Abstract
Angiopoietin2 (Ang2) and its Tie2 receptor have extensive effects on tumor malignancy including angiogenesis and metastasis. In this study, we evaluated the protective effect of Ang2 on doxorubicin-induced apoptosis in HepG2 cells. Ang2 (400ng/ml) attenuated doxorubicin-mediated cytotoxicity by upregulating the expression of Survivin and Ref-1, which was reversed by a soluble extracellular domain of Tie2. Mechanistic study showed Ang2 activated ERK–MSK cascade to induce histone H3 phosphorylation and inducible gene expression. The stimulatory effect of Ang2 on anti-apoptotic genes was attenuated by either MSK inhibitor (H89) or by overexpression of a kinase-deficient MSK1. Activated MSK1 phosphorylated the CREB at Ser133 and phosho-CREB was recruited to Ref-1 promoter rapidly to initiate the gene expression. Moreover, knockdown of MSK1 by specific siRNA also attenuated the pro-survival activity of Ang2 and CREB phosphorylation. Hence, our study suggests the existence of an Ang2−ERK−MSK signaling axis mediating survival responses and drug resistance of tumor cells.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
