Up-regulation of hypoxia-inducible factor 2alpha in renal cell carcinoma associated with loss of Tsc-2 tumor suppressor gene.

In the Eker rat model, inactivation of the Tuberous Sclerosis-2 (Tsc-2) tumor suppressor gene leads to high frequency of spontaneous renal cell carcinoma (RCC). By analogy to human RCC in which mutations in the von Hippel-Lindau (VHL) tumor suppressor gene result in accumulation of hypoxia-inducible factor alpha (HIFalpha) and up-regulation of vascular endothelial growth factor (VEGF), we investigated the regulation of HIF and its target gene VEGF in rat RCC resulting from Tsc-2 defects. To examine HIFalpha activity, a panel of rat renal epithelial cells were analyzed for expression of HIF1alpha and the homologous protein, HIF2alpha, under normoxic and hypoxic conditions. RCC-derived cell lines exhibited high basal levels of HIF activity as determined using hypoxia response element-luciferase reporter constructs. HIF2alpha was stabilized in RCC-derived cell lines and in five of six primary tumors compared with normal kidney, which was consistent with the high levels of hypoxia response element-reporter activity observed in the cell lines. Primary RCCs that developed in Eker rats were highly vascularized, which was similar to their human counterparts. Furthermore, reverse-transcriptase PCR and immunoblotting demonstrated that VEGF was abundantly expressed in both rat RCC cell lines and primary tumors. The 120-, 164-, and 188-amino-acid isoforms of VEGF were expressed at the RNA and protein levels in RCC-derived cell lines, although only a single band was observed in primary tumors. Taken together, these data suggest that RCC caused by loss of the Tsc-2 tumor suppressor gene (which retain wild-type Vhl) up-regulate VEGF via a HIF2alpha-mediated mechanism. Thus, loss of Tsc-2 and VHL tumor suppressor gene function appears to have similar consequences in Eker rats and humans respectively, identifying dysregulation of HIFalpha and VEGF expression as a common pathway for the development of RCC in different species and in tumors with different molecular etiologies.

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[54]  D. Wolf,et al.  Preneoplastic and Neoplastic Lesions of Rat Hereditary Renal Cell Tumors Express Markers of Proximal and Distal Nephron , 1995, Veterinary pathology.

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[56]  T. Goldsworthy,et al.  p53 status in spontaneous and dimethylnitrosamine—induced renal cell tumors from rats , 1995, Molecular carcinogenesis.

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[58]  A. Knudson,et al.  Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

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[63]  A. Knudson,et al.  Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

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[71]  A. Harris,et al.  Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation. , 2002, Cancer research.

[72]  Richard D Klausner,et al.  The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. , 2002, Cancer cell.

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[76]  S. White,et al.  HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[77]  H. Gröne,et al.  Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas. , 2001, Cancer research.

[78]  P. Ratcliffe,et al.  Activation of the HIF pathway in cancer. , 2001, Current opinion in genetics & development.

[79]  M. Ivan,et al.  HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing , 2001, Science.

[80]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[81]  G. Landes,et al.  Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. , 2001, Molecular cell.

[82]  R. Jaenisch,et al.  Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[83]  N. Ferrara.  VEGF: an update on biological and therapeutic aspects. , 2000, Current opinion in biotechnology.

[84]  Till Acker,et al.  Up-regulation of hypoxia-inducible factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function , 2000, Oncogene.

[85]  L. Poellinger,et al.  Mechanism of regulation of the hypoxia‐inducible factor‐1α by the von Hippel‐Lindau tumor suppressor protein , 2000, The EMBO journal.

[86]  A. Harris,et al.  The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages , 2000 .

[87]  M. Ivan,et al.  Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein , 2000, Nature Cell Biology.

[88]  C. Walker,et al.  Requirement for the von Hippel-Lindau tumor suppressor gene for functional epidermal growth factor receptor blockade by monoclonal antibody C225 in renal cell carcinoma. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

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[90]  L. Poellinger,et al.  A Redox Mechanism Controls Differential DNA Binding Activities of Hypoxia-inducible Factor (HIF) 1α and the HIF-like Factor* , 2000, The Journal of Biological Chemistry.

[91]  H. Onda,et al.  Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. , 1999, The Journal of clinical investigation.

[92]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[93]  Yuichi Makino,et al.  Regulation of the Hypoxia-inducible Transcription Factor 1α by the Ubiquitin-Proteasome Pathway* , 1999, The Journal of Biological Chemistry.

[94]  G. Semenza,et al.  Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. , 1999, Annual review of cell and developmental biology.

[95]  Y. Fukushima,et al.  Expression pattern of vascular endothelial growth factor isoform is closely correlated with tumour stage and vascularisation in renal cell carcinoma. , 1999, European journal of cancer.

[96]  T. Noda,et al.  Mice Mutation in Tsc 2 Embryonic Lethality Caused by a GermLine Renal Carcinogenesis , Hepatic Hemangiomatosis , and Updated , 1999 .

[97]  L. Anderson,et al.  von Hippel-Lindau gene mutations in N-nitrosodimethylamine-induced rat renal epithelial tumors. , 1998, Journal of the National Cancer Institute.

