Cutaneous epidermal growth factor receptor system following ultraviolet irradiation: exploring the role of molecular mechanisms

Martínez-Carpio, Pedro Antonio; Trelles, Mario A.

doi:10.1111/j.1600-0781.2010.00534.x

Cited by 12 publications

(17 citation statements)

References 42 publications

(81 reference statements)

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“…Epidermal growth factor receptor (EGFR) located on the cellular membrane of keratinocytes is widely recognized as a key regulator of numerous essential processes underlying skin development, homeostasis, and repair (30,35,38,39). EGFR belongs to a group of membrane bound receptor tyrosine kinases with extracellular ligand-binding domain and cytoplasmic domain possessing intrinsic protein kinase activity (1,25,26,31). EGFR is expressed through all layers of human epidermis with the strongest presence in the basal layer of epidermal keratinocytes (2,10,(24)(25)(26)(27).…”

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confidence: 99%

“…In keratinocytes, EGFR can be activated by disparate mechanisms under physiological or pathological conditions by specific pre-existing ligands, such as epidermal growth factor (EGF), transforming growth factor alpha (TGF-a), etc., and via matrix metalloproteinase (MMP)-mediated cleavage of mature ligands from their membrane-bound precursors (25,30). The autocrine formation of EGFR ligands may be stimulated by the proinflammatory cytokines tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-c) (24,26,27,29).…”

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confidence: 99%

“…Several lines of evidence suggest the existence of two modes of EGFR signaling. Traditional cytoplasmic EGFR route involves transduction of mitogenic signals through activation of numerous signaling cascades, such as phospholipase C-gamma-protein kinase C, Ras-Raf-mitogen-activated protein kinases (MAPKs), phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt), and signal transducer and activator of transcription (STATs) (1,5,22,24,25). In the nuclear pathway, activated EGFR undergoes fast nuclear translocation, where it physically or functionally interacts with other transcription factors possessing DNA-binding activity and STAT3, that leads to upregulation of distinct genes controlling cell proliferation and DNA repair (20,24,44).…”

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confidence: 99%

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Plant Polyphenols Regulate Chemokine Expression and Tissue Repair in Human Keratinocytes Through Interaction with Cytoplasmic and Nuclear Components of Epidermal Growth Factor Receptor System

Pastore

Lulli

Fidanza

et al. 2012

Antioxidants & Redox Signaling

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Aims: To evaluate mechanisms underlying modulation of inflammatory chemokines in primary human keratinocytes (normal human epidermal keratinocytes) and repair-related processes in wound models by plant polyphenols (PPs) with antioxidant and superoxide scavenging properties (verbascoside [Vb], resveratrol [Rv], polydatin [Pd], quercetin [Qr], and rutin). Results: Epidermal growth factor receptor (EGFR)-controlled chemokines CXCL8/interleukin 8 (IL-8), CCL2/monocyte chemotactic protein-1 (MCP-1), and CXCL10/interferon gamma-produced protein of 10 kDa (IP-10) were modulated by transforming growth factor alpha (TGF-a) and by the tumor necrosis factor alpha/interferon gamma combination (T/I). EGFR phosphorylation, nuclear translocation, and downstream cytoplasmic signaling pathways (extracellular regulation kinase [ERK]1/2, p38, STAT3, and PI-3K) were studied. All PPs did not affect TGF-a-induced STAT3 phosphorylation, whereas they suppressed T/I-activated NFkappaB and constitutive and T/I-induced but not TGF-a-induced ERK1/2 phosphorylation. Vb and Qr suppressed total EGFR phosphorylation, but they synergized with TGF-a to enhance nuclear accumulation of phosphorylated EGFR. Vb strongly inhibited TGF-a-induced p38 phosphorylation and T/I-induced NFkappaB and activator protein-1 (AP-1) binding to DNA. Vb was an effective inhibitor of T/I-stimulated chemokine synthesis, and it accelerated scratch wound healing in vitro. Anti-inflammatory and wound healing activities of Vb were confirmed in vivo in the full-thickness excision wound. Although Pd and Rv did not affect EGFR activation/translocation, they and Qr synergized with TGF-a and T/I in the induction of IL-8 transcription/synthesis while opposing enhanced MCP-1 and IP-10 transcription/synthesis connected with pharmacologically impaired EGFR functioning. Innovation: PPs perturb the EGFR system in human keratinocytes, and this effect may be implicated in the regulation of inflammatory and repair-related processes in the skin. Conclusion: Anti-inflammatory and wound healing effects of PPs depend on their interaction with EGFR-controlled cytoplasmic and nuclear pathways rather than on their direct redox properties. Antioxid. Redox Signal. 16, 314-328.

