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  • Original Paper
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SOC1 inhibits HPV-E7-mediated transformation by inducing degradation of E7 protein

Oncogene volume 23, pages 3107–3115 (2004)Cite this article

An Erratum to this article was published on 16 December 2004

Abstract

Human papilloma viruses (HPVs) are small double-stranded DNA viruses that infect mucosal and cutaneous epithelium and induce cervical cancer. It has been shown that interferon (IFN)γ suppresses proliferation of HPV-infected cells by suppressing expression of HPV E7. Here, we found that IFNγ induces not only suppression of E7 transcription but also proteasome-dependent degradation. Suppressor of cytokine signaling-1 (SOCS1)/JAB, a suppressor of cytokine signaling, is known to be induced by IFNγ, and functions as an antioncogene against various hematopoietic oncogenic proteins. SOCS1 contains the SOCS-box, which is shown to recruit ubiquitin transferase to the molecules that interact with SOCS1. We found that SOCS1 interacted with HPV E7 protein and induced ubiquitination and degradation of E7 in a SOCS-box-dependent manner. SOCS1 overexpression also increased Rb protein levels and suppressed proliferation of cervical cancer cell lines infected with HPV. Moreover, E7 protein levels were higher and Rb protein levels were lower in SOCS1-deficient fibroblasts infected with retrovirus vector carrying E7 gene than in wild-type fibroblasts. E7 induced anchorage-independent growth in SOCS1-deficient fibroblasts, but not in wild-type cells. These data suggested that SOCS1 plays an important role in regulating the levels of E7 protein and their transforming potential, and could be a new therapeutic tool for HPV-mediated tumors.

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References

  • Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R and Shah KV . (1995). J. Natl. Cancer Inst., 87, 796–802.

  • De Sepulveda P, Ilangumaran S and Rottapel R . (2000). J. Biol. Chem., 275, 14005–14008.

  • De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P and Rottapel R . (1999). EMBO J., 18, 904–915.

  • Fuerst TR, Niles EG, Studier FW and Moss B . (1986). Proc. Natl. Acad. Sci. USA, 83, 8122–8126.

  • Galm O, Yoshikawa H, Esteller M, Osieka R and Herman JG . (2003). Blood, 101, 2784–2788.

  • Gross G . (1997). Intervirology, 40, 368–377.

  • Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR and Schiller JT . (1989). EMBO J., 8, 3905–3910.

  • Ilangumaran S, Finan D, Raine J and Ilangumaran R . (2003). J. Biol. Chem., 278, 41871–41880.

  • Jeon JH, Cho SY, Kim CW, Shin DM, Kwon JC, Choi KH and Kim IG . (2002). Exp. Mol. Med., 34, 496–499.

  • Jones DL and Munger K . (1996). Semin. Cancer Biol., 7, 327–337.

  • Kalvakolanu DV and Borden EC . (1996). Cancer Invest., 14, 25–53.

  • Kamizono S, Hanada T, Yasukawa H, Minoguchi S, Kato R, Minoguchi M, Hattori K, Hatakeyama S, Yada M, Morita S, Kitamura T, Kato H, Nakayama K and Yoshimura A . (2001). J. Biol. Chem., 276, 12530–12538.

  • Kamura T, Sato S, Haque D, Liu L, Kaelin Jr WG, Conaway RC and Conaway JW . (1998). Genes Dev., 12, 3872–3881.

  • Kato A, Sakai Y, Shioda T, Kondo T, Nakanishi M and Nagai Y . (1996). Genes Cells, 1, 569–579.

  • Kawazoe Y, Naka T, Fujimoto M, Kohzaki H, Morita Y, Narazaki M, Okumura K, Saitoh H, Nakagawa R, Uchiyama Y, Akira S and Kishimoto T . (2001). J. Exp. Med., 193, 263–269.

  • Kim KY, Blatt L and Taylor MW . (2000). J. Gen. Virol., 81, 695–700.

  • Kolakofsky D, Pelet T, Garcin D, Hausmann S, Curran J and Roux L . (1998). J. Virol., 72, 891–899.

  • Koromilas AE, Li S and Matlashewski G . (2001). Cytokine Growth Factor Rev., 12, 157–170.

  • Munger K, Basile JR, Duensing S, Eichten A, Gonzalez SL, Grace M and Zacny VL . (2001). Oncogene, 20, 7888–7898.

  • Munger K and Howley PM . (2002). Virus Res., 89, 213–228.

  • Munger K, Phelps WC, Bubb V, Howley PM and Schlegel R . (1989). J. Virol., 63, 4417–4421.

  • Nagai H, Naka T, Terada Y, Komazaki T, Yabe A, Jin E, Kawanami O, Kishimoto T, Konishi N, Nakamura M, Kobayashi Y and Emi M . (2003). J. Hum. Genet., 48, 65–69.

  • Nicholson SE, Willson TA, Farley A, Starr R, Zhang JG, Baca M, Alexander WS, Metcalf D, Hilton DJ and Nicola NA . (1999). EMBO J., 18, 375–385.

  • Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL and Kitamura T . (1999). EMBO J., 18, 4754–4765.

  • Phelps WC, Yee CL, Munger K and Howley PM . (1988). Cell, 53, 539–547.

  • Reinstein E, Scheffner M, Oren M, Ciechanover A and Schwartz A . (2000). Oncogene, 19, 5944–5950.

  • Rottapel R, Ilangumaran S, Neale C, La Rose J, Ho JM, Nguyen MH, Barber D, Dubreuil P and de Sepulveda P . (2002). Oncogene, 21, 4351–4362.

  • Sakai Y, Kiyotani K, Fukumura M, Asakawa M, Kato A, Shioda T, Yoshida T, Tanaka A, Hasegawa M and Nagai Y . (1999). FEBS Lett., 456, 221–226.

  • Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I and Yoshimura A . (2000). J. Biol. Chem., 275, 29338–29347.

  • Selvey LA, Dunn LA, Tindle RW, Park DS and Frazer IH . (1994). J. Gen. Virol., 75 (Part 7), 1647–1653.

  • Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K and Yoshimura A . (2001). J. Clin. Invest., 108, 1781–1788.

  • Song MM and Shuai K . (1998). J. Biol. Chem., 273, 35056–35062.

  • Stark GR, Kerr IM, Williams BR, Silverman RH and Schreiber RD . (1998). Annu. Rev. Biochem., 67, 227–264.

  • Tan TM and Ting RC . (1995). Cancer Res., 55, 4599–4605.

  • Tomoda K, Kubota Y, Arata Y, Mori S, Maeda M, Tanaka T, Yoshida M, Yoneda-Kato N and Kato JY . (2002). J. Biol. Chem., 277, 2302–2310.

  • Um SJ, Kim EJ, Hwang ES, Kim SJ, Namkoong SE and Park JS . (2000). Int. J. Cancer, 85, 416–423.

  • Venturini F, Braspenning J, Homann M, Gissmann L and Sczakiel G . (1999). Nucleic Acids Res., 27, 1585–1592.

  • von Knebel Doeberitz M, Oltersdorf T, Schwarz E and Gissmann L . (1988). Cancer Res., 48, 3780–3786.

  • Wang J, Sampath A, Raychaudhuri P and Bagchi S . (2001). Oncogene, 20, 4740–4749.

  • Watanabe S, Kanda T and Yoshiike K . (1989). J. Virol., 63, 965–969.

  • Woodworth CD, Lichti U, Simpson S, Evans CH and DiPaolo JA . (1992). Cancer Res., 52, 456–463.

  • Wu EW, Clemens KE, Heck DV and Munger K . (1993). J. Virol., 67, 2402–2407.

  • Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN and Yoshimura A . (1999). EMBO J., 18, 1309–1320.

  • Yonemitsu Y, Kitson C, Ferrari S, Farley R, Griesenbach U, Judd D, Steel R, Scheid P, Zhu J, Jeffery PK, Kato A, Hasan MK, Nagai Y, Masaki I, Fukumura M, Hasegawa M, Geddes DM and Alton EW . (2000). Nat. Biotechnol., 18, 970–973.

  • Yonemitsu Y, Alton EW, Komori K, Yoshizumi T, Sugimachi K and Kaneda Y . (1998). Int. J. Oncol., 12, 1277–1285.

  • Yoshida T, Hanada T, Tokuhisa T, Kosai K, Sata M, Kohara M and Yoshimura A . (2002). J. Exp. Med., 196, 641–653.

  • Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC and Herman JG . (2001). Nat. Genet., 28, 29–35.

  • Zhang JG, Farley A, Nicholson SE, Willson TA, Zugaro LM, Simpson RJ, Moritz RL, Cary D, Richardson R, Hausmann G, Kile BJ, Kent SB, Alexander WS, Metcalf D, Hilton DJ, Nicola NA and Baca M . (1999). Proc. Natl. Acad. Sci. USA, 96, 2071–2076.

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Acknowledgements

We thank Ms Y Kawabata-Honda and Ms S Sata for excellent technical assistance, Ms N Arifuku and Ms F Yamaura for manuscript preparation. This work was supported by Special Grants-in-Aid from the Ministry of Education, Science, Technology, Sports and Culture of Japan, Mochida Memorial Foundation, and the Uehara Memorial Foundation.

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Authors and Affiliations

  1. Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Masaki Kamio, Takafumi Yoshida, Hisanobu Ogata & Akihiko Yoshimura

  2. Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-0054, Japan

    Masaki Kamio, Tsutomu Douchi & Yukihiro Nagata

  3. DNAVEC Research Inc. Tsukuba, Ibaraki, Japan

    Makoto Inoue & Mamoru Hasegawa

  4. Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Yoshikazu Yonemitsu

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Kamio, M., Yoshida, T., Ogata, H. et al. SOC1 inhibits HPV-E7-mediated transformation by inducing degradation of E7 protein. Oncogene 23, 3107–3115 (2004). https://doi.org/10.1038/sj.onc.1207453

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