title: The related transcriptional enhancer factor-1 isoform, TEAD4(216), can repress vascular endothelial growth factor expression in mammalian cells.
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, TEAD4(216), which represses VEGF promoter activity. The TEAD4(216) 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 TEAD4(216) protein is localized to the cytoplasm, whereas the enhancer isoforms are found within the nucleus. The TEAD4(216) isoform can competitively repress the stimulatory activity of the TEAD4(434) and TEAD4(148) enhancers. Synthesis of the native VEGF(165) protein and cellular proliferation is suppressed by the TEAD4(216) isoform. Mutational analysis indicates that nuclear or cytoplasmic localization of any isoform determines whether it acts as an enhancer or repressor, respectively. The TEAD4(216) 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.
authors: Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, United States of America. appukutt@ohsu.edu
authors: Binoy
authors: B
authors: Appukuttan
authors: Trevor J
authors: TJ
authors: McFarland
authors: Andrew
authors: A
authors: Stempel
authors: Jean B
authors: JB
authors: Kassem
authors: Matthew
authors: M
authors: Hartzell
authors: Yi
authors: Y
authors: Zhang
authors: Derek
authors: D
authors: Bond
authors: Kelsey
authors: K
authors: West
authors: Reid
authors: R
authors: Wilson
authors: Andrew
authors: A
authors: Stout
authors: Yuzhen
authors: Y
authors: Pan
authors: Hoda
authors: H
authors: Ilias
authors: Kathryn
authors: K
authors: Robertson
authors: Michael L
authors: ML
authors: Klein
authors: David
authors: D
authors: Wilson
authors: Justine R
authors: JR
authors: Smith
authors: J Timothy
authors: JT
authors: Stout
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D015153:Blotting, Western; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002829:Choroid / Q000098:blood supply / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004728:Endothelium, Corneal / Q000166:cytology / Q000378:metabolism; D005128:Eye Diseases / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D019913:Nuclear Localization Signals; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012045:Regulatory Sequences, Nucleic Acid; D012160:Retina / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D009124:Muscle Proteins; D019913:Nuclear Localization Signals; D012333:RNA, Messenger; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A