title: Oncogenic KRAS regulates BMP4 expression in colon cancer cell lines.
abstract: Activating mutations in the KRAS oncogene are common in colorectal cancer. However, the complete spectrum of KRAS targets that mediate its tumorigenic effect has not yet been fully delineated. We identified bone morphogenetic protein 4 (Bmp4), a transforming growth factor-β family member that regulates development and tissue homeostasis, as a new target of KRAS. In SW480, Hela, and 293 cells, oncogenic KRAS(V12) downregulated BMP4 RNA levels, a BMP4 promoter luciferase construct, and Bmp4 protein levels. The MEK inhibitor PD98059 but not the phosphatidylinositol 3-kinase inhibitor LY294002 blocked this downregulation of BMP4. To identify the region of the BMP4 promoter that mediated this regulation by KRAS, serial 5'-deletions of the promoter were generated. An inhibitory region was identified between -3,285 and -3,258 bp in the Bmp4 promoter. In summary, oncogenic KRAS can downregulate Bmp4 through a transcriptional pathway that depends on ERK. These findings point to a unique link between two pathways that are frequently altered in colon cancer.
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Duerr
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mizukami
authors.forename: Kentaro
authors.initials: K
authors.lastname: Moriichi
authors.forename: Manish
authors.initials: M
authors.lastname: Gala
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Jo
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chung
mesh_terms: D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000235:genetics*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; C117307:KRAS protein, human; D009025:Morpholines; D011518:Proto-Oncogene Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one