Abstract
Protein kinase (PK)Cθ is a critical regulator of mature T-cell activation and proliferation, being implicated in TCR-triggered nuclear factor (NF)-κB activation and providing important survival signals to leukemic T cells. We previously showed that overexpression of pTα/pre-TCR and constitutive activation of NF-κB characterize the T-cell leukemia/lymphoma developing in Notch3-IC transgenic mice. We report here that PKCθ is a downstream target of Notch3 signaling and that its activation and membrane translocation require a functional pre-TCR in order to trigger NF-κB activation in thymocytes and lymphoma cells of transgenic mice. Furthermore, deletion of PKCθ in Notch3-IC transgenic mice reduces the incidence of leukemia, correlating with decreased NF-κB activation. This paper therefore suggests that PKCθ mediates the activation of NF-κB by pre-TCR in immature thymocytes and contributes to the development of Notch3-dependent T-cell lymphoma.
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References
Aifantis I, Azogui O, Feinberg J, Saint-Ruf C, Buer J and von Boehmer H . (1998). Immunity, 9, 649–655.
Aifantis I, Gounari F, Scorrano L, Borowski C and von Boehmer H . (2001). Nat. Immunol., 2, 403–409.
Bain G, Cravatt CB, Loomans C, Alberola-Ila J, Hedrick SM and Murre C . (2001). Nat. Immunol., 2, 165–171.
Bellavia D, Campese AF, Alesse E, Vacca A, Felli MP, Balestri A, Stoppacciaro A, Tiveron C, Tatangelo L, Giovarelli M, Gaetano C, Ruco L, Hoffman ES, Hayday AC, Lendahl U, Frati L, Gulino A and Screpanti I . (2000). EMBO J., 19, 3337–3348.
Bellavia D, Campese AF, Checquolo S, Balestri A, Biondi A, Cazzaniga G, Lendahl U, Fehling HJ, Hayday AC, Frati L, von Boehmer H, Gulino A and Screpanti I . (2002). Proc. Natl. Acad. Sci. USA, 99, 3788–3793.
Carrasco D, Rizzo CA, Dorfman K and Bravo R . (1996). EMBO J., 15, 3640–3650.
Cipriani B, Knowles H, Chen L, Battistini L and Brosnan CF . (2002). J. Immunol., 169, 5761–5770.
Coudronniere N, Villalba M, Englund N and Altman A . (2000). Proc. Natl. Acad. Sci. USA, 97, 3394–3399.
Dixit V and Mak TW . (2002). Cell, 111, 615–619.
Felli MP, Maroder M, Mitsiadis TA, Campese AF, Bellavia D, Vacca A, Mann RS, Frati L, Lendahl U, Gulino A and Screpanti I . (1999). Int. Immunol., 11, 1017–1025.
Hardwick JS and Sefton BM . (1997). J. Biol. Chem., 272, 25429–25432.
Israel A . (2000). Trends Cell Biol., 10, 129–133.
Kong YY, Fischer KD, Bachmann MF, Mariathasan S, Kozieradzki I, Nghiem MP, Bouchard D, Bernstein A, Ohashi PS and Penninger JM . (1998). J. Exp. Med., 188, 2099–2111.
Kordes U, Krappmann D, Heissmeyer V, Ludwig WD and Scheidereit C . (2000). Leukemia, 14, 399–402.
Lin X, O'Mahony A, Mu Y, Geleziunas R and Greene WC . (2000). Mol. Cell. Biol., 20, 2933–2940.
Liu Y, Witte S, Liu YC, Doyle M, Elly C and Altman A . (2000). J. Biol. Chem., 275, 3603–3609.
Maroder M, Bellavia D, Meco D, Napolitano M, Stigliano A, Alesse E, Vacca A, Giannini G, Frati L, Gulino A and Screpanti I . (1996). J. Immunol., 157, 2864–2872.
Monks CR, Kupfer H, Tamir I, Barlow A and Kupfer A . (1997). Nature, 385, 83–86.
Montixi C, Langlet C, Bernard AM, Thimonier J, Dubois C, Wurbel MA, Chauvin JP, Pierres M and He HT . (1998). EMBO J., 17, 5334–5348.
Rayet B and Gelinas C . (1999). Oncogene, 18, 6938–6947.
Sade H, Krishna S and Sarin A . (2003). J. Biol. Chem, 279, 2937–2944.
Saint-Ruf C, Panigada M, Azogui O, Debey P, von Boehmer H and Grassi F . (2000). Nature, 406, 524–527.
Sun Z, Arendt CW, Ellmeier W, Schaeffer EM, Sunshine MJ, Gandhi L, Annes J, Petrzilka D, Kupfer A, Schwartzberg PL and Littman DR . (2000). Nature, 404, 402–407.
Szamel M, Appel A, Schwinzer R and Resch K . (1998). J. Immunol., 160, 2207–2214.
Talora C, Campese AF, Bellavia D, Pascucci M, Checquolo S, Groppioni M, Frati L, Von Boehmer H, Gulino A and Screpanti I . (2003). EMBO Rep., 4, 1067–1071.
Villalba M and Altman A . (2002). Curr. Cancer Drug Targets, 2, 125–137.
Villalba M, Coudronniere N, Deckert M, Teixeiro E, Mas P and Altman A . (2000). Immunity, 12, 151–160.
Villunger A, Ghaffari-Tabrizi N, Tinhofer I, Krumbock N, Bauer B, Schneider T, Kasibhatla S, Greil R, Baier-Bitterlich G, Uberall F, Green DR and Baier G . (1999). Eur. J. Immunol., 29, 3549–3561.
Voll RE, Jimi E, Phillips RJ, Barber DF, Rincon M, Hayday AC, Flavell RA and Ghosh S . (2000). Immunity, 13, 677–689.
von Boehmer H and Fehling HJ . (1997). Annu. Rev. Immunol., 15, 433–452.
Acknowledgements
We are grateful to Dr G Baier for reagents and to Drs H von Boehmer and DR Littman for reagents and helpful discussions. This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Centro Nazionale delle Ricerche (CNR), the Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), the Ministero della Salute and the Biologia e Medicina Molecolare (BEMM) Center of Excellence.
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Felli, M., Vacca, A., Calce, A. et al. PKCθ mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia. Oncogene 24, 992–1000 (2005). https://doi.org/10.1038/sj.onc.1208302
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DOI: https://doi.org/10.1038/sj.onc.1208302
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