title: Regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, the c-jun N-terminal kinase.
abstract: Activity of the c-jun N-terminal kinase (JNK) has been shown in hematopoietic cells transformed by p210 BCR-ABL. However, analysis has not been reported for hematopoietic cells on the consequences of this activity for c-jun promoter regulation within its distinctive proximal 8-base consensus CRE-like element, an element linked to JNK-mediated increase in c-jun transcription. In the present study, regulation of the proximal c-jun promoter was studied in murine myeloid cells transformed by p210 BCR-ABL. Promoter regulation in p210 BCR-ABL transformed cells was compared with regulation of the promoter in nontransformed interleukin-3 (IL-3)-dependent parental cells. The composition of nuclear AP-1 proteins contained within cells with p210 BCR-ABL, and their binding to the c-jun promoter proximal CRE-like element, was compared with the composition and binding of AP-1 proteins in IL-3-treated parental cells without p210 BCR-ABL. The present analysis found fivefold increased c-jun transcription occurring in p210 BCR-ABL transformed murine myeloid cells possessing a corresponding magnitude of increased kinase activity of JNK, compared with IL-3-stimulated parental cells. Augmented JNK activity was accompanied by increased nuclear abundance of c-jun and c-fos proteins that bound specifically to the proximal c-jun promoter CRE element. Also, representative human leukemic cell lines expressing p210 BCR-ABL and possessing abundant kinase activity of JNK, when compared with parental cells that were deficient in JNK activity, had increased c-jun and c-fos proteins. Finally, to show the relevance of these observations in model systems, we studied blast cells from patients with Philadelphia chromosome-positive acute leukemic transformation, and observed comparable activities of JNK catalysis and c-jun/AP-1 protein relative to the cell lines that possessed p210 BCR-ABL and JNK activity. These studies provide a basis for investigating the set of downstream genes which augmented c-jun/AP-1 activity enlists in the process of transformation by p210 BCR-ABL.
authors.affiliation: Walther Cancer Institute, and the Hematology/Oncology Division, the Departments of Medicine, and Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Burgess
authors.forename: E A
authors.initials: EA
authors.lastname: Williamson
authors.forename: L D
authors.initials: LD
authors.lastname: Cripe
authors.forename: S
authors.initials: S
authors.lastname: Litz-Jackson
authors.forename: J A
authors.initials: JA
authors.lastname: Bhatt
authors.forename: K
authors.initials: K
authors.lastname: Stanley
authors.forename: M J
authors.initials: MJ
authors.lastname: Stewart
authors.forename: A S
authors.initials: AS
authors.lastname: Kraft
authors.forename: H
authors.initials: H
authors.lastname: Nakshatri
authors.forename: H S
authors.initials: HS
authors.lastname: Boswell
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D016758:Genes, jun; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D048670:MAP Kinase Kinase 4; D046911:Macromolecular Substances; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D011494:Protein Kinases; D016044:Fusion Proteins, bcr-abl; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases