Abstract
SOCS-1 is an inducible SH2-containing inhibitor of Jak kinases and as such can potently suppress cytokine signaling. SOCS-1 deficient mice die within the first three weeks of life from a myeloproliferative disorder driven by excessive interferon signaling. We report here that SOCS-1 inhibits proliferation signals induced by a variety of oncogenes active within the hematopoietic system. Ectopic expression of SOCS-1 abolished proliferation mediated by a constitutively active form of the KIT receptor, TEL-JAK2, and v-ABL, and reduced metastasis from BCR-ABL transformed cells. SOCS-1, however, did not interfere with v-SRC or RASV12 mediated cellular transformation. A mutant form of SOCS-1 unable to bind through its SH2 domain to tyrosine phosphorylated proteins could still inhibit KIT, but not TEL-JAK2, indicating multiple mechanisms for SOCS-1-mediated tumor suppression. We show that the steady state levels of TEL-JAK2 and to a greater extent v-ABL are diminished in the presence of SOCS-1. Lastly, we show that SOCS-1 −/− fibroblasts are more sensitive than wild type fibroblasts to either spontaneous or oncogene-induced transformation. These data suggest that loss-of-function of SOCS-1 may collaborate with a variety of hematopoietic oncogenes to facilitate tumor progression.
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
Alderton F, Humphrey PP, Sellers LA . 2001 Mol. Pharmacol. 59: 1119–1128
Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, Kay TW, Nicola NA, Hertzog PJ, Metcalf D, Hilton DJ . 1999 Cell 98: 597–608
Andoniou CE, Thien CB, Langdon WY . 1994 EMBO J. 13: 4515–4523
Blake TJ, Shapiro M, Morse III HC, Langdon WY . 1991 Oncogene 6: 653–657
Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME . 1997 Science 278: 477–483
Bulavin DV, Higashimoto Y, Popoff IJ, Gaarde WA, Basrur V, Potapova O, Appella E, Fornace Jr AJ . 2001 Nature 411: 102–107
Daley GQ, Baltimore D . 1988 Proc. Natl. Acad. Sci. USA 85: 9312–9316
Danial NN, Losman JA, Lu T, Yip N, Krishnan K, Krolewski J, Goff SP, Wang JY, Rothman PB . 1998 Mol. Cell. Biol. 18: 6795–6804
De Sepulveda P, Ilangumaran S, Rottapel R . 2000 J. Biol. Chem. 275: 14005–14008
De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R . 1999 EMBO J. 18: 904–915
Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A . 1997 Nature 387: 921–924
Frank DA, Robertson MJ, Bonni A, Ritz J, Greenberg ME . 1995 Proc. Natl. Acad. Sci. USA 92: 7779–7783
Frantsve J, Schwaller J, Sternberg DW, Kutok J, Gilliland DG . 2001 Mol. Cell. Biol. 21: 3547–3557
Frearson JA, Alexander DR . 1997 Bioessays 19: 417–427
Ho JM, Beattie BK, Squire JA, Frank DA, Barber DL . 1999 Blood 93: 4354–4364
Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC . 1999 Science 286: 309–312
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, Yoshimura A . 2001 J. Biol. Chem. 276: 12530–12538
Kamura T, Sato S, Haque D, Liu L, Kaelin Jr WG, Conaway RC, Conaway JW . 1998 Genes Dev. 12: 3872–3881
Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, Kishimoto T . 1988 Nature 332: 83–85
Krystal G . 2000 Semin. Immunol. 12: 397–403
Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA . 1997 Science 278: 1309–1312
Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, Lavi S, Iwai K, Reiss Y, Ciechanover A, Lipkowitz S, Yarden Y . 1999 Mol. Cell 4: 1029–1040
Lupher Jr ML, Rao N, Eck MJ, Band H . 1999 Immunol. Today 20: 375–382
Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima H, Pendeville H, Yasukawa H, Sasaki A, Yoshimura A, Ihle JN . 1999a Cell 98: 617–627
Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN . 1999b Cell 98: 609–616
Mauro MJ, Druker BJ . 2001 Curr. Opin. Oncol. 13: 3–7
Monni R, Santos SC, Mauchauffe M, Berger R, Ghysdael J, Gouilleux F, Gisselbrecht S, Bernard O, Penard-Lacronique V . 2001 Oncogene 20: 849–858
Morita Y, Naka T, Kawazoe Y, Fujimoto M, Narazaki M, Nakagawa R, Fukuyama H, Nagata S, Kishimoto T . 2000 Proc. Natl. Acad. Sci. USA 97: 5405–5410
Nagai H, Kim YS, Lee KT, Chu MY, Konishi N, Fujimoto J, Baba M, Matsubara K, Emi M . 2001 J. Hepatol. 34: 416–421
