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A role for p38 mitogen-activated protein kinase and c-myc in endothelin-dependent rat aortic smooth muscle cell proliferation.

Authors: Chen, S  Qiong, Y  Gardner, DG 
Citation: Chen S, etal., Hypertension. 2006 Feb;47(2):252-8. Epub 2005 Dec 19.
Pubmed: (View Article at PubMed) PMID:16365184
DOI: Full-text: DOI:10.1161/01.HYP.0000198424.93598.6b

We have demonstrated recently that endothelin (ET) stimulates rat aortic smooth muscle cell proliferation through an extracellular signal-regulated kinase (ERK)-dependent mechanism. Approximately 70% of ET-dependent [3H]-thymidine incorporation in these cells signals through this system. In the present study, we show that the residual mitogenic activity requires an intact p38 mitogen-activated protein kinase (p38 MAPK) system and increased c-myc gene expression. ET increased [3H]-thymidine incorporation in rat aortic smooth muscle cells approximately 5-fold. p38 MAPK inhibition with SB203580 or ERK/ERK kinase inhibition with PD98059 each effected approximately 70% inhibition in ET-dependent DNA synthesis, whereas the combination led to nearly complete blockade of the ET effect. ET also increased c-myc RNA levels and c-Myc protein levels in these cells. The increment in c-Myc expression was blocked by SB203580 but not by PD98059. Use of antisense oligonucleotides directed against the translation start site of the c-myc transcript, but not scrambled oligonucleotide sequence, resulted in approximately 60% decrease in ET-dependent [3H]-thymidine incorporation. The combination of antisense c-myc and PD98059 resulted in near complete inhibition of ET-dependent DNA synthesis. Both ET and c-Myc increased expression and promoter activity of E2F, a transcription factor that has been linked to enhanced cell cycle activity. The ET-dependent increment in E2F promoter activity was suppressed after treatment with SB203580 or antisense c-myc but not by PD98059 or a scrambled oligonucleotide sequence. Collectively, these findings demonstrate that ET uses 2 complementary signal transduction cascades (ERK and p38 MAPK) to control proliferative activity of vascular smooth muscle cells.

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CRRD Object Information
CRRD ID: 10059627
Created: 2015-08-20
Species: All species
Last Modified: 2015-08-20
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.