VEGF-A splicing: the key to anti-angiogenic therapeutics?

Harper, Steven J.; Bates, David O.

doi:10.1038/nrc2505

Cited by 452 publications

(432 citation statements)

References 70 publications

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“…VEGFA transcripts, which encode the key ligand secreted by tumors in response to hypoxia to promote the formation of new blood vessels, are extensively alternatively spliced . Perhaps the alternate isoform with the most pertinence to cancer was discovered in 2002, when a variant differing only in the final six amino acids was identified (Bates et al 2002;Harper and Bates 2008). This six-amino-acid change occurred due to the choice of a distal 39 splice site in the final exon (Fig.…”

Section: Regulation Of Angiogenesis: Vegfamentioning

confidence: 99%

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

David

Manley²

2010

Genes Dev.

727

667

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Alternative splicing of mRNA precursors is a nearly ubiquitous and extremely flexible point of gene control in humans. It provides cells with the opportunity to create protein isoforms of differing, even opposing, functions from a single gene. Cancer cells often take advantage of this flexibility to produce proteins that promote growth and survival. Many of the isoforms produced in this manner are developmentally regulated and are preferentially re-expressed in tumors. Emerging insights into this process indicate that pathways that are frequently deregulated in cancer often play important roles in promoting aberrant splicing, which in turn contributes to all aspects of tumor biology.

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Section: Regulation Of Angiogenesis: Vegfamentioning

confidence: 99%

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

David

Manley²

2010

Genes Dev.

727

667

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“…S3). One newly discovered class of isoforms (b isoforms) has anti-angiogenic activity that is opposite to canonical VEGF-A isoforms (29,30). Most solid cancers are associated with a switch from the VEGF-A b isoforms to the pro-angiogenic a isoforms to promote angiogenesis.…”

Section: Random Library Screen For Cytosinementioning

confidence: 99%

Specific and Modular Binding Code for Cytosine Recognition in Pumilio/FBF (PUF) RNA-binding Domains

Dong

Wang

Cassidy-Amstutz

et al. 2011

Journal of Biological Chemistry

140

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Pumilio/fem-3 mRNA-binding factor (PUF) proteins possess a recognition code for bases A, U, and G, allowing designed RNA sequence specificity of their modular Pumilio (PUM) repeats. However, recognition side chains in a PUM repeat for cytosine are unknown. Here we report identification of a cytosine-recognition code by screening random amino acid combinations at conserved RNA recognition positions using a yeast three-hybrid system. This C-recognition code is specific and modular as specificity can be transferred to different positions in the RNA recognition sequence. A crystal structure of a modified PUF domain reveals specific contacts between an arginine side chain and the cytosine base. We applied the C-recognition code to design PUF domains that recognize targets with multiple cytosines and to generate engineered splicing factors that modulate alternative splicing. Finally, we identified a divergent yeast PUF protein, Nop9p, that may recognize natural target RNAs with cytosine. This work deepens our understanding of natural PUF protein target recognition and expands the ability to engineer PUF domains to recognize any RNA sequence.The specific interaction of RNA and protein plays vital roles in RNA regulation including splicing, localization, translation, and degradation. Such recognition may be directed toward unstructured RNA requiring discrimination of RNA sequences, folded RNA motifs, or some combination of sequence and structural specificity (1). Members of the PUF 2 protein family (named after Drosophila Pumilio and Caenorhabditis elegans fem-3 mRNA-binding factor (FBF)) are sequence-specific RNA-binding proteins that regulate networks of mRNAs encoding proteins of related function (2-7). PUF proteins generally recognize the 3Ј-UTR of their target mRNAs to control the mRNA stability and translation (2-7).The RNA-binding domain of PUF proteins, known as the Pumilio homology domain (PUM-HD) or PUF domain, can bind to unstructured RNA sequences in a distinct fashion. The PUF domain of human Pumilio 1 contains eight PUM repeats, each containing three ␣-helices packed together in a curved structure (8 -10). RNA is bound as an extended strand to the concave surface of the PUF domain with the bases contacted by protein side chains. In general, each PUM repeat recognizes a single RNA base through the second helix (␣2) in an antiparallel arrangement, i.e. nucleotides 1-8 are recognized by PUF repeats 8 -1, respectively. The ␣2 helices of PUM repeats contain a 5-residue sequence, designated here as 12XX5, where the side chain at position 2 stacks with the recognized base and the side chains at positions 1 and 5 recognize the edge of the base (8, 11) (see Fig. 1A). Specific residues at these positions direct the base recognition properties of the repeat. This PUF-RNA recognition code makes it possible to modify a PUM repeat to bind a particular RNA base, producing a designed PUF domain that specifically recognizes a given 8-nucleotide RNA target. Such de novo designed RNA binders have been used to track RNA local...

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“…Vascular endothelial growth factor (VEGF) is a proangiogenic glycoprotein that is essential for a variety of cellular processes, including angiogenesis, cell proliferation, and cell migration. [20][21][22][23] VEGF, originally named vascular permeability factor for its profound effects on vascular barrier function, was discovered as a tumor-secreted protein that led to venular hyperpermeability to circulating macromolecules [24][25][26] and is known to increase lung EC permeability. 27 Since its discovery, VEGF has been implicated in a wide range of inflammatory diseases, including pulmonary inflammation, such as ARDS, VILI, fibrosis, and asthma.…”

mentioning

confidence: 99%

Sp1‐Mediated Nonmuscle Myosin Light Chain Kinase Expression and Enhanced Activity in Vascular Endothelial Growth Factor–Induced Vascular Permeability

et al. 2015

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Despite the important role played by the nonmuscle isoform of myosin light chain kinase (nmMLCK) in vascular barrier regulation and the implication of both nmMLCK and vascular endothelial growth factor (VEGF) in the pathogenesis of acute respiratory distress syndrome (ARDS), the role played by nmMLCK in VEGF-induced vascular permeability is poorly understood. In this study, the role played by nmMLCK in VEGF-induced vascular hyperpermeability was investigated. Human lung endothelial cell barrier integrity in response to VEGF is examined in both the absence and the presence of nmMLCK small interfering RNAs. Levels of nmMLCK messenger RNA (mRNA), protein, and promoter activity expression were monitored after VEGF stimulation in lung endothelial cells. nmMYLK promoter activity was assessed using nmMYLK promoter luciferase reporter constructs with a series of nested deletions. nmMYLK transcriptional regulation was further characterized by examination of a key transcriptional factor. nmMLCK plays an important role in VEGFinduced permeability. We found that activation of the VEGF signaling pathway in lung endothelial cells increases MYLK gene product at both mRNA and protein levels. Increased nmMLCK mRNA and protein expression is a result of increased nmMYLK promoter activity, regulated in part by binding of the Sp1 transcription factor on triggering by the VEGF signaling pathway. Taken together, these findings suggest that MYLK is an important ARDS candidate gene and a therapeutic target that is highly influenced by excessive VEGF concentrations in the inflamed lung.

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VEGF-A splicing: the key to anti-angiogenic therapeutics?

Cited by 452 publications

References 70 publications

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

Specific and Modular Binding Code for Cytosine Recognition in Pumilio/FBF (PUF) RNA-binding Domains

Sp1‐Mediated Nonmuscle Myosin Light Chain Kinase Expression and Enhanced Activity in Vascular Endothelial Growth Factor–Induced Vascular Permeability

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