undergo marked downregulation in hair follicle placodes from multiple body sites, whereas the expression of endogenous ligands persist throughout hair follicle initiation. Using embryonic skin organ culture, we show that when skin from the sites of primary pelage and whisker follicle development is exposed to increased levels of two ectopic EGFR ligands (HBEGF and amphiregulin) and the FGFR2(IIIb) receptor ligand KGF, follicle formation is inhibited in a time-and dose-dependent manner. We then used downstream molecular markers and microarray profiling to provide evidence that, in response to KGF and EGF signalling, epidermal differentiation is promoted at the expense of hair follicle fate. We propose that hair follicle initiation in placodes requires downregulation of the two pathways in question, both of which are crucial for the ongoing development of the interfollicular epidermis. We have also uncovered a previously unrecognised role for KGF signalling in the formation of hair follicles in the mouse.

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AP-2α: a regulator of EGF receptor signaling and proliferation in skin epidermis

Cited by 78 publications

References 56 publications

Extracellular Matrix Fibronectin Increases Prostaglandin E2 Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways

Extracellular Matrix Fibronectin Increases Prostaglandin E2 Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways

Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

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