Pim-1 expression is sufficient to induce cytokine independence in murine hematopoietic cells, but is dispensable for BCR-ABL-mediated transformation.
OBJECTIVE
BCR-ABL is a unique oncoprotein of which sole expression can cause cancer. A number of signaling molecules were shown to be activated by BCR-ABL. One of the important molecules that contributes to BCR-ABL-mediated cell proliferation is signal transducer and activator of transcription (STAT) 5. To elucidate the mechanism of BCR-ABL-mediated leukemogenesis, a role of pim-1, one of the important target genes of STAT5, was investigated.


METHODS
A temperature-sensitive mutant of p210(BCR-ABL) was introduced in interleukin-3-dependent murine hematopoietic cell line Ba/F3 cells, and downstream signaling after activation of BCR-ABL was investigated. Effects of the expression of a dominant-negative (dn) Pim-1 and a dn STAT5A in BCR-ABL-driven cell proliferation also were studied in Ba/F3 cells.


RESULTS
We found that pim-1 was markedly up-regulated following activation of BCR-ABL tyrosine kinase with activation of STAT5. Overexpression of pim-1 alone induced cytokine-independent cell growth of Ba/F3 cells in a dose-dependent manner. However, expression of the dn Pim-1 did not affect growth of Ba/F3 cells transformed by BCR-ABL, whereas that of the dn STAT5A did suppress it.


CONCLUSIONS
Pim-1 is one of the redundant molecules that contributes to induction of autonomous cell growth and is dispensable for leukemogenesis by BCR-ABL.
Division of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. tenosaka@ims.u-tokyo.ac.jp
Tetsuya
T
Nosaka
Toshio
T
Kitamura
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D018628:Gene Dosage; D005799:Genes, Dominant; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000473:pathology; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D008894:Milk Proteins; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051573:Proto-Oncogene Proteins c-pim-1; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D013696:Temperature; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D007377:Interleukin-3; D008894:Milk Proteins; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D016044:Fusion Proteins, bcr-abl; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1