HDAC3 functions as a positive regulator in Notch signal transduction

被引：39

作者：

Ferrante, Francesca ^{[1
]}

Giaimo, Benedetto Daniele ^{[1
]}

Bartkuhn, Marek ^{[2
]}

Zimmermann, Tobias ^{[3
]}

Close, Viola ^{[4
,5
]}

Mertens, Daniel ^{[4
,5
]}

Nist, Andrea ^{[6
]}

Stiewe, Thorsten ^{[6
]}

Meier-Soelch, Johanna ^{[7
]}

Kracht, Michael ^{[7
]}

Just, Steffen ^{[8
]}

Kloeble, Patricia ^{[9
]}

Oswald, Franz ^{[9
]}

Borggrefe, Tilman ^{[1
]}

机构：

[1] Univ Giessen, Inst Biochem, Friedrichstr 24, D-35392 Giessen, Germany

[2] Univ Giessen, Inst Genet, Heinrich Buff Ring 58-62, D-35392 Giessen, Germany

[3] Univ Giessen, Bioinformat & Syst Biol, Heinrich Buff Ring 58-62, D-35392 Giessen, Germany

[4] Univ Med Ctr Ulm, Ctr Internal Med, Dept Internal Med 3, Albert Einstein Allee 23, D-89081 Ulm, Germany

[5] German Canc Res Ctr, Cooperat Unit Mech Leukemogenesis B061, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[6] Philipps Univ, Inst Mol Oncol, Genom Core Facil, Hans Meerwein Str 3, D-35043 Marburg, Germany

[7] Univ Giessen, Rudolf Buchheim Inst Pharmacol, Schubertstr 81, D-35392 Giessen, Germany

[8] Univ Med Ctr Ulm, Ctr Internal Med, Dept Internal Med 2, Mol Cardiol, Albert Einstein Allee 23, D-89081 Ulm, Germany

[9] Univ Med Ctr Ulm, Ctr Internal Med, Dept Internal Med 1, Albert Einstein Allee 23, D-89081 Ulm, Germany

来源：

NUCLEIC ACIDS RESEARCH | 2020年 / 48卷 / 07期

关键词：

HISTONE DEACETYLASE 3; COREPRESSOR COMPLEX; GENE-EXPRESSION; INTRACELLULAR DOMAIN; PATHWAY ACTIVATION; MUTATIONS; SHARP; SMRT; ACETYLATION; INSIGHTS;

D O I：

10.1093/nar/gkaa088

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：3496 / 3512

页数：17

共 80 条

[1] Sumoylation of Notch1 represses its target gene expression during cell stress [J].