Abstract
BackgroundZFP36 is an mRNA binding protein that exerts anti-tumor activity in glioblastoma by triggering cell death, associated to an increase in the stability of the kinase RIP1.MethodsWe used cell death assays, size exclusion chromatography, Co-Immunoprecipitation, shRNA lentivectors and glioma neural stem cells to determine the effects of ZFP36 on the assembly of a death complex containing RIP1 and on the induction of necroptosis.ResultsHere we demonstrate that ZFP36 promotes the assembly of the death complex called Ripoptosome and induces RIP1-dependent death. This involves the depletion of the ubiquitine ligases cIAP2 and XIAP and leads to the association of RIP1 to caspase-8 and FADD. Moreover, we show that ZFP36 controls RIP1 levels in glioma neural stem cell lines.ConclusionsWe provide a molecular mechanism for the tumor suppressor role of ZFP36, and the first evidence for Ripoptosome assembly following ZFP36 expression. These findings suggest that ZFP36 plays an important role in RIP1-dependent cell death in conditions where IAPs are depleted.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1388-5) contains supplementary material, which is available to authorized users.
Highlights
ZFP36-transfected cells (ZFP36) is an mRNA binding protein that exerts anti-tumor activity in glioblastoma by triggering cell death, associated to an increase in the stability of the kinase Receptor interacting serine/threonine protein kinase 1 (RIP1)
The key molecular event underlining this process is the depletion of the Inhibitor of Apoptosis Proteins (IAPs) proteins X-linked inhibitor of apoptosis (XIAP) and Cellular inhibitor of apoptosis 2 (cIAP2), which we and others [4, 12] previously described as a target of ZFP36mediated mRNA decay
ZFP36-mediated RIP1 stabilization depends on IAPs degradation and correlates with increased cell death Experimental evidences demonstrate that ZFP36 triggers the degradation of XIAP and cIAP2 mRNAs, which carry Adenine Uridine-rich (AU-rich) elements in their 3′untranslated region (3′UTR) [4, 12]
Summary
ZFP36 is an mRNA binding protein that exerts anti-tumor activity in glioblastoma by triggering cell death, associated to an increase in the stability of the kinase RIP1. A growing body of literature demonstrates the ability of ZFP36 to negatively regulate mRNAs coding for oncogenes in different cellular contexts thereby exerting anti-tumor activities [2,3,4,5]. The key molecular event underlining this process is the depletion of the IAP proteins XIAP and cIAP2, which we and others [4, 12] previously described as a target of ZFP36mediated mRNA decay. We demonstrate that loss of ZFP36 in glioma cancer stem cells leads to the downregulation of RIP1, reinforcing the molecular link between ZFP36 and RIP1
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