Naka T, Fujimoto M, Kishimoto T . 1999 Trends Biochem. Sci. 24: 394–398
Naka T, Matsumoto T, Narazaki M, Fujimoto M, Morita Y, Ohsawa Y, Saito H, Nagasawa T, Uchiyama Y, Kishimoto T . 1998 Proc. Natl. Acad. Sci. USA 95: 15577–15582
Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akira S, Kishimoto T . 1997 Nature 387: 924–929
Narazaki M, Fujimoto M, Matsumoto T, Morita Y, Saito H, Kajita T, Yoshizaki K, Naka T, Kishimoto T . 1998 Proc. Natl. Acad. Sci. USA 95: 13130–13134
Nicholson SE, Willson TA, Farley A, Starr R, Zhang JG, Baca M, Alexander WS, Metcalf D, Hilton DJ, Nicola NA . 1999 EMBO J. 18: 375–385
Ohya K, Kajigaya S, Yamashita Y, Miyazato A, Hatake K, Miura Y, Ikeda U, Shimada K, Ozawa K, Mano H . 1997 J. Biol. Chem. 272: 27178–27182
Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, Monpoux F, Van Rompaey L, Baens M, Van den Berghe H, Marynen P . 1997 Blood 90: 2535–2540
Rohrschneider LR, Fuller JF, Wolf I, Liu Y, Lucas DM . 2000 Genes Dev. 14: 505–520
Rottapel R, Ilangumaran S, De Sepulveda P . 2000 Protein Kinase Functions, Vol. 29: Frontiers in Molecular Biology Woodgett J (ed) Oxford: Oxford University Press pp 247–276
Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS, Peeters P, Van Rompaey L, Van Etten RA, Ilaria Jr R, Marynen P, Gilliland DG . 1998 EMBO J. 17: 5321–5333
Schwaller J, Parganas E, Wang D, Cain D, Aster JC, Williams IR, Lee CK, Gerthner R, Kitamura T, Frantsve J, Anastasiadou E, Loh ML, Levy DE, Ihle JN, Gilliland DG . 2000 Mol. Cell 6: 693–704
Siminovitch KA, Neel BG . 1998 Semin. Immunol. 10: 329–347
Starr R, Hilton DJ . 1999 Bioessays 21: 47–52
Starr R, Metcalf D, Elefanty AG, Brysha M, Willson TA, Nicola NA, Hilton DJ, Alexander WS . 1998 Proc. Natl. Acad. Sci. USA 95: 14395–14399
Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ . 1997 Nature 387: 917–921
Taparowsky E, Suard Y, Fasano O, Shimizu K, Goldfarb M, Wigler M . 1982 Nature 300: 762–765
Tsai S, Bartelmez S, Sitnicka E, Collins S . 1994 Genes Dev. 8: 2831–2841
Tyers M, Rottapel R . 1999 Proc. Natl. Acad. Sci. USA 96: 12230–12232
Weiler SR, Mou S, DeBerry CS, Keller JR, Ruscetti FW, Ferris DK, Longo DL, Linnekin D . 1996 Blood 87: 3688–3693
Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN, Yoshimura A . 1999 EMBO J. 18: 1309–1320
Yasukawa H, Sasaki A, Yoshimura A . 2000 Annu. Rev. Immunol. 18: 143–164
Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC, 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, Baca M . 1999 Proc. Natl. Acad. Sci. USA 96: 2071–2076
Zheng N, Wang P, Jeffrey PD, Pavletich NP . 2000 Cell 102: 533–539
Acknowledgements
This work was supported by grants from the Terry Fox Program Project of the National Cancer Institute of Canada (NCIC), by the Canadian Institutes of Health Research (CIHR) and La Ligue Nationale contre le Cancer. R Rottapel is a CIHR Investigator and D Barber is an NCIC Research Scientist. PD Sepulveda was supported as a Research Fellow by the CIHR and the Ligue Nationale contre le Cancer. The authors thank C Cantin for his expertise in cell sorting and D Birnbaum for NIH3T3 Ras V12 cells.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Rottapel, R., Ilangumaran, S., Neale, C. et al. The tumor suppressor activity of SOCS-1. Oncogene 21, 4351–4362 (2002). https://doi.org/10.1038/sj.onc.1205537
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205537
Keywords
This article is cited by
-
Suppressor of cytokine signaling (SOCS) genes are downregulated in breast cancer
World Journal of Surgical Oncology (2018)
-
SOCS1 inhibits migration and invasion of prostate cancer cells, attenuates tumor growth and modulates the tumor stroma
Prostate Cancer and Prostatic Diseases (2017)
-
SOCS proteins in regulation of receptor tyrosine kinase signaling
Cellular and Molecular Life Sciences (2014)
-
DNA damage activates a complex transcriptional response in murine lymphocytes that includes both physiological and cancer-predisposition programs
BMC Genomics (2013)
-
Suppressor of cytokine signaling 1 blocks mitosis in human melanoma cells
Cellular and Molecular Life Sciences (2013)