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HDAC3 functions as a positive regulator in Notch signal transduction.


Ferrante F, Giaimo BD, Bartkuhn M, Zimmermann T, Close V, Mertens D, Nist A, Stiewe T, Meier-Soelch J, Kracht M, Just S, Klöble P, Oswald F, Borggrefe T

Aberrant Notch signaling plays a pivotal role in T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL). Amplitude and duration of the Notch response is controlled by ubiquitin-dependent proteasomal degradation of the Notch1 intracellular domain (NICD1), a hallmark of the leukemogenic process. Here, we show that HDAC3 controls NICD1 acetylation levels directly affecting NICD1 protein stability. Either genetic loss-of-function of HDAC3 or nanomolar concentrations of HDAC inhibitor apicidin lead to downregulation of Notch target genes accompanied by a local reduction of histone acetylation. Importantly, an HDAC3-insensitive NICD1 mutant is more stable but biologically less active. Collectively, these data show a new HDAC3- and acetylation-dependent mechanism that may be exploited to treat Notch1-dependent leukemias.

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Antibody
Microplex Library Preparation kit

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Published
February, 2020

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Products used in this publication

  • Antibody ChIP-seq grade icon
    C15410174
    H3K27ac Antibody - ChIP-seq Grade
  • RFX5-polyclonal-antibody-diagenode
    C15410206
    Rabbit IgG
  • ChIP kit icon
    C05010012
    MicroPlex Library Preparation Kit v2 (12 indexes)
  • ChIP kit icon
    C05010014
    MicroPlex Library Preparation Kit v2 (48 indexes)

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