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Inactivation of Notch signaling leads to a defective dendritic cell differentiation in cancer
Author(s) -
Cheng Pingyan,
Nefedova Yulia,
Gabrilovich Dmitry I.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1076.20
Subject(s) - hes1 , notch signaling pathway , downregulation and upregulation , stat3 , microbiology and biotechnology , cyclin dependent kinase 8 , hes3 signaling axis , signal transduction , cancer research , transcription factor , biology , progenitor cell , chemistry , stem cell , biochemistry , gene
Notch receptors/transcription regulators play an important role in the fate decision for hematopoietic progenitor cells (HPC). Previously we and others have demonstrated that Notch signaling may play a critical role in the development of dendritic cells (DC). Here we report that Notch signaling is involved in the abnormal differentiation of DC during tumor progression. We have found that Notch signaling (evaluated by the activity of CBF1 transcription factor and the expression of down stream targets Hes1 and Hes5) was dramatically reduced in HPC isolated from tumor‐bearing mice. The downregulation of Notch signaling in HPC caused defective differentiation of DC. Treatment of HPC or tumor‐bearing mice with Stat3 inhibitor JSI‐124 significantly increased Hes1 expression in HPC and DC differentiation. Using macrophages from Stat3−/− mice and induced activation of Stat3 in HPC by IL‐6 we have confirmed that Stat3 negatively regulated Notch signaling. Thus, our data suggest that tumor associated factors inactivate Notch signaling in HPC, leading to abnormal DC differentiation through Stat3 upregulation.