[98]  R. Hammer,et al.  The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. , 1998, Genes & development.

[99]  O. Hino,et al.  Biallelic mutations of the Tsc2 gene in chemically induced rat renal cell carcinoma , 1998, International journal of cancer.

[100]  L. Huang,et al.  Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway , 1998 .

[101]  M. Gassmann,et al.  Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. , 1998, Genes & development.

[102]  M. Lerman,et al.  Inherited carcinomas of the kidney. , 1998, Advances in cancer research.

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[104]  J M Ward,et al.  Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[105]  M. Lerman,et al.  Polymerase chain reaction–single‐strand conformation polymorphism analysis for the VHL gene in chemically induced kidney tumors of rats using intron‐derived primers , 1997, Molecular carcinogenesis.

[106]  A. Harris,et al.  Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[107]  H. Tsuda,et al.  Somatic mutation of the tuberous sclerosis (Tsc2) tumor suppressor gene in chemically induced rat renal carcinoma cell. , 1997, The Journal of urology.

[108]  Y Fujii-Kuriyama,et al.  A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[109]  W. Risau,et al.  HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1α and developmentally expressed in blood vessels , 1997, Mechanisms of Development.

[110]  J. Hogenesch,et al.  Characterization of a Subset of the Basic-Helix-Loop-Helix-PAS Superfamily That Interacts with Components of the Dioxin Signaling Pathway* , 1997, The Journal of Biological Chemistry.

[111]  Y. Kubo,et al.  Intragenic Tsc2 Somatic Mutations as Knudson's Second Hit in Spontaneous and Chemically Induced Renal Carcinomas in the Eker Rat Model , 1997, Japanese journal of cancer research : Gann.

[112]  N. Ferrara,et al.  The biology of vascular endothelial growth factor. , 1997, Endocrine reviews.

[113]  Roudebush Vamc,et al.  THE HEIDELBERG CLASSIFICATION OF RENAL CELL TUMOURS , 1997 .

[114]  S. McKnight,et al.  Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. , 1997, Genes & development.

[115]  D. Livingston,et al.  Activation of Hypoxia-inducible Transcription Factor Depends Primarily upon Redox-sensitive Stabilization of Its α Subunit* , 1996, The Journal of Biological Chemistry.

[116]  R. Klausner,et al.  Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[117]  W. Kaelin,et al.  Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[118]  G. Semenza,et al.  Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1 , 1996, Molecular and cellular biology.

[119]  Y. Ahn,et al.  Renal cell carcinoma development in the rat independent of alterations at the VHL gene locus , 1996, Molecular carcinogenesis.

[120]  S. Toyokuni,et al.  Low Incidence of Point Mutations in H‐, K‐ and N‐ras Oncogenes and p53 Tumor Suppressor Gene in Renal Cell Carcinoma and Peritoneal Mesothelioma of Wistar Rats Induced by Ferric Nitrilotriacetate , 1995, Japanese journal of cancer research : Gann.

[121]  G. Xiao,et al.  Allelic loss at the tuberous sclerosis 2 locus in spontaneous tumors in the Eker rat , 1995, Molecular carcinogenesis.

[122]  D. Wolf,et al.  Preneoplastic and Neoplastic Lesions of Rat Hereditary Renal Cell Tumors Express Markers of Proximal and Distal Nephron , 1995, Veterinary pathology.

[123]  M. Goldberg,et al.  Transcriptional Regulation of the Rat Vascular Endothelial Growth Factor Gene by Hypoxia (*) , 1995, The Journal of Biological Chemistry.

[124]  T. Goldsworthy,et al.  p53 status in spontaneous and dimethylnitrosamine—induced renal cell tumors from rats , 1995, Molecular carcinogenesis.

[125]  Y. Kubo,et al.  A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer , 1995, Nature Genetics.

[126]  A. Knudson,et al.  Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[127]  J. Brooks,et al.  Mutations of the VHL tumour suppressor gene in renal carcinoma , 1994, Nature Genetics.

[128]  M. Goldberg,et al.  Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. , 1994, The Journal of biological chemistry.

[129]  E. Manseau,et al.  Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. , 1993, The American journal of pathology.

[130]  P. Curtin,et al.  A 24-base-pair sequence 3' to the human erythropoietin gene contains a hypoxia-responsive transcriptional enhancer. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[131]  A. Knudson,et al.  Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[132]  T. Goldsworthy,et al.  Hereditary renal cell carcinoma in the Eker rat: a rodent familial cancer syndrome. , 1992, The Journal of urology.

[133]  T. Goldsworthy,et al.  Predisposition to renal cell carcinoma due to alteration of a cancer susceptibility gene. , 1992, Science.

[134]  C. Walker,et al.  Development of a quantitative in vitro transformation assay for kidney epithelial cells. , 1992, Carcinogenesis.

[135]  W. Thoenes,et al.  Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cytological and histopathological elements and their use for diagnostics. , 1986, Pathology, research and practice.

[136]  J. Mossige,et al.  A Dominant Gene for Renal Adenomas in the Rat , 1961, Nature.