Regulation of vascular endothelial growth factor (VEGF) expression is mediated by internal initiation of translation and alternative initiation of transcription

Akiri, Gal; Nahari, Dorit; Finkelstein, Yiftach; Le, Shu-Yun; Elroy‐Stein, Orna; Levi, Ben‐Zion

doi:10.1038/sj.onc.1202019

Cited by 234 publications

(180 citation statements)

References 38 publications

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“…16 It has also been shown that a cryptic promoter is present in a domain originally described as part of the 5¢ non-coding region of the VEGF-A mRNA. 17 In this study, VEGF-A promoter activity in Sall1-transfected cells was significantly higher than that in cells transfected with mock vector or truncated Sall1 gene lacking c-terminal zinc-finger domains. Thus, Sall1 gene transfer induces strong angiogenesis through VEGF-A promoter stimulation by zinc-finger protein activity.…”

Section: Discussionmentioning

confidence: 82%

Zinc-finger transcriptional factor Sall1 induces angiogenesis by activation of the gene for VEGF-A

et al. 2009

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Section: Discussionmentioning

confidence: 82%

Zinc-finger transcriptional factor Sall1 induces angiogenesis by activation of the gene for VEGF-A

et al. 2009

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“…To circumvent this limitation, many of these transcripts feature internal ribosome entry sites (IRES) in their 5 0 UTRs that can promote translation initiation at internal start codons (Hellen and Sarnow, 2001). The VEGF mRNA belongs to this group of transcripts, as its 5 0 UTR contains two IRES elements (Akiri et al, 1998;Huez et al, 1998). Alternative initiation of VEGF mRNA transcription produces an mRNA with a shorter 5 0 UTR truncating one of the IRES elements, which could potentially influence VEGF mRNA translation initiation (Akiri et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Myc regulates VEGF production in B cells by stimulating initiation of VEGF mRNA translation

et al. 2004

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“…In this scenario, mTOR inhibition results in diminished cap-dependent translation, whereas VEGF IRES sequences regulate cap-independent protein translation in an AKT-dependent manner. A functional IRES has been previously identified in the VEGF mRNA (Akiri et al, 1998;Huez et al, 1998;Miller et al, 1998).…”

Section: Downregulation Of Vegf Expression In Akt-transfected MM Cellmentioning

confidence: 99%

AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells

Frost¹,

Shi²,

Hoang³

et al. 2006

Oncogene

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We recently demonstrated that the mammalian target of rapamycin (mTOR) inhibitor, CCI-779, curtailed the growth of a subcutaneous challenge of multiple myeloma (MM) cells in immunodeficient mice. This antitumor effect was associated with prevention of cell proliferation, induction of apoptosis and inhibition of angiogenesis. Interestingly, myeloma tumors with heightened AKT activation were particularly sensitive to a CCI-779-induced antitumor response. To investigate whether part of the differential sensitivity was due to an AKT-regulated effect on angiogenesis, we compared the effects of mTOR inhibitors against isogenic MM cell lines that only differ by their degree of AKT activity. In this model, heightened AKT activity significantly sensitized MM cells to the following inhibitory effects of mTOR inhibition: angiogenesis in vivo, vascular endothelial growth factor (VEGF) expression in vitro and in vivo and VEGF translation (but not transcription). Assessment of p70S6 kinase activity indicated that rapamycin induced comparable mTOR inhibition in both cell lines suggesting that an adverse effect on VEGF cap-dependent translation would be comparable. Internal ribosome entry site (IRES)-mediated cap-independent translation is a salvage pathway for protein expression when mTOR is inhibited, so we analyzed a possible regulatory role of AKT on VEGF IRES activity. We found that elevated AKT activity inhibited VEGF IRES function. These results support a mechanism whereby AKT prevents VEGF IRES activity in myeloma cells during mTOR inhibition resulting in a more complete abrogation of VEGF translation, and ultimately, angiogenesis.

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Regulation of vascular endothelial growth factor (VEGF) expression is mediated by internal initiation of translation and alternative initiation of transcription

Cited by 234 publications

References 38 publications

Zinc-finger transcriptional factor Sall1 induces angiogenesis by activation of the gene for VEGF-A

Zinc-finger transcriptional factor Sall1 induces angiogenesis by activation of the gene for VEGF-A

Myc regulates VEGF production in B cells by stimulating initiation of VEGF mRNA translation

AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells

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