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confidence: 99%

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Plant Polyphenols Regulate Chemokine Expression and Tissue Repair in Human Keratinocytes Through Interaction with Cytoplasmic and Nuclear Components of Epidermal Growth Factor Receptor System

Pastore

Lulli

Fidanza

et al. 2012

Antioxidants & Redox Signaling

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“…This latter pathway has been demonstrated to exist in normal MEKs (39). Further complicating this is the observation that E2F7 can antagonize the pro-apoptotic activity of E2F1 in embryonic tissues as well as in normal or cancer cells (10,17,18,40).…”

Section: Discussionmentioning

confidence: 99%

“…Loss of function mutations of p53, Rb, or upstream regulators of the Rb/E2F axis such as INK4A (p16) are frequently associated with SCC and may result from mutation, deletion or promoter hypermethylation [37][38][39]. Moreover, SCCs are frequently associated with amplification/activation of mitogenic pathways controlled by cyclin D1, cdk4 or EGFR [31,40]. All these events are known to contribute to the dysregulation of proliferation and differentiation [31,40,41].…”

Section: Role Of Uv In Skin Carcinogenesismentioning

confidence: 99%

The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

Rethinam¹

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Among keratinocyte-derived squamous cell carcinoma (SCC), cutaneous SCC (CSCC) is the second most common cutaneous cancer type and the most common of the potentially fatal skin cancers. Approximately 90% of head and neck cancers are SCC (HNSCC) and HNSCC worldwide is the sixth most common cancer type afflicting mankind. While resectable disease may be treated by surgery with radiation or chemoradiation, there are still no curative options for advanced, unresectable disease. However, chemotherapy alone may offer a hope for unresectable, disseminated SCC, where 50-60% of patients have disease recurrence within 2 years and approximately 30% of these develop metastatic disease. The mainstay of chemotherapeutic treatment in SCC is the platinum-based drug, cisplatin, 5-fluorouracil (5-FU), taxanes, and anti-EGFR monoclonal antibody such as Cetuximab. Nonetheless, despite advances in treatment techniques, the 5-year survival rate still remains at around 55%.Therefore, there remains a lack of options for recurrent or metastatic disease.The E2F family of transcription factors has emerged as key regulators of proliferation, differentiation and response to stress and apoptotic stimuli in keratinocytes. Consistent with these roles, dysregulation of E2F expression/activity is a common occurrence in cancer and SCC in particular. Thus, better understanding of the E2F family of proteins is essential to establish how these processes are disrupted during SCC genesis. The E2F network exists as a complex map of interacting pathways, and the complete understanding of the E2F family will not be possible until physiological functions of newly identified inhibitory E2F proteins, E2F7 and E2F8, are fully revealed. I provide strong evidence, from in vitro experiments, that E2F7 plays a unique and non-redundant role in modulating UV-or chemotherapy-induced cytotoxicity whereas E2F8 has a unique and non-redundant capacity to regulate squamous differentiation. In addition, I report on a unique feedback loop between E2F1, E2F7 and E2F8 that highlights a previously unreported interdependent axis.With respect to E2F7-specific functions, my work characterised two previously unidentified pathways as therapeutic targets, E2F7/Sphk1/S1P/AKT and E2F7/RacGAP1/AKT, by which the transcription factor E2F7 suppresses doxorubicin specific sensitivity in SCC cells.Targeting these pathways has the potential to expand the clinical activity of existing chemotherapeutics. I provide, in vitro, in vivo and patient data in this study that shows that E2F7-dependent repression of doxorubicin sensitivity is mediated via the induction of Sphingosine kinase 1 (Sphk1) and Rac GTPase activating protein 1 (RacGAP1). These are iii both novel findings and have significant implications for drug resistant SCC. Specifically, Ishowed that (i) E2F7 is overexpressed in patient SCCs and inhibits sensitivity to doxorubicin, (ii) that E2F7-dependent doxorubicin resistance is mediated via E2F-dependent induction of Sphk1 leading to overproduction of Sphingosine-1-phosphate ...

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Integrative genomic analysis identifies associations of molecular alterations to APOBEC and BRCA1/2 mutational signatures in breast cancer

Treviño

2019

Molec Gen & Gen Med

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Background The observed mutations in cancer are the result of ~30 mutational processes, which stamp particular mutational signatures (MS). Nevertheless, it is still not clear which genomic alterations correlate to several MS. Here, a method to analyze associations of genomic data with MS is presented and applied to The Cancer Genome Atlas breast cancer data revealing promising associations. Methods The MS were discretized into clusters whose extremes were statistically associated with mutations, copy number, and gene expression data. Results Known associations for apolipoprotein B editing complex (APOBEC) and for BRCA1 and BRCA2 support the proposal. For BRCA1/2, mutations in ARAP3, three focal deletions, and one amplification were detected. Around 50 mutated genes for the two APOBEC signatures were identified including three kinesins (KIF13A, KIF1B, KIF4A), three ubiquitins (USP45, UBR4, UBR1), and two demethylases (KDM5B, KDM5C) among other genes also connected to DNA damage pathways. The results suggest novel roles for other genes currently not involved in DNA repair. The altered expression program was very high for the BRCA1/2 signature, high for APOBEC signature 13 clearly associated to immune response, and low for APOBEC signature 2. The remaining signatures show scarce associations. Conclusion Specific genetic alterations can be associated with particular MS.

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Cutaneous epidermal growth factor receptor system following ultraviolet irradiation: exploring the role of molecular mechanisms

Abstract: Our results help to clarify the working and importance of the UV-EGFR system in the human skin.

Cited by 12 publications

References 42 publications

Plant Polyphenols Regulate Chemokine Expression and Tissue Repair in Human Keratinocytes Through Interaction with Cytoplasmic and Nuclear Components of Epidermal Growth Factor Receptor System

Plant Polyphenols Regulate Chemokine Expression and Tissue Repair in Human Keratinocytes Through Interaction with Cytoplasmic and Nuclear Components of Epidermal Growth Factor Receptor System

The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

Integrative genomic analysis identifies associations of molecular alterations to APOBEC and BRCA1/2 mutational signatures in breast cancer

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