p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

Grethe, Simone; Coltella, Nadia; Pörn-Ares, M. Isabella

doi:10.1016/j.bbrc.2006.06.159

Cited by 27 publications

(17 citation statements)

References 52 publications

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“…Consistent with previous reports [18,24,26,27], we have also demonstrated that suppression of the activated p38α by either a pharmacological inhibitor (SB203580) or siRNA protects endothelial cells from apoptosis in response to growth factor withdrawal. The effect of TNF-α on cell survival in the presence or absence of p38 inhibitor, however, has been controversial.…”

Section: Discussionsupporting

confidence: 80%

Differential Roles of JNK, ERK1/2, and p38 Mitogen-Activated Protein Kinases on Endothelial Cell Tissue Repair Functions in Response to Tumor Necrosis Factor-α

et al. 2012

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Tumor necrosis factor (TNF)-α can alter tissue repair functions in a variety of cells including endothelial cells. However, the mechanism by which TNF-α mediates these functional changes has not fully been studied. We investigated the role of mitogen-activated protein kinases (MAPKs) on mediating the regulatory effect of TNF-α on the tissue repair functions of human pulmonary artery endothelial cells (HPAECs). TNF-α protected HPAECs from undergoing apoptosis induced by serum and growth factor deprivation, augmented collagen gel contraction, and stimulated wound closure. TNF-α activated c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and p38. Inhibitors of JNK (SP600125, 5 µm) or ERK1/2 (PD98059, 5 µm) significantly inhibited TNF-α-stimulated cell survival, contraction of collagen gels, and wound closure. In contrast, the p38 inhibitor SB203580 (5 µm) further amplified all of the TNF-α effects on HPAECs. TNF-α specifically activated p38α but not other p38 isoforms and suppression of p38α by an siRNA resulted in further amplification of the TNF-α effect. These results suggest that TNF-α stimulates tissue repair functions of HPAECs, and this may be mediated, at least in part, positively via JNK and ERK1/2, and negatively through p38α. MAPKs may play a role in endothelial cell-mediated tissue repair, especially in an inflammatory milieu where TNF-α is present.

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Section: Discussionsupporting

confidence: 80%

Differential Roles of JNK, ERK1/2, and p38 Mitogen-Activated Protein Kinases on Endothelial Cell Tissue Repair Functions in Response to Tumor Necrosis Factor-α

et al. 2012

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“…Consistent with our findings, Bruening et al (20) reported that a p38 MAPK inhibitor completely blocked arsenite-induced up-regulation of the CMV promoter. Previous studies have shown that p38 MAPK is activated upon treatment with doxorubicin and paclitaxel (28,29). These studies also showed that inhibition of p38 MAPK reduced doxorubicin-and paclitaxel-induced apoptosis, demonstrating an important role for p38 MAPK in the apoptotic process.…”

Section: Discussionmentioning

confidence: 60%

Chemotherapeutic Agents Up-regulate the Cytomegalovirus Promoter: Implications for Bioluminescence Imaging of Tumor Response to Therapy

et al. 2007

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Bioluminescence imaging is widely used to evaluate tumor growth and response to therapy in living animals. In cells expressing luciferase under the control of a constitutive promoter, light output in part depends on viable cell number, so that changes in bioluminescence intensity may be correlated with changes in viable tumor mass over time. We have found that treatment of cancer cell lines expressing luciferase under control of the cytomegalovirus (CMV) promoter with staurosporine, doxorubicin, and paclitaxel results in a transient increase in bioluminescence, which is positively correlated with apoptosis and inversely correlated with cell viability. In contrast, similar treatment of cell lines expressing luciferase under control of the SV40 promoter did not exhibit this result. We found that low doses of staurosporine induced bioluminescence in CMV-but not SV40-driven luciferase cell lines, whereas high doses elicited induction in both, indicating promoter-dependent and promoter-independent mechanisms of bioluminescence induction. The promoter-dependent increase in bioluminescence intensity from CMV-driven luciferase is a result of induction of luciferase mRNA and protein expression. We extended these findings in vivo; doxorubicin treatment resulted in a transient induction in bioluminescence when normalized to tumor volume in CMV-but not SV40-driven luciferase-expressing xenografts. We found that inhibition of the p38 mitogen-activated protein kinase pathway blocked bioluminescence induction by doxorubicin, paclitaxel, and staurosporine in CMV-driven luciferaseexpressing cells. These findings have important implications when using bioluminescence to monitor the efficacy of anticancer therapy and underscore the complex regulation of the CMV promoter, which is widely used for high-level protein expression in mammalian cells. [Cancer Res 2007; 67(21):10445-54]

