TITLE

Downregulation of epidermal growth factor receptor signaling by singlet oxygen through activation of caspase-3 and protein phosphatases

AUTHOR(S)
Zhuang, Shougang; Ouedraogo, Gladys D; Kochevar, Irene E
PUB. DATE
July 2003
SOURCE
Oncogene;7/10/2003, Vol. 22 Issue 28, p4413
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Downregulation of survival signaling pathways contributes to the cytotoxicity of reactive oxygen species (ROS) and may underlie certain therapies for hyperproliferative diseases. We have investigated the role of singlet oxygen, an ROS formed by photosensitization, in the regulation of survival signaling via the epidermal growth factor receptor (EGFR). Exposure of human keratinocytes to singlet oxygen resulted in rapid loss of EGFR, which was not blocked by either inhibition of receptor internalization or by interrupting the major proteolytic pathways (proteasome, lysosome or calpain). However, pretreatment with a caspase-3 inhibitor, DEVD-FMK, inhibited EGFR degradation. Caspase-3 cleavage was detected as early as 5?min after singlet oxygen treatment, and recombinant active caspase-3 completely cleaved EGFR in a keratinocyte membrane fraction. The singlet oxygen-induced loss of EGFR was accompanied by dephosphorylation of EGFR as well as of Akt and extracellular signal-regulated kinase 1/2 (ERK)1/2. Singlet oxygen-induced protein dephosphorylation was not dependent on activation of caspase-3. In contrast, inhibition of protein phosphatases (PPs) with okadaic acid completely blocked dephosphorylation of EGFR, ERK1/2 and Akt as well as degradation of EGFR. These results indicate that the oxidative stress produced by singlet oxygen rapidly disrupts EGFR-mediated signaling by decreasing both the protein level and its phosphorylation. These responses depended on intertwined activation of caspase-3 and PPs.Oncogene (2003) 22, 4413-4424. doi:10.1038/sj.onc.1206604
ACCESSION #
10223334

 

Related Articles

  • Keratinocyte Apoptosis Induced by Ultraviolet B Radiation and CD95 Ligation – Differential Protection through Epidermal Growth Factor Receptor Activation and Bcl-xL Expression. Jost, Monika; Gasparro, Francis P.; Jensen, Pamela J.; Rodeck, Ulrich // Journal of Investigative Dermatology;Jun2001, Vol. 116 Issue 6, p860 

    Previous work has shown that activation of the epidermal growth factor receptor by endogenous or exogenous signals markedly enhances survival of cultured keratinocytes upon cellular stress such as passaging. This is due, in part, to epidermal-growth-factor-receptor-dependent expression of...

  • Ligand-Independent Activation of the EGFR by Lipid Raft Disruption. Lambert, Sylviane; Vind-Kezunovic, Dina; Karvinen, Susanna; Gniadecki, Robert // Journal of Investigative Dermatology;May2006, Vol. 126 Issue 5, p954 

    Normal and immortalized keratinocytes demonstrate large aggregates of lipid rafts, detectable by membrane staining with fluorescently tagged cholera toxin (CTx). As lipid rafts are known to regulate the function of many surface receptors, we wished to investigate their impact on the EGFR in...

  • Apoptosis: Recognizing 'eat-me' signals. Bell, Elaine // Nature Reviews Immunology;Dec2007, Vol. 7 Issue 12, p917 

    The article discusses the identification of two phosphatidylserine (PtdSer) receptors. A study has recognized that the presence of milk fat globule EGF factor 8 (MFEG8), which acts as a linking molecule expressed by macrophages, energizes the engulfment of apoptotic cells. Another study has...

  • IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes. Restivo, Gaetana; Nguyen, Bach-Cuc; Dziunycz, Piotr; Ristorcelli, Elodie; Ryan, Russell J H; Özuysal, Özden Yalçin; Di Piazza, Matteo; Radtke, Freddy; Dixon, Michael J; Hofbauer, Günther F L; Lefort, Karine; Dotto, G Paolo // EMBO Journal;11/16/2011, Vol. 30 Issue 22, p4571 

    While the pro-differentiation and tumour suppressive functions of Notch signalling in keratinocytes are well established, the underlying mechanisms remain poorly understood. We report here that interferon regulatory factor 6 (IRF6), an IRF family member with an essential role in epidermal...

  • Altered [125I] Epidermal Growth Factor Binding and Receptor Distribution in Psoriasis. Nanney, Lillian B.; Stoscheck, Christa M.; Magid, Morgan; King Jr., Lloyd E. // Journal of Investigative Dermatology;Mar1986, Vol. 86 Issue 3, p260 

    Stimulation of growth and differentiation of human epidermis by epidermal growth factor (EGF) is mediated by its binding to specific receptors. Whether EGF receptors primarily mediate cell division or differentiation in hyper proliferative disease such as psoriasis vulgaris is unclear. To study...

  • The Epidermal Growth Factor Receptor System in Skin Repair and Inflammation. Pastore, Saveria; Mascia, Francesca; Mariani, Valentina; Girolomoni, Giampiero // Journal of Investigative Dermatology;Jun2008, Vol. 128 Issue 6, p1365 

    The epidermal growth factor (EGF) family comprises multiple mediators such as transforming growth factor-α, amphiregulin, heparin binding-EGF, and epiregulin, which are crucially involved in the tissue-specific proliferation/differentiation homeostasis. Typically, they act in an autocrine and...

  • Protein Tyrosyl Phosphatase-1B Is Expressed by Normal Human Epidermis, Keratinocytes, and A-431 Cells and Dephosphorylates Substrates of the Epidermal Growth Factor Receptor. Gunaratne, Prabha; Stoscheck, Christa; Gates, Ronald E.; Li, Liying; Nanney, Lillian B.; King, Lloyd E. // Journal of Investigative Dermatology;Nov94, Vol. 103 Issue 5, p701 

    In the epidermis tyrosine kinases such as those found in the epidermal growth factor receptor (EGF-R) phosphorylate regulatory molecules on tyrosine and play an important role in controlling epidermal growth. Phosphotyrosyl phosphatases (PTPase) that dephosphorylate EGF-R and other proteins...

  • Anthralin Decreases Keratinocyte TGF-α Expression and EGF-Receptor Binding In Vitro. Gottlieb, Alice B.; Khandke, Lakshmi; Krane, Jeffrey F.; Staiano-Coico, Lisa; Ashinoff, Robin; Krueger, James G. // Journal of Investigative Dermatology;May92, Vol. 98 Issue 5, p680 

    Anthralin is an effective topical treatment for active psoriasis; however, its mechanism of action is unknown. Both TGF-α and its receptor, the EGF receptor, are overexpressed in active psoriatic, plaques and might, therefore, play a role in psoriatic epidermal hyperplasia. In order to assess...

  • Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. Engelman, Jeffrey A.; Mukohara, Toru; Zejnullahu, Kreshnik; Lifshits, Eugene; Borrás, Ana M.; Gale, Christopher-Michael; Naumov, George N.; Yeap, Beow Y.; Jarrell, Emily; Sun, Jason; Tracy, Sean; Xiaojun Zhao; Heymach, John V.; Johnson, Bruce E.; Cantley, Lewis C.; Jänne, Pasi A.; Borrás, Ana M; Zhao, Xiaojun; Jänne, Pasi A // Journal of Clinical Investigation;Oct2006, Vol. 116 Issue 10, p2695 

    EGFR is frequently mutated and amplified in lung adenocarcinomas sensitive to EGFR inhibitors gefitinib and erlotinib. A secondary mutation, T790M, has been associated with acquired resistance but has not been shown to be sufficient to render EGFR mutant/amplified lung cancers resistant to EGFR...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics