title: GABARBP down-regulates HIF-1α expression through the VEGFR-2 and PI3K/mTOR/4E-BP1 pathways.
abstract: Human γ-aminobutyrate type A (GABAA) receptor-binding protein (GABARBP), a tumor suppressor protein with apoptotic function, can be inhibited in response to angiogenesis through the PI3K/Akt signaling cascades. Here, we investigated whether GABARBP over-expression could regulate vascular endothelial growth factor (VEGF)/hypoxia-inducible factor-1α (HIF-1α) expression and angiogenic activity in a carcinoma model system. GABARBP dramatically inhibited VEGF-induced endothelial cell proliferation, migration, and tube formation, as well as VEGFR-2 phosphorylation in vitro. At the same time, GABARBP exposed potent anti-angiogenic activity and remarkably down-regulated the levels of VEGF and HIF-1α protein expression, key components for angiogenesis. In addressing its biological molecular mechanism, GABARBP was found to effectively inhibit the phosphorylation of down-stream PI3K components, such as PDK1, Akt, mTOR, TSC-2, p70S6K, and 4E-BP1 by directly binding with VEGFR-2. In contrast, p38/JNK phosphorylation was not suppressed by GABARBP. These findings disclose a novel function of GABARBP in suppressing VEGF and HIF-1α protein expression, which is important for tumor angiogenesis and tumor growth. Thus, our data strongly provides novel biological mechanistic insights into the regulatory function of GABARBP in ovarian tumor progression, and the important of pre-clinical certification of GABARBP as a potential angiogenesis agent targeting ovarian tumorigenesis.
authors.affiliation: Department of Obstetrics and Gynecology, Hallym University, 948-1, Daerim 1-dong, Yeongdeungpo-gu, Seoul 150-950, Republic of Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Park
authors.affiliation: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Boh-Ram
authors.initials: BR
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Chonbuk National University Medical School, Jeonju 561-712, Republic of Korea.
authors.forename: Jeong Heon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Hallym University, 948-1, Daerim 1-dong, Yeongdeungpo-gu, Seoul 150-950, Republic of Korea.
authors.forename: Sung Taek
authors.initials: ST
authors.lastname: Park
authors.affiliation: Department of Life Science, Yong In University, 470, Samga-dong, Cheoin-gu, Yongin-si Gyeonggi-do 449-714, Republic of Korea.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Seung Myung
authors.initials: SM
authors.lastname: Dong
authors.affiliation: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do 410-769, Republic of Korea. Electronic address: sbrho@ncc.re.kr.
authors.forename: Seung Bae
authors.initials: SB
authors.lastname: Rho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011963:Receptors, GABA-A / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C116741:GABARAP protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D011963:Receptors, GABA-A; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D040301:Vascular Endothelial Growth Factor Receptor-2; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Anti-angiogenic activity; GABARBP; HIF-1α expression; Protein–protein interaction; VEGF receptor 2