Abstract
Inactivation of U19/EAF2 has been shown previously to lead to tumorigenesis in multiple organs; however, the mechanism of U19/EAF2 tumor suppression remains unclear. In this paper, we report that the expression of an anti-angiogenic protein, thrombospondin-1 (TSP-1) is down-regulated in the prostate and liver of U19/EAF2 knockout mouse. The U19/EAF2 knockout liver displayed increased CD31-positive blood vessels, suggesting that the TSP-1 down-regulation can contribute to increased angiogenesis. TSP-1 is reported to be a p53-target gene and p53 is a known binding partner of ELL, which binds to U19/EAF2. Here, we show that U19/EAF2 can co-localize and co-immunoprecipitate with p53 in transfected cells. In a TSP-1 promoter-driven luciferase reporter assay, p53 transfection suppressed the TSP-1 promoter activity and U19/EAF2 co-transfection blocked the p53 suppression of TSP-1 promoter. However, U19/EAF2 transfection alone had little or no effect on the TSP-1 promoter. The above observations together suggest that U19/EAF2 regulates the expression of TSP-1 via blocking p53 repression of the TSP-1 promoter.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ . (1990). Basic local alignment search tool. J Mol Biol 215: 403–410.
Alvarez AA, Axelrod JR, Whitaker RS, Isner PD, Bentley RC, Dodge RK et al. (2001). Thrombospondin-1 expression in epithelial ovarian carcinoma: association with p53 status, tumor angiogenesis, and survival in platinum-treated patients. Gynecol Oncol 82: 273–278.
Azam N, Vairapandi M, Zhang W, Hoffman B, Liebermann DA . (2001). Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control. J Biol Chem 276: 2766–2774.
Cinatl Jr J, Kotchetkov R, Scholz M, Cinatl J, Vogel JU, Driever PH et al. (1999). Human cytomegalovirus infection decreases expression of thrombospondin-1 independent of the tumor suppressor protein p53. Am J Pathol 155: 285–292.
Donoviel DB, Framson P, Eldridge CF, Cooke M, Kobayashi S, Bornstein P . (1988). Structural analysis and expression of the human thrombospondin gene promoter. J Biol Chem 263: 18590–18593.
Duan X, Zhang H, Liu B, Li XD, Gao QX, Wu ZH . (2008). Apoptosis of murine melanoma cells induced by heavy-ion radiation combined with Tp53 gene transfer. Int J Radiat Biol 84: 211–217.
Framson P, Bornstein P . (1993). A serum response element and a binding site for NF-Y mediate the serum response of the human thrombospondin 1 gene. J Biol Chem 268: 4989–4996.
Freitas TM, Miguel MC, Silveira EJ, Freitas RA, Galvao HC . (2005). Assessment of angiogenic markers in oral hemangiomas and pyogenic granulomas. Exp Mol Pathol 79: 79–85.
Harada H, Nakagawa K, Saito M, Kohno S, Nagato S, Furukawa K et al. (2003). Introduction of wild-type p53 enhances thrombospondin-1 expression in human glioma cells. Cancer Lett 191: 109–119.
Jiang C, Hu H, Malewicz B, Wang Z, Lu J . (2004). Selenite-induced p53 Ser-15 phosphorylation and caspase-mediated apoptosis in LNCaP human prostate cancer cells. Mol Cancer Ther 3: 877–884.
Kwak C, Jin RJ, Lee C, Park MS, Lee SE . (2002). Thrombospondin-1, vascular endothelial growth factor expression and their relationship with p53 status in prostate cancer and benign prostatic hyperplasia. BJU Int 89: 303–309.
Maeda K, Chung YS, Takatsuka S, Ogawa Y, Onoda N, Sawada T et al. (1995). Tumour angiogenesis and tumour cell proliferation as prognostic indicators in gastric carcinoma. Br J Cancer 72: 319–323.
Mitani K, Yamagata T, Iida C, Oda H, Maki K, Ichikawa M et al. (2000). Nonredundant roles of the elongation factor MEN in postimplantation development. Biochem Biophys Res Commun 279: 563–567.
Nelius T, Filleur S, Yemelyanov A, Budunova I, Shroff E, Mirochnik Y et al. (2007). Androgen receptor targets NFkappaB and TSP1 to suppress prostate tumor growth in vivo. Int J Cancer 121: 999–1008.
Reiher FK, Ivanovich M, Huang H, Smith ND, Bouck NP, Campbell SC . (2001). The role of hypoxia and p53 in the regulation of angiogenesis in bladder cancer. J Urol 165: 2075–2081.
Ren B, Yee KO, Lawler J, Khosravi-Far R . (2006). Regulation of tumor angiogenesis by thrombospondin-1. Biochim Biophys Acta 1765: 178–188.
Roe JS, Kim H, Lee SM, Kim ST, Cho EJ, Youn HD . (2006). p53 stabilization and transactivation by a von Hippel-Lindau protein. Mol Cell 22: 395–405.
Selfridge J, Pow AM, McWhir J, Magin TM, Melton DW . (1992). Gene targeting using a mouse HPRT minigene/HPRT-deficient embryonic stem cell system: inactivation of the mouse ERCC-1 gene. Somat Cell Mol Genet 18: 325–336.
Shinobu N, Maeda T, Aso T, Ito T, Kondo T, Koike K et al. (1999). Physical interaction and functional antagonism between the RNA polymerase II elongation factor ELL and p53. J Biol Chem 274: 17003–17010.
Simone F, Luo RT, Polak PE, Kaberlein JJ, Thirman MJ . (2003). ELL-associated factor 2 (EAF2), a functional homolog of EAF1 with alternative ELL binding properties. Blood 101: 2355–2362.
Tokunaga T, Nakamura M, Oshika Y, Tsuchida T, Kazuno M, Fukushima Y et al. (1998). Alterations in tumour suppressor gene p53 correlate with inhibition of thrombospondin-1 gene expression in colon cancer cells. Virchows Arch 433: 415–418.
Wang Z, Tufts R, Haleem R, Cai X . (1997). Genes regulated by androgen in the rat ventral prostate. Proc Natl Acad Sci USA 94: 12999–13004.
Wiederschain D, Kawai H, Gu J, Shilatifard A, Yuan ZM . (2003). Molecular basis of p53 functional inactivation by the leukemic protein MLL-ELL. Mol Cell Biol 23: 4230–4246.
Xiao W, Jiang F, Wang Z . (2006). ELL binding regulates U19/Eaf2 intracellular localization, stability, and transactivation. Prostate 66: 1–12.
Xiao W, Zhang Q, Habermacher G, Yang X, Zhang AY, Cai X et al. (2008). U19/Eaf2 knockout causes lung adenocarcinoma, B-cell lymphoma, hepatocellular carcinoma and prostatic intraepithelial neoplasia. Oncogene 27: 1536–1544.
Xiao W, Zhang Q, Jiang F, Pins M, Kozlowski JM, Wang Z . (2003). Suppression of prostate tumor growth by U19, a novel testosterone-regulated apoptosis inducer. Cancer Res 63: 4698–4704.
Xiao W, Ai J, Habermacher G, Volpert O, Yang X, Zhang AY et al. (2009). U19/Eaf2 binds to and stabilizes von hippel-lindau protein. Cancer Res 69: 2599–2606.
Zhou J, Feng X, Ban B, Liu J, Wang Z, Xiao W . (2009). Elongation factor ELL (Eleven-Nineteen Lysine-rich Leukemia) acts as a transcription factor for direct thrombospondin-1 regulation. J Biol Chem 284: 19142–19152.
Acknowledgements
This work was supported in part by NIH Grant Number R01 CA 120386, R37 DK51993, and Prostate Cancer Specialized Program of Research Excellence (SPORE), P50 CA90386.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Su, F., Pascal, L., Xiao, W. et al. Tumor suppressor U19/EAF2 regulates thrombospondin-1 expression via p53. Oncogene 29, 421–431 (2010). https://doi.org/10.1038/onc.2009.326
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2009.326
Keywords
This article is cited by
-
Genomic signature of parity in the breast of premenopausal women
Breast Cancer Research (2019)
-
EAF2 regulates DNA repair through Ku70/Ku80 in the prostate
Oncogene (2017)
-
Expression and prognostic significance of ELL-associated factor 2 in human prostate cancer
International Urology and Nephrology (2016)
-
MBASED: allele-specific expression detection in cancer tissues and cell lines
Genome Biology (2014)
-
Oncogenes and angiogenesis: a way to personalize anti-angiogenic therapy?
Cellular and Molecular Life Sciences (2013)