Epidermal Growth Factor Receptor and Notch Pathways Participate in the Tumor Suppressor Function of γ-Secretase
ABSTRACT Gamma-secretase, a unique aspartyl protease, is required for the regulated intramembrane proteolysis of Notch and APP, pathways that are implicated, respectively, in the pathogenesis of cancer and Alzheimer disease. However, the mechanism whereby reduction of gamma-secretase causes tumors such as squamous cell carcinoma (SCC) remains poorly understood. Here, we demonstrate that gamma-secretase functions in epithelia as a tumor suppressor in an enzyme activity-dependent manner. Notch signaling is down-regulated and epidermal growth factor receptor (EGFR) is activated in SCC caused by genetic reduction of gamma-secretase. Moreover, the level of EGFR is inversely correlated with the level of gamma-secretase in fibroblasts, suggesting that the up-regulation of EGFR stimulates hyperproliferation in epithelia of mice with genetic reduction of gamma-secretase. Supporting this notion is our finding that the proliferative response of fibroblasts lacking gamma-secretase activity is more sensitive when challenged by either EGF or an inhibitor of EGFR as ompared with wild type cells. Interestingly, the up-regulation of EGFR is independent of Notch signaling, suggesting that the EGFR pathway functions in parallel with Notch in the tumorigenesis of SCC. Collectively, our results establish a novel mechanism linking the EGFR pathway to the tumor suppressor role of gamma-secretase and that mice with genetic reduction of gamma-secretase represent an excellent rodent model for clarifying pathogenesis of SCC and for testing therapeutic strategy to ameliorate this type of human cancer.
- SourceAvailable from: Rui Medeiros
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- "They observed that EGFR levels were robustly increased in fibroblasts deficient in both PS1 and PS2 and the stable transfection of wild-type PS1 but not PS2 corrected EGFR to levels comparable to PS +/+ cells (Repetto et al., 2007). Li and coworkers demonstrated that the levels of EGFR are inversely correlated with the level of γ-secretase in fibroblasts, suggesting that the up-regulation of EGFR stimulates hyperproliferation in epithelia of mice with genetic reduction of γ-secretase (Li et al., 2007). The EGFR pathway seems to have an important role in the development of the nervous system, promoting the growth and differentiation of neural stem cells (Currais et al., 2009). "
ABSTRACT: Presently, neurodegenerative diseases and cancer are the most clinically problematic age-related diseases worldwide. Although being distinct disorders, their developments share common cellular mechanisms. Oncogenesis and neurodegeneration arise from the deregulation of signaling pathways, as a consequence of the resulting imbalance in cellular homeostasis. The epidermal growth factor receptor (EGFR) belongs to an important cellular signaling pathway, which regulates proliferation, differentiation, cell cycle and migration. As transcriptional targets of EGFR, the microRNAs-221/222 (miR-221/222) are important expression regulators. Dysfunctions in their networks are associated with cellular disruptions. The transcriptional activation of these microRNAs (miRNAs) seems to be involved in cell cycle, apoptosis, metastization, and in the acquisition of resistance to therapies. The up-regulation of miR-221/222 is associated with increased expression levels of matrix metalloproteinases (MMPs) and repression of cell cycle inhibitors, which are key molecules in oncogenesis and neurodegeneration processes. The interaction loop between proliferative signaling pathways and miRNA expression could reveal new targets for controlling the molecular behavior of age-related diseases.Frontiers in Genetics 12/2012; 3:286. DOI:10.3389/fgene.2012.00286
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- " Wong et al . 2004 ) . Other evidence shows that , in contrast to its role in cell proliferation in many other cell types , Notch signaling acts as a tumor suppressor in epithelia ( Nicolas et al . 2003 ; Proweller et al . 2006 ; Demehri et al . 2009 ) , and that reduction of g - secretase components can result in skin cancers ( Xia et al . 2001 ; Li et al . 2007 ) . Indeed , it has become clear that compounds targeting g - secretase for the potential treatment of AD should alter Ab production without signifi - cantly lowering the normal , physiologically reg - ulated release of the Notch intracellular domain . The g - secretase inhibitor that had advanced the furthest in clinical trials , LY450"
ABSTRACT: Presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD). The encoded multipass membrane proteins were subsequently found to be the catalytic components of γ-secretases, membrane-embedded aspartyl protease complexes responsible for generating the carboxyl terminus of the amyloid β-protein (Aβ) from the amyloid protein precursor (APP). The protease complex also cleaves a variety of other type I integral membrane proteins, most notably the Notch receptor, signaling from which is involved in many cell differentiation events. Although γ-secretase is a top target for developing disease-modifying AD therapeutics, interference with Notch signaling should be avoided. Compounds that alter Aβ production by γ-secretase without affecting Notch proteolysis and signaling have been identified and are currently at various stages in the drug development pipeline.Cold Spring Harbor Perspectives in Medicine 01/2012; 2(1):a006304. DOI:10.1101/cshperspect.a006304 · 7.56 Impact Factor
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- "γ-secretase activity is also an attractive target. Both genetic and pharmaceutical lowering of γ-secretase activity decrease production of Aβ (Li et al. 2007a,b). However, γ-secretase activity is also essential for processing Notch and a variety of other transmembrane proteins (Louvi & Artavanis-Tsakonas 2006). "
ABSTRACT: Alzheimer's disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single-pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases, including the intramembranous γ-secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ elimination. Lessons learned from biochemical and genetic studies of APP processing will be crucial to the development of therapeutic targets to treat AD.Annual Review of Neuroscience 07/2010; 34:185-204. DOI:10.1146/annurev-neuro-061010-113613 · 22.66 Impact Factor