The Jab1/COP9 signalosome subcomplex is a downstream mediator of Bcr-Abl kinase activity and facilitates cell-cycle progression.
Jab1 is a multifunctional protein associated with the signaling pathway, cell-cycle regulation, and development, and acts as a key subunit of COP9 signalosome (CSN). Jab1 promotes degradation of the cyclin-dependent kinase inhibitor p27(Kip1) by transportation from the nucleus to the cytoplasm. However, there has been no clear evidence for whether and how Jab1 contributes to malignant transformation in human cancers. Here we show that Bcr-Abl tyrosine kinase facilitates the down-regulation of p27 by modulating complex formation of Jab1/CSN through the mitogen-activated protein (MAP) kinase and phosphatidylinositol 3 (PI3) kinase signaling pathways. Nearly half of the chronic myelogenous leukemia cell lines and the murine hematopoietic precursor cells expressing Bcr-Abl exhibited a marked increase in the small loose Jab1 complex located in the cytoplasm. Inhibition of Bcr-Abl kinase by STI571 induced G1 arrest and caused a recovery of the p27 level with reduction of the small Jab1 complex from the cytoplasm. Either blockade of the MAP kinase and PI3 kinase pathways by specific inhibitors or Jab1 knockdown by small interfering RNA (siRNA) prevented p27 down-regulation as well as formation of the small complex. Thus, regulation of p27 via modulation of the Jab1 subcomplex is a novel mechanism whereby Bcr-Abl oncogenic signals accelerate abnormal cell proliferation.
Tomoda
Kiichiro
K
Department of Animal Molecular Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara, Japan.
Kato
Jun-ya
JY
Tatsumi
Eiji
E
Takahashi
Takayuki
T
Matsuo
Yoshinobu
Y
Yoneda-Kato
Noriko
N
D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D000075686:COP9 Signalosome Complex; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells; D046912:Multiprotein Complexes; D010447:Peptide Hydrolases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex