UVB-induced Epidermal Growth Factor Receptor Phosphorylation is Critical for Downstream Signaling and Keratinocyte Survival¶

Péus, Dominik; Vasa, R; Meves, Alexander; Beyerle, Astrid; Pittelkow, Mark R.

doi:10.1562/0031-8655(2000)072<0135:uiegfr>2.0.co;2

Cited by 77 publications

(26 citation statements)

References 42 publications

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“…We have shown here that RhoB is dispensable for the UVB-induced p38 activation since RhoB down-regulation did not impair p38 phosphorylation. Moreover, it has been reported that UVB-induced p38 activation is independent of EGFR phosphorylation (39). Overall these data suggested that p38 UVB activation should be independent of the EGFR/RhoB pathway.…”

Section: Discussionmentioning

confidence: 58%

RhoB Protects Human Keratinocytes from UVB-induced Apoptosis through Epidermal Growth Factor Receptor Signaling

Canguilhem

Pradines

Baudouin

et al. 2005

Journal of Biological Chemistry

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Exposure of the skin to UVB light results in the formation of DNA photolesions that can give rise to cell death, mutations, and the onset of carcinogenic events. Specific proteins are activated by UVB and then trigger signal transduction pathways that lead to cellular responses. An alteration of these signaling molecules is thought to be a fundamental event in tumor promotion by UVB irradiation. RhoB, encoding a small GTPase has been identified as a DNA damage-inducible gene. RhoB is involved in epidermal growth factor (EGF) receptor trafficking, cytoskeletal organization, cell transformation, and survival. We have analyzed the regulation of RhoB and elucidated its role in the cellular response of HaCaT keratinocytes to relevant environmental UVB irradiation. We report here that the activated GTP-bound form of RhoB is increased rapidly within 5 min of exposure to UVB, and then RhoB protein levels increased concomitantly with EGF receptor (EGFR) activation. Inhibition of UVB-induced EGFR activation prevents RhoB protein expression and AKT phosphorylation but not the early activation of RhoB. Blocking UVB-induced RhoB expression with specific small interfering RNAs inhibits AKT and glycogen synthase kinase-3␤ phosphorylation through inhibition of EGFR expression. Moreover, down-regulation of RhoB potentiates UVB-induced cell apoptosis. In contrast, RhoB overexpression protects keratinocytes against UVB-induced apoptosis. These results indicated that RhoB is regulated upon UVB exposure by a two-step process consisting of an early EGFR-independent RhoB activation followed by an EGFR-dependent induction of RhoB expression. Moreover, we have demonstrated that RhoB is essential in regulating keratinocyte cell survival after UVB exposure, suggesting its potential role in photocarcinogenesis.Among solar UV radiation that reaches the surface of the earth, UVB wavelengths are the most energetic. Directly absorbed by DNA and proteins, they account for much of the damaging biological effects of UV irradiation including premature skin aging and cancer (1). UVB acts as a carcinogen through both DNA damage and epigenetic effects. The initiation process in UVB-induced skin carcinogenesis involves UV light-induced DNA damage such as p53 or HA-ras mutations and represents an irreversible process (reviewed in Ref. 2). By contrast, UVBmediated skin tumor promotion involves the clonal expansion of initiated cells through activation of numerous signal transduction pathways, such as the MAPK 2 signaling cascades that coordinate cell cycle arrest, regulation of DNA repair, and apoptosis (3).It appears evident that after UVB exposure, the cell needs to integrate two opposing responses, with the final fate of keratinocytes depending on the balance between pro-and anti-apoptotic pathways. On the one hand, eliminating cells with excessive DNA damage is essential to preserve the health of the skin. UV-induced apoptosis plays this role through a complex mechanism triggered in three independent ways, via DNA damage-induced activation of caspas...

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Section: Discussionmentioning

confidence: 58%

RhoB Protects Human Keratinocytes from UVB-induced Apoptosis through Epidermal Growth Factor Receptor Signaling

Canguilhem

Pradines

Baudouin

et al. 2005

Journal of Biological Chemistry

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“…Induction of apoptosis could play a role in the decreased proliferation of ECE16-1 cells in response to retinoids as downstream effectors of the EGFR signaling have been implicated in apoptosis (47). The proapoptotic responses appear to be mediated via SAPK/JNK and p38 (48), while activated AKT is antiapoptotic (49).…”

Section: Figmentioning

confidence: 99%

Retinoids Suppress Epidermal Growth Factor-associated Cell Proliferation by Inhibiting Epidermal Growth Factor Receptor-dependent ERK1/2 Activation

