EGF receptor signaling inhibits keratinocyte apoptosis: evidence for mediation by Bcl-XL

Stoll, Stefan; Benedict, Mary A.; Mitra, Raj S.; Hiniker, Annie; Elder, James T.; Núñez, Gabriel

doi:10.1038/sj.onc.1201657

Cited by 102 publications

(77 citation statements)

References 37 publications

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“…The exact mechanism of the regulation of Bcl-x expression is still unknown. It has been shown that the reduction in apoptosis of keratinocytes induced by EGF activation is mediated by Bcl-xl (Stoll et al, 1998). In this study, ERK activation was not examined.…”

Section: Discussionmentioning

confidence: 86%

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Bryckaert

Guillonneau²,

Hecquet³

et al. 1999

Oncogene

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Retinal pigmented epithelial (RPE) cells are of central importance in the maintenance of neural retinal function. Changes in the RPE cells associated with repair activities have been described as metaplasia, while RPE cell apoptosis is responsible for the development of a variety of retinal degenerations. We investigated the regulation of the anti-apoptotic properties of the ®broblast growth factors (FGF) 2 in serum-free cultures of RPE cells. In the absence of serum, con¯uent stationary RPE cells died by apoptosis via a caspase 3-dependent pathway. The addition of FGF2 greatly reduced apoptosis over a 7-day culture period. We demonstrated the involvement of an autocrine loop involving endogenous FGF1 in the mechanisms that govern FGF2-induced resistance to apoptosis by showing: (1) higher levels of apoptosis in cells treated with antisense FGF1 oligonucleotide or after neutralization of excreted FGF1; (2) the long-term activation of FGFR1 and of ERK2, (3) the inhibition of FGFR1 and ERK2 activation and an increase in apoptosis if excreted FGF1 was neutralized. FGF2 also increased the de novo synthesis and the production of Bcl-xl before the onset of apoptosis. Both inhibition of ERK2 activation, which decreased Bcl-xl synthesis, and downregulation of Bcl-x by antisense oligonucleotide treatment inhibited the survival-promoting activity of FGF2. Thus, FGF2-induced cell survival is a progressive adaptive phenomenon involving ERK2 activation by excreted FGF1 and ERK2-dependent Bcl-x production.

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Section: Discussionmentioning

confidence: 86%

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Bryckaert

Guillonneau²,

Hecquet³

et al. 1999

Oncogene

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“…In support of this hypothesis, recent studies have suggested that Bcl-x L may play a role in protecting keratinocytes from death signals induced by cell adhesion receptors and the EGF-R (Rodeck et al, 1997;Stoll et al, 1998). In addition, skin from transgenic mice that overexpress Bcl-x L has been shown to be much more resistant to UV radiation (Pena et al, 1997), suggesting that Bcl-x L may be important in keratinocytes to survive UVinduced damage.…”

Section: Discussionmentioning

confidence: 96%

“…Recent studies have demonstrated the importance of cell adhesion and the activation of the epidermal growth factor receptor (EGF-R) to keratinocyte cell survival (Rodeck et al, 1997;Stoll et al, 1998). In these studies, the inhibition of cell adhesion or the blocking of EGF-R activation caused keratinocytes to become more susceptible to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

et al. 1999

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The epidermis is continually exposed to harmful mutagens that have the potential to cause DNA damage. To protect the skin from accumulating mutated cells, keratinocytes have developed a highly regulated mechanism of eliminating damaged cells through apoptosis. Bclx L is a well-described cell survival protein that when overexpressed in skin can protect keratinocytes from UV radiation-induced apoptosis. To begin to unravel the complex mechanisms that keratinocytes use to survive, we wanted to characterize the role of endogenous Bcl-x L in protecting cells from death. In this study, we describe the development and characterization of an antisense inhibitor to Bcl-x L . We show that this inhibitor reduces Bcl-x L RNA and protein in a concentration-dependent, sequence-speci®c manner. Furthermore, treatment of keratinocytes and epithelial cells with this inhibitor sensitizes these cells to UV-B radiation and cisplatinum treatment-induced apoptosis. Thus, these results o er direct evidence that Bcl-x L is critical in the protection of skin and epithelial cells from apoptosis and provide a basis for the role of Bcl-x L in keratinocyte and epithelial cell survival.

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“…3D). Bcl-2 family proteins inhibit apoptosis induced by variety of stimuli, including Fasmediated apoptosis (37)(38)(39). We assessed the expression of the antiapoptotic protein Bcl-xL by Western blotting 10 h after the injection of anti-Fas antibody.…”

Section: Expression Of Egf-r Ligands In Mouse Liver After the Adminismentioning

confidence: 99%

Novel Role for Amphiregulin in Protection from Liver Injury

Berasain

Garcı́a-Trevijano

Castillo

et al. 2005

Journal of Biological Chemistry

119

123

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Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor ␣, heparinbinding epidermal growth factor-like growth factor, betacellulin, epiregulin, and amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases.

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EGF receptor signaling inhibits keratinocyte apoptosis: evidence for mediation by Bcl-XL

Cited by 102 publications

References 37 publications

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

Novel Role for Amphiregulin in Protection from Liver Injury

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