Journal of Experimental Medicine, Vol 179, 1855-1865, Copyright © 1994 by Rockefeller University Press

ARTICLES

Negative regulation of p120GAP GTPase promoting activity by p210bcr/abl: implication for RAS-dependent Philadelphia chromosome positive cell growth

T Skorski, P Kanakaraj, DH Ku, M Nieborowska-Skorska, E Canaani, G Zon, B Perussia and B Calabretta
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.

The p210bcr/abl tyrosine kinase appears to be responsible for initiating and maintaining the leukemic phenotype in chronic myelogenous leukemia (CML) patients. p21ras-p120GAP interactions play a central role in transducing mitogenic signals. Therefore, we investigated whether p21ras and p120GAP are regulated by p210bcr/abl, and whether this activation is functionally significant for CML cell proliferation. We report that transient expression of p210bcr/abl in fibroblast-like cells induces simultaneous activation of p21ras and inhibition of GTPase-promoting activity of p120GAP, and confirm these data showing that downregulation of p210bcr/abl expression in CML cells with bcr/abl antisense oligodeoxynucleotides induces both inhibition of p21ras activation and stimulation of GTPase-promoting activity of p120GAP. Tyrosine phosphorylation of two p120GAP-associated proteins, p190 and p62, which may affect p120GAP activity, also depends on p210bcr/abl tyrosine kinase expression. Direct dependence of these effects on the kinase activity is proven in experiments in which expression of c-MYB protein in fibroblast-like cells or downregulation of c-MYB expression resulting in analogous inhibition of CML cell proliferation does not result in the same changes. Use of specific antisense oligodeoxynucleotides to downregulate p21ras expression revealed a requirement for functional p21ras in the proliferation of Philadelphia chromosome-positive CML primary cells. Thus, the p210bcr/abl-dependent regulation of p120GAP activity is responsible, in part, for the maintenance of p21ras in the active GTP-bound form, a crucial requirement for CML cell proliferation.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Hickey, F. B., Cotter, T. G. (2006). BCR-ABL Regulates Phosphatidylinositol 3-Kinase-p110{gamma} Transcription and Activation and Is Required for Proliferation and Drug Resistance. J. Biol. Chem. 281: 2441-2450 [Abstract] [Full Text]  
• Ren, S.-y., Bolton, E., Mohi, M. G., Morrione, A., Neel, B. G., Skorski, T. (2005). Phosphatidylinositol 3-Kinase p85{alpha} Subunit-Dependent Interaction with BCR/ABL-Related Fusion Tyrosine Kinases: Molecular Mechanisms and Biological Consequences. Mol. Cell. Biol. 25: 8001-8008 [Abstract] [Full Text]  
• Calabretta, B., Perrotti, D. (2004). The biology of CML blast crisis. Blood 103: 4010-4022 [Abstract] [Full Text]  
• Kurzrock, R., Albitar, M., Cortes, J. E., Estey, E. H., Faderl, S. H., Garcia-Manero, G., Thomas, D. A., Giles, F. J., Ryback, M. E., Thibault, A., De Porre, P., Kantarjian, H. M. (2004). Phase II Study of R115777, a Farnesyl Transferase Inhibitor, in Myelodysplastic Syndrome. JCO 22: 1287-1292 [Abstract] [Full Text]  
• Gustafson, W. C., Ray, S., Jamieson, L., Thompson, E. A., Brasier, A. R., Fields, A. P. (2004). Bcr-Abl Regulates Protein Kinase C{iota} (PKC{iota}) Transcription via an Elk1 Site in the PKC{iota} Promoter. J. Biol. Chem. 279: 9400-9408 [Abstract] [Full Text]  
• Clark, S. S., Zhong, L., Filiault, D., Perman, S., Ren, Z., Gould, M., Yang, X. (2003). Anti-Leukemia Effect of Perillyl Alcohol in Bcr/Abl-Transformed Cells Indirectly Inhibits Signaling through Mek in a Ras- and Raf-Independent Fashion. Clin. Cancer Res. 9: 4494-4504 [Abstract] [Full Text]  
