title: Novel permissive role of epidermal growth factor in transforming growth factor beta (TGF-beta) signaling and growth suppression. Mediation by stabilization of TGF-beta receptor type II.
abstract: Transforming growth factor beta (TGF-beta) signals through TGF-beta receptor serine/threonine kinases (TbetaRI and TbetaRII) and Smads, regulating cell growth and apoptosis. Although loss of TGF-beta receptor levels is strongly selected for during the progression of most cancers, tumor cells frequently escape from complete loss of TGF-beta receptors through unknown mechanisms. Here, we provide the first evidence that epidermal growth factor (EGF) signaling, which is generally enhanced in cancer, is permissive for regulation of gene expression and growth suppression by TGF-beta in LNCaP prostate adenocarcinoma cells. Our results support that these permissive effects occur through enhanced stability of TbetaRII mRNA and reversal of TGF-beta-mediated TbetaRII mRNA loss. Changes in stability of TbetaRII mRNA occur soon after EGF or TGF-beta1 addition (optimal within 3 h) and are independent of de novo protein synthesis or transcription. Remarkably, such loss of TbetaRII by TGF-beta can be mediated by a kinase-dead TbetaRII (K277R), as well as by other forms of this receptor harboring mutations at prominent autophosphorylation sites. Moreover, Smad3 small interfering RNA, which blocks TGF-beta-induced AP-1 promoter activity, does not block changes in the expression of TbetaRII by EGF or TGF-beta. We have also shown that changes in TbetaRII levels by EGF are EGF receptor-kinase-dependent and are controlled by signals downstream of MEK1/2. Our findings provide invaluable insights on the role of the EGF receptor-kinase in enhancing TGF-beta responses during prostate carcinogenesis.
authors.affiliation: The Case Comprehensive Cancer Center, The Division of General Medical Sciences and the Department of Pharmacology, Case School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Kyung
authors.initials: K
authors.lastname: Song
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Krebs
authors.forename: David
authors.initials: D
authors.lastname: Danielpour
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free / Q000378:metabolism; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008297:Male; D009154:Mutation; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D016895:Culture Media, Serum-Free; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D048369:MAP Kinase Kinase 1