title: Introduction of wild-type p53 enhances thrombospondin-1 expression in human glioma cells.
abstract: Malignant gliomas are distinguished from low-grade gliomas by their intense angiogenesis. In gliomas, p53 is the most frequently altered gene and is involved in the early phase of glioma development. In contrast, homozygous p16 gene deletion is more common in high-grade gliomas. In order to understand the mechanism by which gliomas become more angiogenic during the malignant transformation, we examined the relationship between thrombospondin-1, a negative regulator in angiogenesis, and these tumor suppressor genes in malignant gliomas. Human glioma cell line U-251 MG, which has mutated p53 and deleted p16, was transduced with recombinant replication-defective adenovirus vectors containing the cDNA of wild-type p53, p16, and p21. Only the induction of wild-type p53 enhanced expression of thrombospondin-1 mRNA and the protein in U-251 MG cells. Furthermore, thrombospondin-1 that was secreted in the culture medium was significantly increased (3.8-fold) as compared with that of the viral control 36 h after infection with Ad5CMV-p53. In the presence of wild-type p53 plasmid DNA, the promoter activity was increased 7.4-fold as compared with an empty expression vector control. These studies may suggest that mutation of p53 gene endows gliomas with an angiogenic phenotype by reducing thrombospondin-1 production as well as enhancing the angiogenesis inducers in the early phase of malignant progression.
authors.affiliation: Department of Neurosurgery, Ehime University School of Medicine, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan. harada@m.iheme-u.ac.jp
authors.forename: Hironobu
authors.initials: H
authors.lastname: Harada
authors.forename: Kou
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Saito
authors.forename: Shohei
authors.initials: S
authors.lastname: Kohno
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Nagato
authors.forename: Koji
authors.initials: K
authors.lastname: Furukawa
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kumon
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hamada
authors.forename: Takanori
authors.initials: T
authors.lastname: Ohnishi
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D017930:Genes, Reporter; D019942:Genes, p16; D016158:Genes, p53; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D019700:Thrombospondin 1 / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018076:DNA, Complementary; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D019700:Thrombospondin 1; D016159:Tumor Suppressor Protein p53; D008156:Luciferases