Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis.
BCR/ABL oncogenic tyrosine kinase activates STAT5, which plays an important role in leukemogenesis. The downstream effectors of the BCR/ABL-->STAT5 pathway remain poorly defined. We show here that expression of the antiapoptotic protein A1, a member of the Bcl-2 family, and the serine/threonine kinase pim-1 are enhanced by BCR/ABL. This up-regulation requires activation of STAT5 by the signaling from SH3+SH2 domains of BCR/ABL. Enhanced expression of A1 and pim-1 played a key role in the BCR/ABL-mediated cell protection from apoptosis. In addition, pim-1 promoted proliferation of the BCR/ABL-transformed cells. Both A1 and pim-1 were required to induce interleukin 3-independent cell growth, inhibit activation of caspase 3, and stimulate cell cycle progression. Moreover, simultaneous up-regulation of both A1 and pim-1 was essential for in vitro transformation and in vivo leukemogenesis mediated by BCR/ABL. These data indicate that induction of A1 and pim-1 expression may play a critical role in the BCR/ABL-dependent transformation.
Nieborowska-Skorska
Malgorzata
M
Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
Hoser
Grazyna
G
Kossev
Plamen
P
Wasik
Mariusz A
MA
Skorski
Tomasz
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000209:etiology*; D051379:Mice; D008894:Milk Proteins; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051573:Proto-Oncogene Proteins c-pim-1; D051818:Replication Protein C; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D016044:Fusion Proteins, bcr-abl; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D051818:Replication Protein C