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NF-kappaB/STAT3/PI3K signaling crosstalk in iMyc E mu B lymphoma

Authors
 Joo Hyun Nam  ;  Dong Hun Shin  ;  Jung Eun Min  ;  Sang-Kyu Ye  ;  Ju-Hong Jeon  ;  Sung Joon Kim 
Citation
 MOLECULAR CANCER, Vol.9 : 97, 2010 
Journal Title
MOLECULAR CANCER
Issue Date
2010
MeSH
Animals ; Apoptosis/physiology ; Blotting, Western ; Cell Line, Tumor ; DNA Fragmentation ; Disease Models, Animal ; Electrophoretic Mobility Shift Assay ; Enhancer Elements, Genetic ; Enzyme Activation/physiology ; Enzyme-Linked Immunosorbent Assay ; Gene Expression/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Genes, Immunoglobulin Heavy Chain ; Genes, myc ; Immunoprecipitation ; Lymphoma,B-Cell/genetics ; Lymphoma,B-Cell/metabolism* ; Mice ; NF-kappaB/genetics ; NF-kappaB/metabolism* ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism* ; Receptor Cross-Talk/physiology* ; Reverse Transcriptase Polymerase Chain Reaction ; STAT3Transcription Factor/genetics ; STAT3Transcription Factor/metabolism* ; Signal Transduction/genetics*
Keywords
Reverse Transcription Polymerase Chain Reaction ; Electrophoretic Mobility Shift Assay ; PI3K Signaling ; Signaling Crosstalk ; Spleen Masse
Abstract
BACKGROUND: Myc is a well known driver of lymphomagenesis, and Myc-activating chromosomal translocation is the recognized hallmark of Burkitt lymphoma, an aggressive form of non-Hodgkin's lymphoma. We developed a model that mimics this translocation event by inserting a mouse Myc cDNA gene into the immunoglobulin heavy chain locus, just upstream of the intronic Emu enhancer. These mice, designated iMyc E mu, readily develop B-cell lymphoma. To study the mechanism of Myc-induced lymphoma, we analyzed signaling pathways in lymphoblastic B-cell lymphomas (LBLs) from iMyc E mu mice, and an LBL-derived cell line, iMyc E mu-1.

RESULTS: Nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) were constitutively activated in iMyc E mu mice, not only in LBLs but also in the splenic B-lymphocytes of young animals months before tumors developed. Moreover, inhibition of either transcription factor in iMyc E mu-1 cells suppressed growth and caused apoptosis, and the abrogation of NF-kappaB activity reduced DNA binding by both STAT3 and Myc, as well as Myc expression. Inhibition of STAT3 signaling eliminated the activity of both NF-kappaB and Myc, and resulted in a corresponding decrease in the level of Myc. Thus, in iMyc E mu-1 cells NF-kappaB and STAT3 are co-dependent and can both regulate Myc. Consistent with this, NF-kappaB and phosphorylated STAT3 were physically associated with one another. In addition, LBLs and iMyc E mu-1 cells also showed constitutive AKT phosphorylation. Blocking AKT activation by inhibiting PI3K reduced iMyc E mu-1 cell proliferation and caused apoptosis, via downregulation of NF-kappaB and STAT3 activity and a reduction of Myc levels. Co-treatment with NF-kappaB, STAT3 or/and PI3K inhibitors led to additive inhibition of iMyc E mu-1 cell proliferation, suggesting that these signaling pathways converge.

CONCLUSIONS: Our findings support the notion that constitutive activation of NF-kappaB and STAT3 depends on upstream signaling through PI3K, and that this activation is important for cell survival and proliferation, as well as for maintaining the level of Myc. Together, these data implicate crosstalk among NF-kappaB, STAT3 and PI3K in the development of iMyc E mu B-cell lymphomas.
Files in This Item:
T201005339.pdf Download
DOI
10.1186/1476-4598-9-97
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
Yonsei Authors
Park, Eun Sung(박은성)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/103063
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