title: Transcription factor interactions mediate EGF-dependent COX-2 expression.
abstract: Cyclooxygenase-2 (COX-2) is linked to poor prognosis in patients with malignant gliomas. Amplification/overexpression of epidermal growth factor receptor (EGFR) is commonly seen in these tumors. EGFR signaling, through activation of the p38-MAPK/PKC-δ/Sp1 cascade, plays an essential role in the regulation of COX-2 expression in glioma cells. Here, we report that Src kinase contributes upstream to this signaling cascade. In addition, more detailed analysis revealed the involvement of FOXM1, a member of the forkhead box family of transcriptional activators, in EGF-dependent COX-2 induction. FOXM1 protein increased after stimulation with EGF, although its role in modulating COX-2 expression does not depend on this increase. While a conventional FOXM1 responsive element resides in a distal region (-2872/-2539 relative to the transcriptional start site) of the COX-2 promoter, this is not required for EGF-dependent induction of COX-2. Instead, FOXM1 forms a cooperative interaction with Sp1 at the Sp1-binding site (-245/-240 relative to the start site) of the COX-2 promoter to mediate EGF-induced COX-2 expression. Definition of this novel interaction provides a clearer understanding of the mechanistic basis for EGF induction of COX-2.
  
  
  CONCLUSIONS
  These data provide a guide for the evaluation of potential newer therapeutic targets that have relevance in this disease.
authors: Department of Radiation Oncology, Emory University, 1365 Clifton Road, NE, Suite CT-104, Atlanta, GA 30322, USA.
authors: Kaiming
authors: K
authors: Xu
authors: Hui-Kuo G
authors: HK
authors: Shu
mesh_terms: D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism*; D004790:Enzyme Induction; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000473:pathology; D006801:Humans; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D020218:Response Elements; D015398:Signal Transduction / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D016329:Sp1 Transcription Factor; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases
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