Versican G1 domain enhances adenoviral-mediated transgene expression and can be modulated by inhibitors of the Janus kinase (JAK)/STAT and Src family kinase pathways.
Submitted by Cristhian J Ildefonso on
Title | Versican G1 domain enhances adenoviral-mediated transgene expression and can be modulated by inhibitors of the Janus kinase (JAK)/STAT and Src family kinase pathways. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Akinfenwa, PY, Bond, WS, Ildefonso, CJ, Hurwitz, MY, Hurwitz, RL |
Journal | J Biol Chem |
Volume | 292 |
Issue | 35 |
Pagination | 14381-14390 |
Date Published | 2017 09 01 |
ISSN | 1083-351X |
Keywords | Adenoviridae, Animals, Antineoplastic Agents, Cell Line, Tumor, Cercopithecus aethiops, COS Cells, DNA, Recombinant, DNA, Viral, Genes, Reporter, Genetic Vectors, Humans, Janus Kinases, Neoplasm Proteins, Neoplasms, Peptide Fragments, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors, Recombinant Fusion Proteins, Signal Transduction, src-Family Kinases, STAT Transcription Factors, Versicans, Virus Replication |
Abstract | To examine the biochemical influences that may contribute to the success of gene therapy for ocular disorders, the role of versican, a vitreous component, in adenoviral-mediated transgene expression was examined. Versican is a large chondroitin sulfate-containing, hyaluronic acid-binding proteoglycan present in the extracellular matrix and in ocular vitreous body. Y79 retinoblastoma cells and CD44-negative SK-N-DZ neuroblastoma cells transduced with adenoviral vectors in the presence of versican respond with an activation of transgene expression. Proteolysis of versican generates a hyaluronan-binding G1 domain. The addition of recombinant versican G1 to SK-N-DZ cells results in a similar activation of transgene expression, and treatment with dasatinib, an inhibitor of Src family kinases, also mimics the effects of versican. Enhancement is accompanied by an increase in signal transducer and activator of transcription 5 (STAT5) phosphorylation and is abrogated by treatment with C188-9, a STAT3/5 inhibitor, or with ruxolitinib, a Janus kinase 1/2 (JAK1/2) inhibitor. These data implicate versican G1 in enhancing adenoviral vector transgene expression in a hyaluronic acid-CD44 independent manner that is down-regulated by inhibitors of the JAK/STAT pathway and enhanced by inhibitors of the Src kinase pathway. |
DOI | 10.1074/jbc.M116.773549 |
Alternate Journal | J. Biol. Chem. |
PubMed ID | 28684419 |
PubMed Central ID | PMC5582833 |
Grant List | F31 GM085793 / GM / NIGMS NIH HHS / United States T32 DK064717 / DK / NIDDK NIH HHS / United States T32 EY007001 / EY / NEI NIH HHS / United States |