Epidermal Growth Factor Receptor and Notch Pathways Participate in the Tumor Suppressor Function of -Secretase

Department of Pathology, The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2007; 282(44):32264-73. DOI: 10.1074/jbc.M703649200
Source: PubMed


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.

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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). "
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    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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    • "Hypoxia-induced increased motility and invasiveness requires Notch signaling, and activated Notch mimics hypoxia in the induction of EMT. In this process, Notch signaling controls Snail-1 expression by two distinct but synergistic mechanisms [115]. "
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    ABSTRACT: Historically, cell-signaling pathways have been studied as the compilation of isolated elements into a unique cascade that transmits extracellular stimuli to the tumor cell nucleus. Today, growing evidence supports the fact that intracellular drivers of tumor progression do not flow in a single linear pathway, but disseminate into multiple intracellular pathways. An improved understanding of the complexity of cancer depends on the elucidation of the underlying regulatory networks at the cellular and intercellular levels and in their temporal dimension. The high complexity of the intracellular cascades causes the complete inhibition of the growth of one tumor cell to be very unlikely, except in cases in which the so-called “oncogene addiction” is known to be a clear trigger for tumor catastrophe, such as in the case of gastrointestinal stromal tumors or chronic myeloid leukemia. In other words, the separation and isolation of the driver from the passengers is required to improve accuracy in cancer treatment. This review will summarize the signaling pathway crossroads that govern renal cell carcinoma proliferation and the emerging understanding of how these pathways facilitate tumor escape. We outline the available evidence supporting the putative links between different signaling pathways and how they may influence tumor proliferation, differentiation, apoptosis, angiogenesis, metabolism and invasiveness. The conclusion is that tumor cells may generate their own crossroads/crosstalk among signaling pathways, thereby reducing their dependence on stimulation of their physiologic pathways.
    International Journal of Molecular Sciences 12/2012; 13(10):12710-33. DOI:10.3390/ijms131012710 · 2.86 Impact Factor
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    • "Instead of cognitive problems, HS patients [14] and semagacestat-treated patients all experienced an increased incidence of non-melanoma skin cancer. Similarly, mice with reduced levels of γ-secretase [15], [16] or Notch signaling [17], [18] are more prone to skin cancer, which implicates Notch signaling as the substrate responsible for the oncogenic effects in humans. These recent findings raise doubt regarding the role of Notch signaling in the observed cognitive decline in the γ-secretase-deficient mouse brain and upon γ-secretase inhibitor treatment for AD. "
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    ABSTRACT: Previous studies suggest that loss of γ-secretase activity in postnatal mouse brains causes age-dependent memory impairment and neurodegeneration. Due to the diverse array of γ-secretase substrates, it remains to be demonstrated whether loss of cleavage of any specific substrate(s) is responsible for these defects. The bulk of the phenotypes observed in mammals deficient for γ-secretase or exposed to γ-secretase inhibitors are caused by the loss of Notch receptor proteolysis. Accordingly, inhibition of Notch signaling is the main cause for untoward effects for γ-secretase inhibitors as therapeutics for Alzheimer's disease. Therefore, we wished to determine if loss of canonical Notch signaling is responsible for the age-dependent neurodegeneration observed upon γ-secrectase deficiency in the mouse brain. We generated postnatal forebrain-specific RBPj conditional knockout (cKO) mice using the CamKII-Cre driver and examined behavior and brain pathology in 12-18 month old animals. Since all four mammalian Notch receptor homologues signal via this DNA binding protein, these mice lack canonical Notch signaling. We found that loss of RBPj in mature excitatory neurons was well tolerated, with no evidence for neurodegeneration or of learning and memory impairment in mice aged up to 18 months. The only phenotypic deficit we observed in the RBPj-deficient mice was a subtle abnormality in olfactory preferences, particularly in females. We conclude that the loss of canonical Notch signaling through the four receptors is not responsible for age-dependent neurodegeneration or learning and memory deficits seen in γ-secretase deficient mice.
    PLoS ONE 10/2012; 7(10):e48180. DOI:10.1371/journal.pone.0048180 · 3.23 Impact Factor
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