• Slupianek, A., Hoser, G., Majsterek, I., Bronisz, A., Malecki, M., Blasiak, J., Fishel, R., Skorski, T. (2002). Fusion Tyrosine Kinases Induce Drug Resistance by Stimulation of Homology-Dependent Recombination Repair, Prolongation of G2/M Phase, and Protection from Apoptosis. Mol. Cell. Biol. 22: 4189-4201 [Abstract] [Full Text]  
• Gelfanov, V. M., Burgess, G. S., Litz-Jackson, S., King, A. J., Marshall, M. S., Nakshatri, H., Boswell, H. S. (2001). Transformation of interleukin-3-dependent cells without participation of Stat5/bcl-xL: cooperation of akt with raf/erk leads to p65 nuclear factor {kappa}B-mediated antiapoptosis involving c-IAP2. Blood 98: 2508-2517 [Abstract] [Full Text]  
• Reichert, A., Heisterkamp, N., Daley, G. Q., Groffen, J. (2001). Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336. Blood 97: 1399-1403 [Abstract] [Full Text]  
• Peters, D. G., Hoover, R. R., Gerlach, M. J., Koh, E. Y., Zhang, H., Choe, K., Kirschmeier, P., Bishop, W. R., Daley, G. Q. (2001). Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood 97: 1404-1412 [Abstract] [Full Text]  
• Jonuleit, T., van der Kuip, H., Miething, C., Michels, H., Hallek, M., Duyster, J., Aulitzky, W. E. (2000). Bcr-Abl kinase down-regulates cyclin-dependent kinase inhibitor p27 in human and murine cell lines. Blood 96: 1933-1939 [Abstract] [Full Text]  
• Cong, F., Yuan, B., Goff, S. P. (1999). Characterization of a Novel Member of the DOK Family That Binds and Modulates Abl Signaling. Mol. Cell. Biol. 19: 8314-8325 [Abstract] [Full Text]  
• Zou, X., Calame, K. (1999). Signaling Pathways Activated by Oncogenic Forms of Abl Tyrosine Kinase. J. Biol. Chem. 274: 18141-18144 [Full Text]  
• Majewski, M., Nieborowska-Skorska, M., Salomoni, P., Slupianek, A., Reiss, K., Trotta, R., Calabretta, B., Skorski, T. (1999). Activation of Mitochondrial Raf-1 Is Involved in the Antiapoptotic Effects of Akt. Cancer Res. 59: 2815-2819 [Abstract] [Full Text]  
• Carlo-Stella, C., Regazzi, E., Sammarelli, G., Colla, S., Garau, D., Gazit, A., Savoldo, B., Cilloni, D., Tabilio, A., Levitzki, A., Rizzoli, V. (1999). Effects of the Tyrosine Kinase Inhibitor AG957 and an Anti-Fas Receptor Antibody on CD34+ Chronic Myelogenous Leukemia Progenitor Cells. Blood 93: 3973-3982 [Abstract] [Full Text]  
• Nieborowska-Skorska, M., Wasik, M. A., Slupianek, A., Salomoni, P., Kitamura, T., Calabretta, B., Skorski, T. (1999). Signal Transducer and Activator of  Transcription (STAT)5 Activation by BCR/ABL Is Dependent on Intact Src Homology (SH)3 and SH2 Domains of BCR/ABL and Is Required for Leukemogenesis. J. Exp. Med. 189: 1229-1242 [Abstract] [Full Text]  
• Beaupre, D. M., Kurzrock, R. (1999). RAS and Leukemia: From Basic Mechanisms to Gene-Directed Therapy. JCO 17: 1071-1071 [Abstract] [Full Text]  
• LaMontagne, K. R. Jr., Hannon, G., Tonks, N. K. (1998). Protein tyrosine phosphatase PTP1B suppresses p210 bcr-abl-induced transformation of Rat-1 fibroblasts and promotes differentiation of K562 cells. Proc. Natl. Acad. Sci. USA 95: 14094-14099 [Abstract] [Full Text]  
• Skorski, T., Wlodarski, P., Daheron, L., Salomoni, P., Nieborowska-Skorska, M., Majewski, M., Wasik, M., Calabretta, B. (1998). BCR/ABL-mediated leukemogenesis requires the activity of the small GTP-binding protein Rac. Proc. Natl. Acad. Sci. USA 95: 11858-11862 [Abstract] [Full Text]  
• Kurachi, H., Wada, Y., Tsukamoto, N., Maeda, M., Kubota, H., Hattori, M., Iwai, K., Minato, N. (1997). Human SPA-1 Gene Product Selectively Expressed in Lymphoid Tissues Is a Specific GTPase-activating Protein for Rap1 and Rap2. SEGREGATE EXPRESSION PROFILES FROM A rap1GAP GENE PRODUCT. J. Biol. Chem. 272: 28081-28088 [Abstract] [Full Text]  
• Kashige, N., Carpino, N., Kobayashi, R. (2000). Tyrosine phosphorylation of p62dok by p210bcr-abl inhibits RasGAP activity. Proc. Natl. Acad. Sci. USA 97: 2093-2098 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS