title: c-Jun blocks cell differentiation but not growth inhibition or apoptosis of chronic myelogenous leukemia cells induced by STI571 and by histone deacetylase inhibitors.
abstract: The constitutively active Bcr-Abl tyrosine kinase plays a crucial role in chronic myelogenous leukemia (CML) pathogenesis. The Bcr-Abl protein induces the upregulation of proto-oncogene c-Jun, which is involved in Bcr-Abl transforming activity in Bcr-Abl positive cells. Recent studies reported that c-Jun inhibited hemoglobin synthesis in human CML cell line K562. However, c-Jun also plays a critical role in cell proliferation and apoptosis. In this study, we investigated the physiological roles of c-Jun in cell proliferation, apoptosis and erythroid differentiation of K562 cells. Firstly, we generated K562 cell lines stably overexpressing c-Jun. These clones have the same proliferation rate as the parental cell line in general culture medium. Endogenous c-Jun expression was analyzed to determine the effective concentration of STI571 for inhibiting Bcr-Abl signaling. Western blots show that STI571 inhibited c-Jun expression in a dose-dependent manner, reaching a maximum inhibition at 1 microM. STI571 could inhibit c-Jun expression in K562 cells, but not in c-Jun-overexpression cells. c-Jun did not alter growth inhibition and apoptotic induction by STI571 treatment, but inhibited STI571-induced erythroid differentiation. Moreover, c-Jun did not alter growth inhibition and apoptotic induction by histone deacetylase (HDAC) inhibitors (apicidin, sodium butyrate, and MS275) treatment, but inhibited HDAC inhibitors-induced erythroid differentiation. These results suggest that c-Jun may modulate anticancer drugs-induced cell differentiation but not growth inhibition and apoptosis in CML cells.
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan. cmbhhm@tmu.edu.tw
authors.forename: Huei-Mei
authors.initials: HM
authors.lastname: Huang
authors.forename: Juo-Chuan
authors.initials: JC
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D041905:Erythroid Cells / Q000187:drug effects / Q000473:pathology; D005914:Globins / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C000715470:MAS1 protein, human; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D005914:Globins