Tumor necrosis factor-a-mediated suppression of dual-specificity phosphatase 4: crosstalk between NF¿B and MAPK regulates endothelial cell survival

Kao, DD. etc
Molecular and Cellular Biochemistry, 2013

We investigated the effects of tumor necrosis factor-a (TNF-a) exposure on mitogen-activated protein kinase signaling in human microvascular endothelial cells. TNF-a caused a significant suppression of a dual specificity phosphatase, DUSP4, that regulates ERK1/2 activation. Thus, we hypothesized that suppression of DUSP4 enhances cell survival by increasing ERK1/2 signaling in response to growth factor stimulation. In support of this concept, TNF-a pre-exposure increased growth factor-mediated ERK1/2 activation, whereas overexpression of DUSP4 with an adenovirus decreased ERK1/2 compared to an empty adenovirus control. Overexpression of DUSP4 also significantly decreased cell viability, lessened recovery in an in vitro wound healing assay, and decreased DNA synthesis. Pharmacological inhibition of NF¿B activation or a dominant negative construct of the inhibitor of ¿B significantly lessened TNF-a-mediated suppression of DUSP4 expression by 70–84 % and attenuated ERK activation, implicating NF¿B-dependent pathways in the TNF-a-mediated suppression of DUSP4 that contributes to ERK1/2 signaling. Taken together, our findings show that DUSP4 attenuates ERK signaling and reduces cell viability, suggesting that the novel crosstalk between NF¿B and MAPK pathways contributes to cell survival.

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Molecular and Cellular Biochemistry
Brigham and Women¿s Hospital