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Stabilization of the G-quadruplex at the VEGF IRES represses cap-independent translation.

ABSTRACT: The activation of translation contributes to malignant transformation and is an emerging target for cancer therapies. RNA G-quadruplex structures are general inhibitors of cap-dependent mRNA translation and were recently shown to be targeted for oncoprotein translational activation. In contrast however, the G-quadruplex within the 5'UTR of the human vascular endothelial growth factor A (VEGF) has been shown to be essential for IRES-mediated translation. Since VEGF has a pivotal role in tumor angiogenesis and is a major target of anti-tumoral therapies, we investigated the structure/function relationship of the VEGF G-quadruplex and defined whether it could have a therapeutic potential. We found that the G-quadruplex within the VEGF IRES is dispensable for cap-independent function and activation in stress conditions. However, stabilization of the VEGF G-quadruplex by increasing the G-stretches length or by replacing it with the one of NRAS results in strong inhibition of IRES-mediated translation of VEGF. We also demonstrate that G-quadruplex ligands stabilize the VEGF G-quadruplex and inhibit cap-independent translation in vitro. Importantly, the amount of human VEGF mRNA associated with polysomes decreases in the presence of a highly selective stabilizing G-quadruplex ligand, resulting in reduced VEGF protein expression. Together, our results uncover the existence of functionally silent G-quadruplex structures that are susceptible to conversion into efficient repressors of cap-independent mRNA translation. These findings have implications for the in vivo applications of G-quadruplex-targeting compounds and for anti-angiogenic therapies.

SUBMITTER: Cammas A

PROVIDER: S-EPMC4615567 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Stabilization of the G-quadruplex at the VEGF IRES represses cap-independent translation.

Cammas Anne A Dubrac Alexandre A Morel Benjamin B Lamaa Assala A Touriol Christian C Teulade-Fichou Marie-Paule MP Prats Hervé H Millevoi Stefania S

RNA biology 20150101 3

The activation of translation contributes to malignant transformation and is an emerging target for cancer therapies. RNA G-quadruplex structures are general inhibitors of cap-dependent mRNA translation and were recently shown to be targeted for oncoprotein translational activation. In contrast however, the G-quadruplex within the 5'UTR of the human vascular endothelial growth factor A (VEGF) has been shown to be essential for IRES-mediated translation. Since VEGF has a pivotal role in tumor ang ...[more]

PMID: 25826664

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Project description:Senecavirus A (SVA) is a picornavirus that causes vesicular disease in swine and the only member of the Senecavirus genus. Like in all members of Picornaviridae, the 5' untranslated region (5'UTR) of SVA contains an internal ribosome entry site (IRES) that initiates cap-independent translation. For example, the replacement of the IRES of foot-and-mouth disease virus (FMDV) with its relative bovine rhinitis B virus (BRBV) affects the viral translation efficiency and virulence. Structurally, the IRES from SVA resembles that of hepatitis C virus (HCV), a flavivirus. Given the roles of the IRES in cap-independent translation for picornaviruses, we sought to functionally characterize the IRES of this genus by studying chimeric viruses generated by exchanging the native SVA IRES with that of HCV either entirely or individual domains. First, the results showed that a chimeric SVA virus harboring the IRES from HCV, H-SVA, is viable and replicated normally in rodent-derived BHK-21 cells but displays replication defects in porcine-derived ST cells. In the generation of chimeric viruses in which domain-specific elements from SVA were replaced with those of HCV, we identified an essential role for the stem-loop I element for IRES activity and recombinant virus recovery. Furthermore, a series of stem-loop I mutants allowed us to functionally characterize discrete IRES regions and correlate impaired IRES activities, using reporter systems with our inability to recover recombinant viruses in two different cell types. Interestingly, mutant viruses harboring partially defective IRES were viable. However, no discernable replication differences were observed, relative to the wild-type virus, suggesting the cooperation of additional factors, such as intermolecular viral RNA interactions, act in concert in regulating IRES-dependent translation during infection. Altogether, we found that the stem-loop I of SVA is an essential element for IRES-dependent translation activity and viral replication.

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Stabilization of the G-quadruplex at the VEGF IRES represses cap-independent translation.

Publications

Stabilization of the G-quadruplex at the VEGF IRES represses cap-independent translation.

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