The related transcriptional enhancer factor-1 Isoform, TEAD4216, can repress vascular endothelial growth factor expression in mammalian cells

Binoy Appukuttan, Trevor J. McFarland, Andrew Stempel, Jean B. Kassem, Matthew Hartzell, Yi Zhang, Derek Bond, Kelsey West, Reid Wilson, Andrew Stout, Yuzhen Pan, Hoda Ilias, Kathryn Robertson, Michael Klein, David Wilson, Justine R. Smith, J. Timothy Stout

Research output: Contribution to journalArticle

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Abstract

Increased cellular production of vascular endothelial growth factor (VEGF) is responsible for the development and progression of multiple cancers and other neovascular conditions, and therapies targeting post-translational VEGF products are used in the treatment of these diseases. Development of methods to control and modify the transcription of the VEGF gene is an alternative approach that may have therapeutic potential. We have previously shown that isoforms of the transcriptional enhancer factor 1-related (TEAD4) protein can enhance the production of VEGF. In this study we describe a new TEAD4 isoform, TEAD4216, which represses VEGF promoter activity. The TEAD4216 isoform inhibits human VEGF promoter activity and does not require the presence of the hypoxia responsive element (HRE), which is the sequence critical to hypoxia inducible factor (HIF)-mediated effects. The TEAD4216 protein is localized to the cytoplasm, whereas the enhancer isoforms are found within the nucleus. The TEAD4216 isoform can competitively repress the stimulatory activity of the TEAD4434 and TEAD4148 enhancers. Synthesis of the native VEGF165 protein and cellular proliferation is suppressed by the TEAD4216 isoform. Mutational analysis indicates that nuclear or cytoplasmic localization of any isoform determines whether it acts as an enhancer or repressor, respectively. The TEAD4216 isoform appears to inhibit VEGF production independently of the HRE required activity by HIF, suggesting that this alternatively spliced isoform of TEAD4 may provide a novel approach to treat VEGF-dependent diseases.

Original languageEnglish (US)
Article numbere31260
JournalPLoS One
Volume7
Issue number6
DOIs
StatePublished - Jun 22 2012

Fingerprint

vascular endothelial growth factors
Vascular Endothelial Growth Factor A
Protein Isoforms
Cells
hypoxia
cells
promoter regions
therapeutics
proteins
alternative splicing
Proteins
production economics
Transcription
cell proliferation
cytoplasm
transcription (genetics)
Cytoplasm
Genes
Cell Proliferation
neoplasms

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Appukuttan, B., McFarland, T. J., Stempel, A., Kassem, J. B., Hartzell, M., Zhang, Y., ... Stout, J. T. (2012). The related transcriptional enhancer factor-1 Isoform, TEAD4216, can repress vascular endothelial growth factor expression in mammalian cells. PLoS One, 7(6), [e31260]. https://doi.org/10.1371/journal.pone.0031260

The related transcriptional enhancer factor-1 Isoform, TEAD4216, can repress vascular endothelial growth factor expression in mammalian cells. / Appukuttan, Binoy; McFarland, Trevor J.; Stempel, Andrew; Kassem, Jean B.; Hartzell, Matthew; Zhang, Yi; Bond, Derek; West, Kelsey; Wilson, Reid; Stout, Andrew; Pan, Yuzhen; Ilias, Hoda; Robertson, Kathryn; Klein, Michael; Wilson, David; Smith, Justine R.; Stout, J. Timothy.

In: PLoS One, Vol. 7, No. 6, e31260, 22.06.2012.

Research output: Contribution to journalArticle

Appukuttan, B, McFarland, TJ, Stempel, A, Kassem, JB, Hartzell, M, Zhang, Y, Bond, D, West, K, Wilson, R, Stout, A, Pan, Y, Ilias, H, Robertson, K, Klein, M, Wilson, D, Smith, JR & Stout, JT 2012, 'The related transcriptional enhancer factor-1 Isoform, TEAD4216, can repress vascular endothelial growth factor expression in mammalian cells', PLoS One, vol. 7, no. 6, e31260. https://doi.org/10.1371/journal.pone.0031260
Appukuttan, Binoy ; McFarland, Trevor J. ; Stempel, Andrew ; Kassem, Jean B. ; Hartzell, Matthew ; Zhang, Yi ; Bond, Derek ; West, Kelsey ; Wilson, Reid ; Stout, Andrew ; Pan, Yuzhen ; Ilias, Hoda ; Robertson, Kathryn ; Klein, Michael ; Wilson, David ; Smith, Justine R. ; Stout, J. Timothy. / The related transcriptional enhancer factor-1 Isoform, TEAD4216, can repress vascular endothelial growth factor expression in mammalian cells. In: PLoS One. 2012 ; Vol. 7, No. 6.
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