Sah¹,

Eckert²,

Chandraratna³

et al. 2002

Journal of Biological Chemistry

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Human papillomavirus (HPV) is an important etiological agent in the genesis of cervical cancer. HPV-positive cervical tumors and human papillomavirus-positive cell lines display increased epidermal growth factor receptor (EGFR) expression, which is associated with increased cell proliferation. ECE16-1 cells are an HPVimmortalized human ectocervical epithelial cell line that is a model of HPV-associated cervical neoplasia and displays elevated EGFR levels. In the present study, we evaluated the effects of receptor-selective retinoid ligands on EGFR-associated signal transduction. We show that retinoic acid receptor (RAR)-selective ligands reduce EGFR level and the magnitude and duration of EGFR activation in EGF-stimulated cells. These effects are reversed by cotreatment with an RAR antagonist. To identify the mechanism, we examined the effects of retinoid treatments on EGF-dependent signaling. Stimulation with EGF causes a biphasic activation of the ERK1/2 MAPK. The first peak of activation is present at 20 min, and the second is present at 36 h. This activation subsequently leads to an increase in the cyclin D1 level and increased cell proliferation. Simultaneous treatment with EGF and a RAR-selective retinoid inhibits both phases of ERK1/2 activation, completely eliminates the cyclin D1 induction, and suppresses EGF-dependent cell proliferation. This effect is specific as retinoid treatment does not alter the level or activity of other EGFRregulated kinases, including AKT and the MAPKs p38 and JNK. Retinoid X receptor-selective ligands, in contrast, did not regulate these responses. These results suggest that RAR ligand-associated down-regulation of EGFR activity reduces cell proliferation by reducing the magnitude and duration of EGF-dependent ERK1/2 activation.Retinoids are analogs of vitamin A that control cell growth and differentiation of a variety of epithelial tissues, including the lining of the uterine cervix (1, 2). Under conditions of retinoid deprivation, the normal mucus-producing cervical epithelium is converted to squamous-like metaplastic epithelium, a process that is reversed by readministration of vitamin A (3, 4). Both preneoplastic and dysplastic cervical lesions have been reported to revert to normal following retinoid treatment (5), suggesting that retinoids may be efficacious for the treatment of cervical disease (6).Human cervical cancer cells are characterized by the presence of the high risk forms of the human papillomavirus (7, 8). HPV16 1 is the predominant subtype (9). HPV encodes two oncogenes, E6 and E7, which immortalize cervical cells in culture, and are believed to play a key causal role, along with chemical mutagens, in the genesis of cervical cancer (10). Retinoid regulation of cervical cell function has been studied in both normal and HPV16-immortalized human cervical epithelial cells. These studies show that, at physiological levels, retinoids do not affect the growth of normal human ectocervical cells but markedly suppress the growth of HPV16-immortalized cells. Moreover,...

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“…Two mechanisms are believed to contribute to the selective expansion of p53-mutant cells: their resistance to UV-induced apoptosis and their proliferative advantage over normal keratinocytes in response to stimulation with UV radiation. While evidence supports the role of mutant p53 in enabling apoptosis resistance in keratinocytes (Ziegler et al, 1994;Tron et al, 1998;Zhang et al, 2001;Mudgil et al, 2003), the possibility that mutant p53 provides keratinocyte progenitors with proliferative advantages remains largely unexplored, even though two phenotypes may be related to the same underlying molecular changes (Kuhn et al, 1999;van Hogerlinden et al, 1999;Peus et al, 2000;Marconi et al, 2003). Nevertheless, discontinuation of UV irradiation has been shown to result in the fast spontaneous regression of some mutant p53 clones in mouse skin, although the mechanisms involved in this process are unclear (Berg et al, 1996;Rebel et al, 2001;Remenyik et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…As a tumor promoter, UV radiation induces cell proliferation by stimulating the production of various growth factors and cytokines as well as the activation of their receptors (De-Metys et al, 1995; Rosette and Karin, 1996;Bender et al, 1997;Kuhn et al, 1999;Jost et al, 2000;Peus et al, 2000;Ullrich, 2000;Walterscheid et al, 2002). In addition, cell survival and growth following UV irradiation involves activation of NF-kB, mitogen-activated protein kinase, and phosphoinositide-3 0 -kinase/Akt pathways (Coffer et al, 1995;De-Metys et al, 1995;Rosette and Karin, 1996;Bender et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

et al. 2005

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Chronic exposure to ultraviolet (UV) radiation causes skin cancer in humans and mice. We have previously shown that in hairless SKH-hr1 mice, UVB-induced p53 mutations arise very early, well before tumor development. In this study, we investigated whether discontinuation of UVB exposure before the onset of skin tumors results in the disappearance of p53 mutations in the skin of hairless SKH-hr1 mice. Irradiation of mice at a dose of 2.5 kJ/m 2 three times a week for 8 weeks induced p53 mutations in the epidermal keratinocytes of 100% of the mice. UVB irradiation was discontinued after 8 weeks, but p53 mutations at most hotspot codons were still present even 22 weeks later. During that period, the percent of mice carrying p53 V154A/R155C , p53 H175H/H176Y , and p53 R275C mutant alleles remained at or near 100%, whereas the percentage of mice with p53 R270C mutation decreased by 45%. As expected, discontinuation of UVB after 8 weeks resulted in a delay in tumor development. A 100% of tumors carried p53 V154A/R155C mutant alleles, 76% carried p53 H175H/H176Y mutants, and 24 and 19% carried p53 R270C and p53 R275C mutants, respectively. These results suggest that different UVB-induced p53 mutants may provide different survival advantages to keratinocytes in the absence of further UVB exposure and that skin cancer development can be delayed but not prevented by avoidance of further exposure to UVB radiation.

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UVB-induced Epidermal Growth Factor Receptor Phosphorylation is Critical for Downstream Signaling and Keratinocyte Survival¶

Cited by 77 publications

References 42 publications

RhoB Protects Human Keratinocytes from UVB-induced Apoptosis through Epidermal Growth Factor Receptor Signaling

RhoB Protects Human Keratinocytes from UVB-induced Apoptosis through Epidermal Growth Factor Receptor Signaling

Retinoids Suppress Epidermal Growth Factor-associated Cell Proliferation by Inhibiting Epidermal Growth Factor Receptor-dependent ERK1/2 Activation

Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

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