Epidermal growth factor activates nuclear factor-κB in human proximal tubule cells

Häussler, Ulla; Wichert, Götz von; Schmid, Roland M.; Keller, Frieder; Schneider, Günter

doi:10.1152/ajprenal.00434.2003

Cited by 33 publications

(38 citation statements)

References 68 publications

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“…In many tumors, overexpression of EGFR leads to constitutive activation of the receptor and has been shown to correlate with tumor proliferation, metastasis, resistance to chemotherapy, and hence, poor prognosis (Mendelsohn and Baselga, 2000). That EGF can activate nuclear factor-kB (NF-kB) has been demonstrated (Obata et al, 1996;Habib et al, 1998;Sun and Carpenter, 1998;Biswas et al, 2000;Haussler et al, 2005), the mechanism of its activation, however, remains elusive. Whether EGF induces NF-kB activation through a pathway similar to that of tumor-necrosis factor (TNF) was investigated in the present study.…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor (EGF) activates nuclear factor-κB through IκBα kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IκBα

et al. 2007

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Section: Introductionmentioning

confidence: 99%

Epidermal growth factor (EGF) activates nuclear factor-κB through IκBα kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IκBα

et al. 2007

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“…NFκB can be activated by EGF in nonmalignant cells, including the human embryonic kidney cell line 293 (7) and human kidney proximal tubule cells (37). We have now found that EGFR also mediates NFκB activation in nonmalignant human mammary epithelial cells and that this activation is inhibited by the EGFR tyrosine kinase inhibitor erlotinib.…”

Section: Discussionmentioning

confidence: 91%

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

Dermawan

Stark

2014

Proc. Natl. Acad. Sci. U.S.A.

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Activation of nuclear factor κB (NFκB) is a central event in the responses of normal cells to inflammatory signals, and the abnormal constitutive activation of NFκB is important for the survival of most cancer cells. In nonmalignant human cells, EGF stimulates robust activation of NFκB. The kinase activity of the EGF receptor (EGFR) is required, because the potent and specific inhibitor erlotinib blocks the response. Down-regulating EGFR expression or inhibiting EGFR with erlotinib impairs constitutive NFκB activation in several different types of cancer cells and, conversely, increased activation of NFκB leads to erlotinib resistance in these cells. We conclude that EGF is an important mediator of NFκB activation in cancer cells. To explore the mechanism, we selected an erlotinibresistant cell line in which the guanine nucleotide exchange factor Son of Sevenless 1 (SOS1), well known to be important for EGFdependent signaling to MAP kinases, is overexpressed. Increased expression of SOS1 increases NFκB activation in several different types of cancer cells, and ablation of SOS1 inhibits EGF-induced NFκB activation in these cells, indicating that SOS1 is a functional component of the pathway connecting EGFR to NFκB activation. Importantly, the guanine nucleotide exchange activity of SOS1 is not required for NFκB activation.

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“…Higher levels of NFB regulated chemokines have been observed in melanoma and appear to accelerate the progression and metastasis of the tumour 237,238 . Indeed NFB becomes constitutively upregulated in melanoma through the development of an autocrine loop where NFB upregulates the same chemokines which are responsible for initiating its activation 239 .…”

Section: The Nfb Pathwaymentioning

confidence: 99%

“…The theory that Bfl-1 would become upregulated during the transformation of melanocytes is supported by the fact that the NFB pathway, which is responsible in the regulation of Bfl-1 expression, has been shown to become upregulated after the transformation of melanocytes 239 and NFB regulated chemokines were observed at a higher level in melanoma than healthy cells 237,238 . Indeed, Bfl-1 overexpression, much like Bcl-2, was not seen to be tumourigenic itself in mice 391 .…”

Section: : Concluding Remarksmentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Epidermal growth factor activates nuclear factor-κB in human proximal tubule cells

Cited by 33 publications

References 68 publications

Epidermal growth factor (EGF) activates nuclear factor-κB through IκBα kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IκBα

Epidermal growth factor (EGF) activates nuclear factor-κB through IκBα kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IκBα

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

Role of the pro-survival molecule Bfl-1 in melanoma

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