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Proteasomal inhibition effects Notch signaling (937.2)
Author(s) -
Chambers Elaina,
Hsu Aaron,
White Brandon
Publication year - 2014
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.28.1_supplement.937.2
Subject(s) - notch signaling pathway , hes1 , microbiology and biotechnology , notch proteins , transcription factor , ubiquitin , chromatin , hes3 signaling axis , biology , signal transduction , cancer research , chemistry , gene , genetics
T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive cancer with poor clinical outcome and aberrant Notch signaling has been shown to play a central role in disease pathogenesis. Therefore, it is crucial to elucidate the mechanism underlying Notch deregulation. Upon release from the membrane, the Notch Intracellular Domain (NICD) translocates to the nucleus where is associates with CSL, displacing co‐repressors and recruiting co‐activators (such as Mastermind and CBP/p300), thus resulting in the transcription of target genes (Hes1 and Myc). Our earlier work demonstrated that the NICD could be turned over through a phosphorylation, and subsequent ubiquitination mechanism of degradation. However, it remains unclear if turnover occurs on chromatin or in the nucleoplasm. It is also known that Notch translocation can be pharmacologically inhibited by the drug DAPT. The current work examines the interplay at hand between the inhibition of Notch translocation and the ubiquitin‐mediated proteasomal degradation of Notch. Current data suggest that proteasomal inhibition enhances or “rescues” the transcription of Notch target genes which have been inhibited by DAPT, thus implying that Notch has the ability to “recycle” itself, despite the ubiquitin signal, and that Notch continues participating in gene transcription. These data clearly indicate that Notch signaling is more complex than previously believed, and elucidating the mechanisms underlying its deregulation will greatly benefit the biomedical community as it will effectively enable us to target the Notch pathway in cancer treatment. Grant Funding Source : Support of research was through NSF‐RUI Grant#1052039 to JBW.