{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:36:26Z","timestamp":1791174986100,"version":"4.1.0"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"4","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,2,13]]},"abstract":"<jats:p>\n                    Mutations of the VHL tumor suppressor gene occur in patients with\n VHL disease and in the majority of sporadic clear cell renal carcinomas\n (VHL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    RCC). Loss of VHL protein function is associated\n with constitutive expression of mRNAs encoding hypoxia-inducible\n proteins, such as vascular endothelial growth factor. Overproduction of\n angiogenic factors might explain why VHL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    RCC tumors\n are so highly vascularized, but whether this overproduction is\n sufficient for oncogenesis still remains unknown. In this report, we\n examined the activity of transforming growth factor-\u03b1 (TGF-\u03b1),\n another VHL-regulated growth factor. We show that TGF-\u03b1 mRNA and\n protein are hypoxia-inducible in VHL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    RCC cells\n expressing reintroduced VHL. In addition to its overexpression by\n VHL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    RCC cells, TGF-\u03b1 can also act as a specific\n growth-stimulatory factor for VHL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    RCC cells expressing\n reintroduced wild-type VHL, as well as primary renal proximal tubule\n epithelial cells, the likely site of origin of RCC. This role is in\n contrast to those of other growth factors overexpressed by\n VHL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    RCC cells, such as vascular endothelial growth\n factor and TGF-\u03b21, which do not stimulate RCC cell proliferation. A\n TGF-\u03b1-specific antisense oligodeoxynucleotide blocked TGF-\u03b1\n production in VHL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    RCC cells, which led to the\n dependence of those cells on exogenous growth factors to sustain growth\n in culture. Growth of VHL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    RCC cells was also\n significantly reduced by a drug that specifically inhibits the\n epidermal growth factor receptor, the receptor through which TGF-\u03b1\n stimulates proliferation. These results suggest that the generation of\n a TGF-\u03b1 autocrine loop as a consequence of VHL inactivation in renal\n proximal tubule epithelial cells may provide the uncontrolled growth\n stimulus necessary for the initiation of tumorigenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.98.4.1387","type":"journal-article","created":{"date-parts":[[2012,7,26]],"date-time":"2012-07-26T19:12:10Z","timestamp":1343329930000},"page":"1387-1392","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":11,"title":["Role of transforming growth factor-\u03b1 in von Hippel\u2013 Lindau (VHL)\n                    <sup>\u2212\/\u2212<\/sup>\n                    clear cell renal carcinoma cell proliferation: A possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis"],"prefix":"10.1073","volume":"98","author":[{"given":"Natalie","family":"de Paulsen","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine and Kidney Research\r Center, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada\r K1H 8M5; Max Planck Institute for Biochemistry,\r 82152 Martinsried, Germany; Office of the Director,\r National Cancer Institute, National Institutes of Health, Bethesda, MD\r 20814; and Department of Biochemistry and Molecular\r Biology, Stanley S. Scott Cancer Center, Louisiana State University\r Health Sciences Center, New Orleans, LA 70112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Brychzy","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine and Kidney Research\r Center, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada\r K1H 8M5; Max Planck Institute for Biochemistry,\r 82152 Martinsried, Germany; Office of the Director,\r National Cancer Institute, National Institutes of Health, Bethesda, MD\r 20814; and Department of Biochemistry and Molecular\r Biology, Stanley S. Scott Cancer Center, Louisiana State University\r Health Sciences Center, New Orleans, LA 70112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christine","family":"Fournier","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine and Kidney Research\r Center, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada\r K1H 8M5; Max Planck Institute for Biochemistry,\r 82152 Martinsried, Germany; Office of the Director,\r National Cancer Institute, National Institutes of Health, Bethesda, MD\r 20814; and Department of Biochemistry and Molecular\r Biology, Stanley S. Scott Cancer Center, Louisiana State University\r Health Sciences Center, New Orleans, LA 70112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard D.","family":"Klausner","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine and Kidney Research\r Center, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada\r K1H 8M5; Max Planck Institute for Biochemistry,\r 82152 Martinsried, Germany; Office of the Director,\r National Cancer Institute, National Institutes of Health, Bethesda, MD\r 20814; and Department of Biochemistry and Molecular\r Biology, Stanley S. Scott Cancer Center, Louisiana State University\r Health Sciences Center, New Orleans, LA 70112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Gnarra","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine and Kidney Research\r Center, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada\r K1H 8M5; Max Planck Institute for Biochemistry,\r 82152 Martinsried, Germany; Office of the Director,\r National Cancer Institute, National Institutes of Health, Bethesda, MD\r 20814; and Department of Biochemistry and Molecular\r Biology, Stanley S. Scott Cancer Center, Louisiana State University\r Health Sciences Center, New Orleans, LA 70112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnim","family":"Pause","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine and Kidney Research\r Center, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada\r K1H 8M5; Max Planck Institute for Biochemistry,\r 82152 Martinsried, Germany; Office of the Director,\r National Cancer Institute, National Institutes of Health, Bethesda, MD\r 20814; and Department of Biochemistry and Molecular\r Biology, Stanley S. Scott Cancer Center, Louisiana State University\r Health Sciences Center, New Orleans, LA 70112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine and Kidney Research\r Center, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada\r K1H 8M5; Max Planck Institute for Biochemistry,\r 82152 Martinsried, Germany; Office of the Director,\r National Cancer Institute, National Institutes of Health, Bethesda, MD\r 20814; and Department of Biochemistry and Molecular\r Biology, Stanley S. 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