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Oncogene. 1998 Apr 23;16(16):2095-102.

Epidermal growth factor activation of NF-kappaB is mediated through IkappaBalpha degradation and intracellular free calcium.

Author information

1
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

Abstract

The transcription factor NF-kappa-B is normally sequestered in the cytoplasm by its inhibitory subunit IkappaB. Most extracellular signals activate NF-kappa-B through a mechanism involving the phosphorylation and proteasome-dependent degradation of IkappaB. EGF activates NF-kappaB in A-431 carcinoma cells, which overexpress EGF receptors and in mouse embryo fibroblasts, which have a normal complement of receptors. Supershift experiments indicate that the NF-kappa-B complexes induced by EGF are composed of p50/p50 homodimers and p65/p50 heterodimers, but not c-rel. EGF stimulation enhances the degradation of IkappaBalpha, but not IkappaBbeta nor an N-terminal deletion mutant of IkappaBalpha. Treatment of cells with a proteasome inhibitor, such as ALLN or MG132, blocks EGF-mediated NF-kappaB activation, indicating that EGF-induced NF-kappa-B activation requires proteasome-dependent IkappaB degradation. Also, Bapta A/M (a cell-permeable chelator of intracellular calcium) blocks EGF-induced NF-kappa-B activation and IkappaBalpha degradation, suggesting a requirement of intracellular free Ca2+ for this growth factor response. Protein kinase C inhibition, in contrast, did not influence EGF activation of NF-kappaB.

PMID:
9572490
DOI:
10.1038/sj.onc.1201731
[Indexed for MEDLINE]
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