Regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, the c-jun N-terminal kinase.
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.
Burgess
G S
GS
Walther Cancer Institute, and the Hematology/Oncology Division, the Departments of Medicine, and Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Williamson
E A
EA
Cripe
L D
LD
Litz-Jackson
S
S
Bhatt
J A
JA
Stanley
K
K
Stewart
M J
MJ
Kraft
A S
AS
Nakshatri
H
H
Boswell
H S
HS
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
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