Adenoviral gene transfer of PDGF downregulates gas gene product PDGFalphaR and prolongs ERK and Akt/PKB activation.
The delivery of platelet-derived growth factor (PDGF) for tissue engineering of skin and periodontal wounds has become an active area of interest. However, little is known regarding the extended effects of PDGF on cell signaling via gene therapy and how such an approach facilitates the exiting of cells from growth arrest and entry to competence required for cell cycling. We show in vitro expression and secretion of PDGF-AA by recombinant adenovirus encoding the PDGF-A gene (Ad-PDGF-A). The bioactive PDGF-AA protein released induces sustained downregulation of PDGFalphaR that is encoded by a growth arrest-specific (gas) gene. Ad-PDGF-A induces sustained phosphorylation of PDGFalphaR as well as prolonged phosphorylation of downstream extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Furthermore, the phosphorylation of PDGFalphaR is abolished by cotransducing cells with adenovirus encoding a dominant negative mutant of the PDGF-A gene that disrupts PDGF bioactivity. These findings demonstrate the prolonged effects of adenoviral delivery of PDGF and aid in the better understanding of sustained PDGF signaling.
Chen
Qi-Ping
QP
Center for Biorestoration of Oral Health, Department of Periodontics, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-1078, USA.
Giannobile
William V
WV
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D015536:Down-Regulation / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology; D018014:Gene Transfer Techniques; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D016895:Culture Media, Serum-Free; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases