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. 1997 Sep;17(9):5629–5639. doi: 10.1128/mcb.17.9.5629

The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity.

D Mukhopadhyay 1, B Knebelmann 1, H T Cohen 1, S Ananth 1, V P Sukhatme 1
PMCID: PMC232411  PMID: 9271438

Abstract

The von Hippel-Lindau tumor suppressor gene (VHL) has a critical role in the pathogenesis of clear-cell renal cell carcinoma (RCC), as VHL mutations have been found in both von Hippel-Lindau disease-associated and sporadic RCCs. Recent studies suggest that vascular endothelial growth factor (VEGF) mRNA is upregulated in RCC- and von Hippel-Lindau disease-associated tumors. We have therefore assessed the effect of the VHL gene product on VEGF expression. VEGF promoter-luciferase constructs were transiently cotransfected with a wild-type VHL (wt-VHL) vector in several cell lines, including 293 embryonic kidney and RCC cell lines. wt-VHL protein inhibited VEGF promoter activity in a dose-dependent manner up to 5- to 10-fold. Deletion analysis defined a 144-bp region of the VEGF promoter necessary for VHL repression. This VHL-responsive element is GC rich and specifically binds the transcription factor Sp1 in crude nuclear extracts. In Drosophila cells, cotransfected VHL represses Sp1-mediated activation but not basal activity of the VEGF promoter. We next demonstrated in coimmunoprecipitates that VHL and Sp1 were part of the same complex and, by using a glutathione-S-transferase-VHL fusion protein and purified Sp1, that VHL and Sp1 directly interact. Furthermore, endogenous VEGF mRNA levels were suppressed in permanent RCC cell lines expressing wt-VHL, and nuclear run-on studies indicated that VHL regulation of VEGF occurs at least partly at the transcriptional level. These observations support a new mechanism for VHL-mediated transcriptional repression via a direct inhibitory action on Sp1 and suggest that loss of Sp1 inhibition may be important in the pathogenesis of von Hippel-Lindau disease and RCC.

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Selected References

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  1. Ackerman S. L., Minden A. G., Williams G. T., Bobonis C., Yeung C. Y. Functional significance of an overlapping consensus binding motif for Sp1 and Zif268 in the murine adenosine deaminase gene promoter. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7523–7527. doi: 10.1073/pnas.88.17.7523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alemany J., Borras T., de Pablo F. Transcriptional stimulation of the delta 1-crystallin gene by insulin-like growth factor I and insulin requires DNA cis elements in chicken. Proc Natl Acad Sci U S A. 1990 May;87(9):3353–3357. doi: 10.1073/pnas.87.9.3353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aso T., Lane W. S., Conaway J. W., Conaway R. C. Elongin (SIII): a multisubunit regulator of elongation by RNA polymerase II. Science. 1995 Sep 8;269(5229):1439–1443. doi: 10.1126/science.7660129. [DOI] [PubMed] [Google Scholar]
  4. Borellini F., Glazer R. I. Induction of Sp1-p53 DNA-binding heterocomplexes during granulocyte/macrophage colony-stimulating factor-dependent proliferation in human erythroleukemia cell line TF-1. J Biol Chem. 1993 Apr 15;268(11):7923–7928. [PubMed] [Google Scholar]
  5. Borellini F., He Y. F., Aquino A., Yu G., Josephs S. F., Glazer R. I. Increased DNA binding and transcriptional activity associated with transcription factor Sp1 in K562 cells transfected with the myeloid-specific c-fes tyrosine kinase gene. J Biol Chem. 1991 Aug 25;266(24):15850–15854. [PubMed] [Google Scholar]
  6. Brown L. F., Berse B., Jackman R. W., Tognazzi K., Manseau E. J., Dvorak H. F., Senger D. R. Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol. 1993 Nov;143(5):1255–1262. [PMC free article] [PubMed] [Google Scholar]
  7. Cao X., Mahendran R., Guy G. R., Tan Y. H. Detection and characterization of cellular EGR-1 binding to its recognition site. J Biol Chem. 1993 Aug 15;268(23):16949–16957. [PubMed] [Google Scholar]
  8. Chen F., Kishida T., Yao M., Hustad T., Glavac D., Dean M., Gnarra J. R., Orcutt M. L., Duh F. M., Glenn G. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat. 1995;5(1):66–75. doi: 10.1002/humu.1380050109. [DOI] [PubMed] [Google Scholar]
  9. Chen L. I., Nishinaka T., Kwan K., Kitabayashi I., Yokoyama K., Fu Y. H., Grünwald S., Chiu R. The retinoblastoma gene product RB stimulates Sp1-mediated transcription by liberating Sp1 from a negative regulator. Mol Cell Biol. 1994 Jul;14(7):4380–4389. doi: 10.1128/mcb.14.7.4380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  11. Cohen H. T., Bossone S. A., Zhu G., McDonald G. A., Sukhatme V. P. Sp1 is a critical regulator of the Wilms' tumor-1 gene. J Biol Chem. 1997 Jan 31;272(5):2901–2913. doi: 10.1074/jbc.272.5.2901. [DOI] [PubMed] [Google Scholar]
  12. Courey A. J., Tjian R. Analysis of Sp1 in vivo reveals multiple transcriptional domains, including a novel glutamine-rich activation motif. Cell. 1988 Dec 2;55(5):887–898. doi: 10.1016/0092-8674(88)90144-4. [DOI] [PubMed] [Google Scholar]
  13. Crossey P. A., Richards F. M., Foster K., Green J. S., Prowse A., Latif F., Lerman M. I., Zbar B., Affara N. A., Ferguson-Smith M. A. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet. 1994 Aug;3(8):1303–1308. doi: 10.1093/hmg/3.8.1303. [DOI] [PubMed] [Google Scholar]
  14. Datta P. K., Raychaudhuri P., Bagchi S. Association of p107 with Sp1: genetically separable regions of p107 are involved in regulation of E2F- and Sp1-dependent transcription. Mol Cell Biol. 1995 Oct;15(10):5444–5452. doi: 10.1128/mcb.15.10.5444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dawson P. A., Hofmann S. L., van der Westhuyzen D. R., Südhof T. C., Brown M. S., Goldstein J. L. Sterol-dependent repression of low density lipoprotein receptor promoter mediated by 16-base pair sequence adjacent to binding site for transcription factor Sp1. J Biol Chem. 1988 Mar 5;263(7):3372–3379. [PubMed] [Google Scholar]
  16. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Duan D. R., Humphrey J. S., Chen D. Y., Weng Y., Sukegawa J., Lee S., Gnarra J. R., Linehan W. M., Klausner R. D. Characterization of the VHL tumor suppressor gene product: localization, complex formation, and the effect of natural inactivating mutations. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6459–6463. doi: 10.1073/pnas.92.14.6459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Duan D. R., Pause A., Burgess W. H., Aso T., Chen D. Y., Garrett K. P., Conaway R. C., Conaway J. W., Linehan W. M., Klausner R. D. Inhibition of transcription elongation by the VHL tumor suppressor protein. Science. 1995 Sep 8;269(5229):1402–1406. doi: 10.1126/science.7660122. [DOI] [PubMed] [Google Scholar]
  19. Feng Y., Gunter L. E., Organ E. L., Cavener D. R. Translation initiation in Drosophila melanogaster is reduced by mutations upstream of the AUG initiator codon. Mol Cell Biol. 1991 Apr;11(4):2149–2153. doi: 10.1128/mcb.11.4.2149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Foster K., Prowse A., van den Berg A., Fleming S., Hulsbeek M. M., Crossey P. A., Richards F. M., Cairns P., Affara N. A., Ferguson-Smith M. A. Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet. 1994 Dec;3(12):2169–2173. doi: 10.1093/hmg/3.12.2169. [DOI] [PubMed] [Google Scholar]
  21. Gnarra J. R., Tory K., Weng Y., Schmidt L., Wei M. H., Li H., Latif F., Liu S., Chen F., Duh F. M. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994 May;7(1):85–90. doi: 10.1038/ng0594-85. [DOI] [PubMed] [Google Scholar]
  22. Gnarra J. R., Zhou S., Merrill M. J., Wagner J. R., Krumm A., Papavassiliou E., Oldfield E. H., Klausner R. D., Linehan W. M. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10589–10594. doi: 10.1073/pnas.93.20.10589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gu B., Kuddus R., DeLuca N. A. Repression of activator-mediated transcription by herpes simplex virus ICP4 via a mechanism involving interactions with the basal transcription factors TATA-binding protein and TFIIB. Mol Cell Biol. 1995 Jul;15(7):3618–3626. doi: 10.1128/mcb.15.7.3618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Gu B., Rivera-Gonzalez R., Smith C. A., DeLuca N. A. Herpes simplex virus infected cell polypeptide 4 preferentially represses Sp1-activated over basal transcription from its own promoter. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9528–9532. doi: 10.1073/pnas.90.20.9528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Gualberto A., Baldwin A. S., Jr p53 and Sp1 interact and cooperate in the tumor necrosis factor-induced transcriptional activation of the HIV-1 long terminal repeat. J Biol Chem. 1995 Aug 25;270(34):19680–19683. doi: 10.1074/jbc.270.34.19680. [DOI] [PubMed] [Google Scholar]
  27. Hagen G., Müller S., Beato M., Suske G. Sp1-mediated transcriptional activation is repressed by Sp3. EMBO J. 1994 Aug 15;13(16):3843–3851. doi: 10.1002/j.1460-2075.1994.tb06695.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Haley J. D., Waterfield M. D. Contributory effects of de novo transcription and premature transcript termination in the regulation of human epidermal growth factor receptor proto-oncogene RNA synthesis. J Biol Chem. 1991 Jan 25;266(3):1746–1753. [PubMed] [Google Scholar]
  29. Hamanaka R., Kohno K., Seguchi T., Okamura K., Morimoto A., Ono M., Ogata J., Kuwano M. Induction of low density lipoprotein receptor and a transcription factor SP-1 by tumor necrosis factor in human microvascular endothelial cells. J Biol Chem. 1992 Jul 5;267(19):13160–13165. [PubMed] [Google Scholar]
  30. Hung H. L., High K. A. Liver-enriched transcription factor HNF-4 and ubiquitous factor NF-Y are critical for expression of blood coagulation factor X. J Biol Chem. 1996 Jan 26;271(4):2323–2331. doi: 10.1074/jbc.271.4.2323. [DOI] [PubMed] [Google Scholar]
  31. Iliopoulos O., Kibel A., Gray S., Kaelin W. G., Jr Tumour suppression by the human von Hippel-Lindau gene product. Nat Med. 1995 Aug;1(8):822–826. doi: 10.1038/nm0895-822. [DOI] [PubMed] [Google Scholar]
  32. Iliopoulos O., Levy A. P., Jiang C., Kaelin W. G., Jr, Goldberg M. A. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10595–10599. doi: 10.1073/pnas.93.20.10595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Inagaki Y., Truter S., Ramirez F. Transforming growth factor-beta stimulates alpha 2(I) collagen gene expression through a cis-acting element that contains an Sp1-binding site. J Biol Chem. 1994 May 20;269(20):14828–14834. [PubMed] [Google Scholar]
  34. Jackson S. P., MacDonald J. J., Lees-Miller S., Tjian R. GC box binding induces phosphorylation of Sp1 by a DNA-dependent protein kinase. Cell. 1990 Oct 5;63(1):155–165. doi: 10.1016/0092-8674(90)90296-q. [DOI] [PubMed] [Google Scholar]
  35. Jackson S. P., Tjian R. Purification and analysis of RNA polymerase II transcription factors by using wheat germ agglutinin affinity chromatography. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1781–1785. doi: 10.1073/pnas.86.6.1781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Jensen D. E., Rich C. B., Terpstra A. J., Farmer S. R., Foster J. A. Transcriptional regulation of the elastin gene by insulin-like growth factor-I involves disruption of Sp1 binding. Evidence for the role of Rb in mediating Sp1 binding in aortic smooth muscle cells. J Biol Chem. 1995 Mar 24;270(12):6555–6563. doi: 10.1074/jbc.270.12.6555. [DOI] [PubMed] [Google Scholar]
  37. Karlseder J., Rotheneder H., Wintersberger E. Interaction of Sp1 with the growth- and cell cycle-regulated transcription factor E2F. Mol Cell Biol. 1996 Apr;16(4):1659–1667. doi: 10.1128/mcb.16.4.1659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kessler P. M., Vasavada S. P., Rackley R. R., Stackhouse T., Duh F. M., Latif F., Lerman M. I., Zbar B., Williams B. R. Expression of the Von Hippel-Lindau tumor suppressor gene, VHL, in human fetal kidney and during mouse embryogenesis. Mol Med. 1995 May;1(4):457–466. [PMC free article] [PubMed] [Google Scholar]
  39. Kibel A., Iliopoulos O., DeCaprio J. A., Kaelin W. G., Jr Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science. 1995 Sep 8;269(5229):1444–1446. doi: 10.1126/science.7660130. [DOI] [PubMed] [Google Scholar]
  40. Kishida T., Stackhouse T. M., Chen F., Lerman M. I., Zbar B. Cellular proteins that bind the von Hippel-Lindau disease gene product: mapping of binding domains and the effect of missense mutations. Cancer Res. 1995 Oct 15;55(20):4544–4548. [PubMed] [Google Scholar]
  41. Kitadai Y., Yasui W., Yokozaki H., Kuniyasu H., Haruma K., Kajiyama G., Tahara E. The level of a transcription factor Sp1 is correlated with the expression of EGF receptor in human gastric carcinomas. Biochem Biophys Res Commun. 1992 Dec 30;189(3):1342–1348. doi: 10.1016/0006-291x(92)90221-6. [DOI] [PubMed] [Google Scholar]
  42. Latif F., Tory K., Gnarra J., Yao M., Duh F. M., Orcutt M. L., Stackhouse T., Kuzmin I., Modi W., Geil L. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317–1320. doi: 10.1126/science.8493574. [DOI] [PubMed] [Google Scholar]
  43. Lee J. S., Galvin K. M., Shi Y. Evidence for physical interaction between the zinc-finger transcription factors YY1 and Sp1. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6145–6149. doi: 10.1073/pnas.90.13.6145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Leggett R. W., Armstrong S. A., Barry D., Mueller C. R. Sp1 is phosphorylated and its DNA binding activity down-regulated upon terminal differentiation of the liver. J Biol Chem. 1995 Oct 27;270(43):25879–25884. doi: 10.1074/jbc.270.43.25879. [DOI] [PubMed] [Google Scholar]
  45. Li J., Perrella M. A., Tsai J. C., Yet S. F., Hsieh C. M., Yoshizumi M., Patterson C., Endege W. O., Zhou F., Lee M. E. Induction of vascular endothelial growth factor gene expression by interleukin-1 beta in rat aortic smooth muscle cells. J Biol Chem. 1995 Jan 6;270(1):308–312. doi: 10.1074/jbc.270.1.308. [DOI] [PubMed] [Google Scholar]
  46. Li R., Knight J. D., Jackson S. P., Tjian R., Botchan M. R. Direct interaction between Sp1 and the BPV enhancer E2 protein mediates synergistic activation of transcription. Cell. 1991 May 3;65(3):493–505. doi: 10.1016/0092-8674(91)90467-d. [DOI] [PubMed] [Google Scholar]
  47. Lin S. Y., Black A. R., Kostic D., Pajovic S., Hoover C. N., Azizkhan J. C. Cell cycle-regulated association of E2F1 and Sp1 is related to their functional interaction. Mol Cell Biol. 1996 Apr;16(4):1668–1675. doi: 10.1128/mcb.16.4.1668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Liu Y., Cox S. R., Morita T., Kourembanas S. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5' enhancer. Circ Res. 1995 Sep;77(3):638–643. doi: 10.1161/01.res.77.3.638. [DOI] [PubMed] [Google Scholar]
  49. Maher E. R., Yates J. R., Harries R., Benjamin C., Harris R., Moore A. T., Ferguson-Smith M. A. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990 Nov;77(283):1151–1163. doi: 10.1093/qjmed/77.2.1151. [DOI] [PubMed] [Google Scholar]
  50. Merika M., Orkin S. H. Functional synergy and physical interactions of the erythroid transcription factor GATA-1 with the Krüppel family proteins Sp1 and EKLF. Mol Cell Biol. 1995 May;15(5):2437–2447. doi: 10.1128/mcb.15.5.2437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Miltenberger R. J., Farnham P. J., Smith D. E., Stommel J. M., Cornwell M. M. v-Raf activates transcription of growth-responsive promoters via GC-rich sequences that bind the transcription factor Sp1. Cell Growth Differ. 1995 May;6(5):549–556. [PubMed] [Google Scholar]
  52. Mukhopadhyay D., Tsiokas L., Sukhatme V. P. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 1995 Dec 15;55(24):6161–6165. [PubMed] [Google Scholar]
  53. Murata Y., Kim H. G., Rogers K. T., Udvadia A. J., Horowitz J. M. Negative regulation of Sp1 trans-activation is correlated with the binding of cellular proteins to the amino terminus of the Sp1 trans-activation domain. J Biol Chem. 1994 Aug 12;269(32):20674–20681. [PubMed] [Google Scholar]
  54. Nehls M. C., Rippe R. A., Veloz L., Brenner D. A. Transcription factors nuclear factor I and Sp1 interact with the murine collagen alpha 1 (I) promoter. Mol Cell Biol. 1991 Aug;11(8):4065–4073. doi: 10.1128/mcb.11.8.4065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Perkins N. D., Agranoff A. B., Pascal E., Nabel G. J. An interaction between the DNA-binding domains of RelA(p65) and Sp1 mediates human immunodeficiency virus gene activation. Mol Cell Biol. 1994 Oct;14(10):6570–6583. doi: 10.1128/mcb.14.10.6570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Rahman A., Esmaili A., Saatcioglu F. A unique thyroid hormone response element in the human immunodeficiency virus type 1 long terminal repeat that overlaps the Sp1 binding sites. J Biol Chem. 1995 Dec 29;270(52):31059–31064. doi: 10.1074/jbc.270.52.31059. [DOI] [PubMed] [Google Scholar]
  57. Saffer J. D., Jackson S. P., Annarella M. B. Developmental expression of Sp1 in the mouse. Mol Cell Biol. 1991 Apr;11(4):2189–2199. doi: 10.1128/mcb.11.4.2189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Saffer J. D., Jackson S. P., Thurston S. J. SV40 stimulates expression of the transacting factor Sp1 at the mRNA level. Genes Dev. 1990 Apr;4(4):659–666. doi: 10.1101/gad.4.4.659. [DOI] [PubMed] [Google Scholar]
  59. Schaufele F., West B. L., Reudelhuber T. L. Overlapping Pit-1 and Sp1 binding sites are both essential to full rat growth hormone gene promoter activity despite mutually exclusive Pit-1 and Sp1 binding. J Biol Chem. 1990 Oct 5;265(28):17189–17196. [PubMed] [Google Scholar]
  60. Seto E., Lewis B., Shenk T. Interaction between transcription factors Sp1 and YY1. Nature. 1993 Sep 30;365(6445):462–464. doi: 10.1038/365462a0. [DOI] [PubMed] [Google Scholar]
  61. Siemeister G., Weindel K., Mohrs K., Barleon B., Martiny-Baron G., Marmé D. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res. 1996 May 15;56(10):2299–2301. [PubMed] [Google Scholar]
  62. Sif S., Capobianco A. J., Gilmore T. D. The v-Rel oncoprotein increases expression from Sp1 site-containing promoters in chicken embryo fibroblasts. Oncogene. 1993 Sep;8(9):2501–2509. [PubMed] [Google Scholar]
  63. Srivastva K. K., Cable E. E., Bonkovsky H. L. Purifying nascent mRNA from nuclear run-on assays using guanidinium isothiocyanate. Biotechniques. 1993 Aug;15(2):226–227. [PubMed] [Google Scholar]
  64. Suzuki M., Kuroda C., Oda E., Tsunoda S., Nakamura T., Nakajima T., Oda K. G10BP, an E1A-inducible negative regulator of Sp1, represses transcription of the rat fibronectin gene. Mol Cell Biol. 1995 Oct;15(10):5423–5433. doi: 10.1128/mcb.15.10.5423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Swevers L., Cherbas L., Cherbas P., Iatrou K. Bombyx EcR (BmEcR) and Bombyx USP (BmCF1) combine to form a functional ecdysone receptor. Insect Biochem Mol Biol. 1996 Mar;26(3):217–221. doi: 10.1016/0965-1748(95)00097-6. [DOI] [PubMed] [Google Scholar]
  66. Takahashi A., Sasaki H., Kim S. J., Tobisu K., Kakizoe T., Tsukamoto T., Kumamoto Y., Sugimura T., Terada M. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994 Aug 1;54(15):4233–4237. [PubMed] [Google Scholar]
  67. Tischer E., Mitchell R., Hartman T., Silva M., Gospodarowicz D., Fiddes J. C., Abraham J. A. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991 Jun 25;266(18):11947–11954. [PubMed] [Google Scholar]
  68. Tsuchiya H., Iseda T., Hino O. Identification of a novel protein (VBP-1) binding to the von Hippel-Lindau (VHL) tumor suppressor gene product. Cancer Res. 1996 Jul 1;56(13):2881–2885. [PubMed] [Google Scholar]
  69. Warren R. S., Yuan H., Matli M. R., Ferrara N., Donner D. B. Induction of vascular endothelial growth factor by insulin-like growth factor 1 in colorectal carcinoma. J Biol Chem. 1996 Nov 15;271(46):29483–29488. doi: 10.1074/jbc.271.46.29483. [DOI] [PubMed] [Google Scholar]
  70. Weidner U., Peter S., Strohmeyer T., Hussnätter R., Ackermann R., Sies H. Inverse relationship of epidermal growth factor receptor and HER2/neu gene expression in human renal cell carcinoma. Cancer Res. 1990 Aug 1;50(15):4504–4509. [PubMed] [Google Scholar]
  71. Wizigmann-Voos S., Breier G., Risau W., Plate K. H. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. 1995 Mar 15;55(6):1358–1364. [PubMed] [Google Scholar]
  72. Xu J., Thompson K. L., Shephard L. B., Hudson L. G., Gill G. N. T3 receptor suppression of Sp1-dependent transcription from the epidermal growth factor receptor promoter via overlapping DNA-binding sites. J Biol Chem. 1993 Jul 25;268(21):16065–16073. [PubMed] [Google Scholar]
  73. Yao M., Shuin T., Misaki H., Kubota Y. Enhanced expression of c-myc and epidermal growth factor receptor (C-erbB-1) genes in primary human renal cancer. Cancer Res. 1988 Dec 1;48(23):6753–6757. [PubMed] [Google Scholar]
  74. Zhu L., van den Heuvel S., Helin K., Fattaey A., Ewen M., Livingston D., Dyson N., Harlow E. Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein. Genes Dev. 1993 Jul;7(7A):1111–1125. doi: 10.1101/gad.7.7a.1111. [DOI] [PubMed] [Google Scholar]

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