p38 MAPK Signalling in Endothelial Apoptosis

Simone Grethe

Research output: ThesisDoctoral Thesis (compilation)

90 Downloads (Pure)

Abstract

Endothelial apoptosis plays an important role in atherosclerosis, and a direct proapoptotic effect of chemotherapeutics on the tumour vasculature, emphasizes the great potency of antiangiogenic therapy in the treatment of cancer. We investigated signalling pathways in endothelial apoptosis induced by the inflammatory cytokine tumour necrosis factor alpha (TNF), the main target of which is the endothelium, and by the anticancer drug doxorubicin. Doxorubicin (also called Adriamycin) is a widely used anthracycline against a broad range of tumours and has been shown to exert its antitumoural effect via directly targeting the tumour vasculature. However, endothelial apoptosis is also implicated in doxorubicin-mediated cardiotoxicity, an undesirable side effect of the cancer therapy.

The main objective was to elucidate the role of p38 mitogen activated kinase (p38) in such systems, using the endothelial cell line EA.hy926. We found that p38 plays an important proapoptotic role in both, TNF- and doxorubicin-induced apoptosis. In TNF-induced cell death, p38 mediates phosphorylation of Bcl-xL, which is followed by Bcl-xL degradation in the proteasomes. Furthermore, we observed that p38 signalling inhibits the MEK/ERK survival pathway and the phosphorylation of its downstream target Bad, which ocurris through an increased activatity of the protein phosphatase 2A (PP2A). In addition to pharmacological inhibition, we used lentiviral vector transfection of EA.hy926 cells to express a dominant negative mutant Flag-p38 MAPK harboring T180A and Y182 F amino acid substitutions. Similarly to the TNF- induced cell death, we found a p38-mediated downregulation of Bcl-xL in cells undergoing doxorubicin-induced apoptosis. In contrast, MEK/ERK signalling appeared to be proapoptotic in this system. Interestingly, p38 signalling inhibited the PI3-K/Akt survival pathway and the phosphorylation of Bad. Results from a phosphatase assay showed that doxorubicin-induced p38 activity in endothelial cells could maintain PP2A activity at a normal level and thereby prevents phosphorylation of Akt and Bad. In summary, p38 exerts a strong proapoptotic action in endothelial cells exposed to TNF or doxorubicin by simultaneously decreasing the level of antiapoptotic Bcl-xL and increasing the level of proapoptotic Bad.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Experimental Pathology, Malmö
Supervisors/Advisors
  • Ares, Isabella, Supervisor
Award date2005 Sep 17
Publisher
Print ISBNs91-85439-70-3
Publication statusPublished - 2005

Bibliographical note

Defence details

Date: 2005-09-17
Time: 09:00
Place: Patholgy Main lecture hall, entrance 78, floor 2, MAS

External reviewer(s)

Name: Hallberg, Bengt
Title: docent
Affiliation: Umeå universitet

---


<div class="article_info">S. Grethe, M.P.S. Ares, T. Andersson and M.I. Pörn-Ares. <span class="article_issue_date">2004</span>. <a href="javascript:downloadFile(545215)" class="article_link">p38 MAPK mediates TNF-induced apoptosis in endothelial cells via phosphorylation and downregulation of Bcl-xL</a> <span class="journal_series_title">Experimental Cell Research</span>, <span class="journal_volume">vol 298</span> <span class="journal_pages">pp 632-642</span>. <span class="journal_distributor">Academic Press, Elsevier</span></div>
<div class="article_info">Simone Grethe and M. Isabella Pörn-Ares. <span class="article_issue_date">2005</span>. <span class="article_title">p38 MAPK regulates phosphorylation of Bad via PP2A-dependent suppression of MEK1/2-ERK1/2 survival pathway in TNF-alpha induced apoptosis</span> <span class="journal_series_title">Cellular Signalling</span>, <span class="journal_distributor">Cellular Signalling</span> (accepted)</div>
<div class="article_info">Simone Grethe, Nadia Coltella, Maria Flavia Di Renzo and M. Isabella Pörn-Ares. <span class="article_issue_date"></span>. <span class="article_title">p38 MAPK Downregulates Akt-Mediated Bad Phosphorylation in Doxorubicin-Induced Endothelial Apoptosis</span> (manuscript)</div>

Subject classification (UKÄ)

  • Cancer and Oncology

Keywords

  • Naturvetenskap
  • Natural science
  • PP2A
  • Bad
  • Bcl-xL
  • doxorubicin
  • TNF
  • p38 MAPK
  • Apoptosis
  • endothelial cells

Fingerprint

Dive into the research topics of 'p38 MAPK Signalling in Endothelial Apoptosis'. Together they form a unique fingerprint.

Cite this