Presenilin modulates EGFR signaling and cell transformation by regulating the ubiquitin ligase Fbw7

The epidermal growth factor receptor (EGFR) and Notch signaling pathways have antagonistic roles during epidermal differentiation and carcinogenesis. The molecular mechanisms regulating the crosstalk between EGFR and Notch during epidermal transformation are largely unknown. We found enhanced EGFR-d...

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Bibliographic Details
Published in:Oncogene Vol. 29; no. 20; pp. 2950 - 2961
Main Authors: Rocher-Ros, V, Marco, S, Mao, J-H, Gines, S, Metzger, D, Chambon, P, Balmain, A, Saura, C A
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 20.05.2010
Nature Publishing Group
Nature Publishing Group [1987-....]
Subjects:
631/208/200
631/80/86
692/420/755
Animals
Apoptosis
Biochemistry, Molecular Biology
Biological and medical sciences
Blotting, Western
Carcinogenesis
Catalysis
Cell Biology
Cell physiology
Cell Proliferation
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Cell Transformation, Neoplastic
Cells, Cultured
Cellular signal transduction
Embryo, Mammalian - cytology
Embryo, Mammalian - metabolism
Epidermal growth factor
Epidermal growth factor receptors
Epidermis
F-Box Proteins - metabolism
F-Box-WD Repeat-Containing Protein 7
Fibroblasts - cytology
Fibroblasts - metabolism
Fluorescent Antibody Technique
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation
Genetic aspects
Genetic regulation
Genetics
Growth factor receptors
Human Genetics
Hyperplasia
Immunoenzyme Techniques
Integrases - metabolism
Internal Medicine
Intracellular signalling
Keratinocytes
Keratinocytes - cytology
Keratinocytes - metabolism
Life Sciences
Ligases
Medicine
Medicine & Public Health
Mice
Mice, Knockout
Molecular and cellular biology
Molecular biology
Molecular modelling
Notch1 protein
Oncology
original-article
Physiological aspects
Presenilin
Presenilins - physiology
Proteasomes
Receptor, Epidermal Growth Factor - metabolism
Secretase
Signal transduction
Signal Transduction - physiology
Transcription
Ubiquitin
Ubiquitin - metabolism
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
France
Spain
carcinogenesis
γ-secretase
Fbw7
Notch
epidermis
Carbon-nitrogen ligases
Enzyme
Ligases
Presenilin
Epidermis
Carcinogenesis
Ubiquitin-protein ligase
Cell signaling
ISSN:0950-9232, 1476-5594, 1476-5594
Online Access:Get full text
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Summary:The epidermal growth factor receptor (EGFR) and Notch signaling pathways have antagonistic roles during epidermal differentiation and carcinogenesis. The molecular mechanisms regulating the crosstalk between EGFR and Notch during epidermal transformation are largely unknown. We found enhanced EGFR-dependent signaling, proliferation and oncogenic transformation caused by loss of presenilins (PS), the catalytic components of γ-secretase that generates the Notch1 intracellular domain (NICD). The underlying mechanism for abnormal EGFR signaling in PS-deficient cells involves γ-secretase-independent transcriptional upregulation of the E3 ubiquitin ligase Fbw7. Fbw7α, which targets NICD for degradation, regulates positively EGFR by affecting a proteasome-dependent ubiquitination step essential for constitutive degradation and stability of EGFR. To investigate the pathological relevance of this findings in vivo , we generated a novel epidermal conditional PS-deficient (ePS cDKO) mouse by deleting both PS in keratinocytes of the basal layer of the epidermis. The ePS cDKO mice develop epidermal hyperplasia associated with enhanced expression of both EGFR and Fbw7 and reduced NICD levels in keratinocytes. These findings establish a novel role for PS on epidermal growth and transformation by reciprocally regulating the EGFR and Notch signaling pathways through Fbw7.
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ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/onc.2010.57