TY - JOUR
T1 - A p38-p65 transcription complex induced by endothelin-1 mediates signal transduction in cancer cells
AU - von Brandenstein, Melanie Gerstung
AU - Ngum Abety, Anna
AU - Depping, Reinhard
AU - Roth, Tanja
AU - Koehler, Matthias
AU - Dienes, Hans Peter
AU - Fries, Jochen W.U.
N1 - Funding Information:
M.G.v.B. is the recipient of a doctoral research fellowship from the Cologne Fortune program of the University of Cologne.
Funding Information:
JWUF is supported by a grant from the Imhoff Stiftung, and private donations (both to JWUF).
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2008/9
Y1 - 2008/9
N2 - Endothelin-1 is a powerful mitogen for various tumor and non-tumor cells. Its signaling cascade induces the inflammatory NF-κB complex, leading to expression of a number of target genes. In this context, MAPK p38 has been regarded as a potential phosphate donor for the p65 subunit of NF-κB. In the present study in HeLa cells, we have found that ET-1 induced signalling activates the NF-κB transcription complex (TC) in the nucleus at 6 h specifically via ET-A - but not ET-B receptor. The TC contains p65, p38 (α and β) - binding to the NLS of p65 in the cytoplasm - as well as p50, but no IκBα. Specific p38 inhibition by SB203580 or by siRNA interferes markedly with gene expression of several target genes. Complex formation occurs in the cytoplasm, and both transcription factors transmigrate as a complex in the nucleus. Overexpression of p38, treatment with Chrysin, MG132, or dimethylformamide shows dependence of TC on p38 as partner. In other tumor cells lines studied, ET-1 activates TC, with p38 as an important complex partner of p65. TC-induction by ET-1 contains about twice the amount of p38 than by TNFα. Thus, p38 may be an additional therapeutic target to control inflammatory gene expression in tumor cells.
AB - Endothelin-1 is a powerful mitogen for various tumor and non-tumor cells. Its signaling cascade induces the inflammatory NF-κB complex, leading to expression of a number of target genes. In this context, MAPK p38 has been regarded as a potential phosphate donor for the p65 subunit of NF-κB. In the present study in HeLa cells, we have found that ET-1 induced signalling activates the NF-κB transcription complex (TC) in the nucleus at 6 h specifically via ET-A - but not ET-B receptor. The TC contains p65, p38 (α and β) - binding to the NLS of p65 in the cytoplasm - as well as p50, but no IκBα. Specific p38 inhibition by SB203580 or by siRNA interferes markedly with gene expression of several target genes. Complex formation occurs in the cytoplasm, and both transcription factors transmigrate as a complex in the nucleus. Overexpression of p38, treatment with Chrysin, MG132, or dimethylformamide shows dependence of TC on p38 as partner. In other tumor cells lines studied, ET-1 activates TC, with p38 as an important complex partner of p65. TC-induction by ET-1 contains about twice the amount of p38 than by TNFα. Thus, p38 may be an additional therapeutic target to control inflammatory gene expression in tumor cells.
UR - http://www.scopus.com/inward/record.url?scp=49149084106&partnerID=8YFLogxK
U2 - 10.1016/j.bbamcr.2008.04.003
DO - 10.1016/j.bbamcr.2008.04.003
M3 - Journal articles
C2 - 18457675
AN - SCOPUS:49149084106
SN - 0167-4889
VL - 1783
SP - 1613
EP - 1622
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 9
ER -
