Acetylation controls Notch3 stability and function in T-cell leukemia

Palermo, Rocco; Checquolo, Saula; Giovenco, A; Grazioli, Paola; Kumar, Vivek; Campese, Antonio Francesco; Giorgi, Alessandra; Napolitano, Monica; Canettieri, Gianluca; Ferrara, Grazia; Schininà, Maria Eugenia; Maroder, Marella; Frati, Luigi; Gulino, Alberto; Vacca, Alessandra; Screpanti, Isabella

doi:10.1038/onc.2011.533

Cited by 54 publications

(42 citation statements)

References 42 publications

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“…We found that NICD-MYC fusions had turnover rates essentially identical to those of their non-tagged versions in extract (Figure S1C). In contrast, all NICD paralogs degraded at similar rates in cultured human cells (Figure S1D), consistent with previous reports (Fryer et al, 2004; Malyukova et al, 2007; Mo et al, 2007; Palermo et al, 2012; Tsunematsu et al, 2004). …”

Section: Resultssupporting

confidence: 92%

Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

et al. 2016

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SUMMARY Upon Notch pathway activation, the receptor is cleaved to release the Notch intracellular domain (NICD), which translocates to the nucleus to activate gene transcription. Using Xenopus egg extracts, we have identified a Notch1-specific destruction signal (N1-Box). We show that mutations in the N1-Box inhibit NICD1 degradation and that the N1-Box is transferable for the promotion of degradation of heterologous proteins in Xenopus egg extracts and in cultured human cells. Mutation of the N1-Box enhances Notch1 activity in cultured human cells and zebrafish embryos. Human cancer mutations within the N1-Box enhance Notch1 signaling in transgenic zebrafish, highlighting the physiological relevance of this destruction signal. We find that binding of the Notch nuclear factor, CSL, to the N1-Box blocks NICD1 turnover. Our studies reveal a mechanism by which degradation of NICD1 is regulated by the N1-Box to minimize stochastic flux and to establish a threshold for Notch1 pathway activation.

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Section: Resultssupporting

confidence: 92%

Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

et al. 2016

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“…Protein acetylation is reversible, and is regulated by histone deacetylases (HDACs), NAD-dependent protein deacetylases and histone acetyltransferases. 124 Preclinical studies have reported that HDAC inhibitors that stabilize protein hyperacetylation have resulted in a significant decrease in both in vivo and in vitro growth of T-cell leukemia in NOTCH3 transgenic mice. 124 By comparison, hSIRT1 in association with NICD, by functioning as an NICD deacetylase, promotes NICD destabilization and alters NICD protein turnover in endothelial cells lacking active SRT1 protein.…”

Section: Inhibition Of Notch Signallingmentioning

confidence: 99%

“…124 Preclinical studies have reported that HDAC inhibitors that stabilize protein hyperacetylation have resulted in a significant decrease in both in vivo and in vitro growth of T-cell leukemia in NOTCH3 transgenic mice. 124 By comparison, hSIRT1 in association with NICD, by functioning as an NICD deacetylase, promotes NICD destabilization and alters NICD protein turnover in endothelial cells lacking active SRT1 protein. 125 Inhibition of NICD1 has been seen with both p300 and Tip60 HATs, 125,126 but NICD3 inhibition is apparently p300 HAT-dependent.…”

Section: Inhibition Of Notch Signallingmentioning

confidence: 99%

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NUMB inhibition of NOTCH signalling as a therapeutic target in prostate cancer

et al. 2014

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Prostate cancer is among the most prevalent life-threatening cancers diagnosed in the male population today. Various methods have been exploited in an attempt to treat this disease but these treatments, alongside preventative tactics, have been insufficient to control mortality rates and have usually resulted in detrimental adverse events. An opportunity to devise more-specific and potentially more-effective approaches for the eradication of prostate tumours can be found by targeting specific biological pathways. NUMB (protein numb homologue), a key regulator of cell fate, represents an attractive, actionable target in prostate cancer. NUMB participates in the observed deregulation of NOTCH (neurogenic locus notch homologue protein) signalling in prostate tumours, and the NUMB–NOTCH interaction regulates cell fate. NUMB has potential both as a target for control of prostate tumorigenesis and as a biomarker for identification of patients with prostate cancer who are likely to benefit from NOTCH inhibition.

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“…The peptide mixtures were analyzed by matrixassisted laser-desorption ionization-time-of-flight (MALDI-ToF) mass spectrometry (AutoFlexII, BrukerDaltonics) and the resulting peptide mass fingerprints were used to identify proteins with the Mascot search engine (Palermo et al, 2012).…”

Section: Protein Identification By Mass Spectrometry Analysismentioning

confidence: 99%

Nuclear accumulation of mRNAs underlies G4C2 repeat-induced translational repression in a cellular model of C9orf72 ALS

Rossi

Serrano

Gerbino

et al. 2015

Journal of Cell Science

108

129

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A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2) 31 repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2) 31 repeats widely affected the distribution of Pur-alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra-cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and contribute to the pathogenesis of C9orf72 ALS.

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Acetylation controls Notch3 stability and function in T-cell leukemia

Cited by 54 publications

References 42 publications

Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

NUMB inhibition of NOTCH signalling as a therapeutic target in prostate cancer

Nuclear accumulation of mRNAs underlies G4C2 repeat-induced translational repression in a cellular model of C9orf72 ALS

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