title: K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc.
abstract: KRAS, BRAF, and PI3KCA are the most frequently mutated oncogenes in human colon cancer. To explore their effects on morphogenesis, we used the colon cancer-derived cell line Caco-2. When seeded in extracellular matrix, individual cells proliferate and generate hollow, polarized cysts. The expression of oncogenic phosphatidylinositol 3-kinase (PI3KCA H1047R) in Caco-2 has no effect, but K-Ras V12 or B-Raf V600E disrupts polarity and tight junctions and promotes hyperproliferation, resulting in large, filled structures. Inhibition of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase blocks the disruption of morphology, as well as the increased levels of c-myc protein induced by K-Ras V12 and B-Raf V600E. Apical polarity is already established after the first cell division (two-cell stage) in Caco-2 three-dimensional cultures. This is disrupted by expression of K-Ras V12 or B-Raf V600E but can be rescued by ribonucleic acid interference-mediated depletion of c-myc. We conclude that ERK-mediated up-regulation of c-myc by K-Ras or B-Raf oncogenes disrupts the establishment of apical/basolateral polarity in colon epithelial cells independently of its effect on proliferation.
authors: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Kirti
authors: K
authors: Magudia
authors: Aurelia
authors: A
authors: Lahoz
authors: Alan
authors: A
authors: Hall
mesh_terms: D018938:Caco-2 Cells; D016764:Cell Polarity / Q000235:genetics*; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)