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“…However, the net biological effects on these cells are complex and variable. For example, under certain circumstances, TNF may induce EC apoptosis while at other times it may promote EC proliferation and angiogenesis (5,6). Some of this complexity may be explained by time-dependent alterations in signaling complexes.…”

Section: Tnfmentioning

confidence: 99%

FOXO3a Regulates Oxygen-responsive Expression of Tumor Necrosis Factor Receptor 2 in Human Dermal Microvascular Endothelial Cells

Ding

Kirkiles-Smith

Pober

2009

Journal of Biological Chemistry

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Microvascular endothelial cell (EC) expression of tumor necrosis factor receptor (TNFR) 2 is induced in situ by ischemia/reperfusion injury. To assess effects of molecular oxygen on TNFR2 expression, we subjected cultured human dermal microvascular ECs (HDMECs) to hypoxic conditions (1% O 2 ) or to hypoxic conditions followed by return to normoxic conditions. TNFR2 mRNA and protein are expressed under normoxic conditions but are rapidly reduced by hypoxia; they fall even further upon reoxygenation but rebound by 6 -9 h. TNFR1 expression is unaffected by hypoxia or reoxygenation in these same cells. We identified a potential FOXO3a binding site in the 5 enhancer region of the TNFR2 gene. FOXO3a from normoxic but not hypoxic HDMECs binds an oligonucleotide sequence matching this site, and the endogenous enhancer binds FOXO3a at this site in HDMECs under normoxic but not hypoxic conditions. Unphosphorylated FOXO3a is present in the nucleus of HDMECs under normoxic conditions. Hypoxia leads to FOXO3a phosphorylation at an Akt/protein kinase B target site and subsequent nuclear export; these processes are reversed by reoxygenation and blocked by LY294002, a phosphatidylinositol 3-kinase inhibitor that blocks Akt activation. LY294002 also prevents the hypoxia-mediated decrease in TNFR2 expression. Transiently transfected FOXO3a activates a TNFR2 promoter/reporter construct in HDMECs, whereas small interference RNA knockdown of FOXO3a reduces TNFR2 but not TNFR1 expression under normoxic conditions. Reduction in TNFR2 by small interference RNA sensitizes HDMECs to TNFR1-mediated apoptosis. We conclude that FOXO3a regulates oxygen-dependent changes in expression of TNFR2 in HDMECs, controlling sensitivity to TNF-mediated apoptosis.

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p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

Cited by 27 publications

References 52 publications

Differential Roles of JNK, ERK1/2, and p38 Mitogen-Activated Protein Kinases on Endothelial Cell Tissue Repair Functions in Response to Tumor Necrosis Factor-α

Differential Roles of JNK, ERK1/2, and p38 Mitogen-Activated Protein Kinases on Endothelial Cell Tissue Repair Functions in Response to Tumor Necrosis Factor-α

Chemotherapeutic Agents Up-regulate the Cytomegalovirus Promoter: Implications for Bioluminescence Imaging of Tumor Response to Therapy

FOXO3a Regulates Oxygen-responsive Expression of Tumor Necrosis Factor Receptor 2 in Human Dermal Microvascular Endothelial Cells

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