title: Basal and Src kinase-mediated activation of the EphA2 promoter requires a cAMP-responsive element but is CREB-independent.
abstract: We have previously identified the EphA2 receptor tyrosine kinase as a potentially important injury-responsive gene and a transcriptional target of Src kinase activity in renal ischemia-reperfusion injury (IRI). In the present study, we confirmed, using EphA2 gene trap mice that the endogenous EphA2 promoter is strongly activated following renal IRI. We also examined in more detail the mechanisms responsible for Src kinase-induced activation of the -2 kb human EphA2 promoter and found that the minimal Src-responsive elements were contained in the -145 to +137 region of the human EphA2 gene. This region contains a canonical cAMP-responsive element (CRE) that we found to be critical for both basal and Src kinase-induced transcriptional activity. However, despite activation of the prototypical CRE-binding factor CREB by the Src kinase Fyn, siRNA-mediated knockdown of CREB had no significant impact on either basal or Fyn-induced EphA2 promoter activity. Similarly, activation of CREB by the adenylate cyclase agonist forskolin failed to induce EphA2 promoter activation. Thus, Src kinase-induced activation of the EphA2 promoter is CRE-dependent but CREB-independent.
authors.affiliation: Department of Medicine, McGill University, and the McGill University Health Centre Research Institute, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Du
authors.forename: Cindy
authors.initials: C
authors.lastname: Baldwin
authors.forename: Erika
authors.initials: E
authors.lastname: Hooker
authors.forename: Pauline
authors.initials: P
authors.lastname: Glorion
authors.forename: Serge
authors.initials: S
authors.lastname: Lemay
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D036104:Receptor, EphA2 / Q000235:genetics*; D015427:Reperfusion Injury / Q000235:genetics* / Q000473:pathology; D020218:Response Elements; D015533:Transcriptional Activation; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D005576:Colforsin; D000242:Cyclic AMP; D036104:Receptor, EphA2; D019061:src-Family Kinases; D000262:Adenylyl Cyclases