Non-degradative ubiquitination of the Notch1 receptor by the E3 ligase MDM2 activates the Notch signalling pathway

Pettersson, Susanne; Sczaniecka, Matylda; McLaren, Lorna; Russell, Fiona Margaret M; Gladstone, Karen; Hupp, Ted R.; Wallace, Maura

doi:10.1042/bj20121249

Cited by 48 publications

(54 citation statements)

References 39 publications

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“…PanIN2/3 lesions and PDAC also exhibited elevated nuclear HES1, indicating active Notch signaling, a feature not obvious in chronic pancreatitis (Figure 1A). Expression of MDM2, which is mainly known as a negative regulator of p53 but has numerous other functions including Notch signaling activation (Fahraeus and Olivares-Illana, 2014; Pettersson et al, 2013), was also upregulated in human pancreatitis and PDAC (Figure 1A and S1A). MDM2 expression correlated with p62, NRF2 and NQO1 (R = 0.359, p < 0.001; R = 0.559, p < 0.001; and R = 0.403 and p < 0.001, respectively), suggesting a link between MDM2 and the p62-NRF2 axis.…”

Section: Resultsmentioning

confidence: 99%

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

et al. 2017

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SUMMARY Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors such as chronic pancreatitis, acinar cell damage and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals.

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Section: Resultsmentioning

confidence: 99%

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

et al. 2017

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“…MDM2 AD also provides a second binding site to p53 and Notch, thus leading to the suggestion of a two-site binding model for these interactions (21,22). The MDM2 AD binds to p53 core domain with measurable affinity in pulldown and ITC assays, induces a Pab240-reactive conformational change, and inhibits p53 DNA binding in the full-length complex (14,15).…”

Section: Discussionmentioning

confidence: 99%

Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding

Wei

Song

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The MDMX oncoprotein is an important regulator of tumor suppressor p53 activity during embryonic development. Despite sequence homology to the ubiquitin E3 ligase MDM2, MDMX depletion activates p53 without significant increase in p53 level, implicating a degradation-independent mechanism. We present evidence that MDMX inhibits the sequence-specific DNA binding activity of p53. This function requires the cooperation between MDMX and CK1α, and phosphorylation of S289 on MDMX. Depletion of MDMX or CK1α increases p53 DNA binding without stabilization of p53. A proteolytic fragment release assay revealed that in the MDMX-p53 complex, the MDMX acidic domain and RING domain interact stably with the p53 DNA binding domain. These interactions are referred to as secondary interactions because they only occur after the canonicalspecific binding between the MDMX and p53 N termini, but exhibit significant binding stability in the mature complex. CK1α cooperates with MDMX to inhibit p53 DNA binding by further stabilizing the MDMX acidic domain and p53 core domain interaction. These results suggest that secondary intermolecular interaction is important in p53 regulation by MDMX, which may represent a common phenomenon in complexes containing multidomain proteins.T he p53 tumor suppressor is a transcription factor that plays critical roles in promoting DNA repair, cell cycle arrest, or apoptosis in response to various types of damage and stress (1). p53 binds to specific DNA sequences as a tetramer. The core domain involved in DNA binding has poor thermostability and can undergo rapid spontaneous denaturation at physiological temperatures (2). Single amino acid mutations in the p53 DNA binding domain occur in more than 50% of human tumors, resulting in p53 misfolding and accumulation to high levels (3-5). The p53 mutants found in tumors are generally deficient for DNA binding and fail to regulate expression of its target genes.p53 is present at low levels in unstressed tissues because of rapid turnover. This regulation is achieved mainly through MDM2 binding to p53 and acting as an ubiquitin E3 ligase to promote its proteasomal degradation (6, 7). MDMX is a p53 binding protein with strong sequence homology to MDM2 (8). Similar to MDM2, MDMX can bind to p53 N-terminal transactivation domain and inhibit p53 transactivation of target genes (9). However, MDMX lacks robust ubiquitin ligase activity and is unable to target p53 for proteasomal degradation. The prevailing view is that MDMX mainly functions by regulating p53 transcriptional activity, whereas MDM2 regulates p53 degradation (10). MDMX forms a heterodimer with MDM2 through the C-terminal RING domains. An important role of MDMX-MDM2 interaction is the regulation of MDMX stability. MDMX level is controlled by MDM2-mediated ubiquitination in a stressdependent fashion (11, 12). Significant degradation of MDMX occurs after DNA damage through phosphorylation on several C-terminal sites, with S367 phosphorylation by Chk2 being most critical (13). MDMX knockdown in cell culture ge...

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“…Recently, Mdm2 (Murine double minute), another E3 ubiquitin ligase of the RING family known as a main regulator of p53 tumor suppressor protein, has been proposed to play a role in Notch signaling: first by upregulating the ubiquitination of Numb [91], leading to Numb degradation, and thus indirectly to an increase of Notch signaling; second by directly targeting Notch 1, resulting in stabilization and activation of NIC [92]. However another study proposes Notch 4 to be a substrate for Mdm2-mediated ubiquitination and degradation, in a manner inversely proportional to the quantity of p53 protein in the cell [93].…”

Section: How Ubiquitinations Regulate Notch Pathwaymentioning

confidence: 99%

Ubiquitinations in the Notch Signaling Pathway

Moretti

Brou

2013

IJMS

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The very conserved Notch pathway is used iteratively during development and adulthood to regulate cell fates. Notch activation relies on interactions between neighboring cells, through the binding of Notch receptors to their ligands, both transmembrane molecules. This inter-cellular contact initiates a cascade of events eventually transforming the cell surface receptor into a nuclear factor acting on the transcription of specific target genes. This review highlights how the various processes undergone by Notch receptors and ligands that regulate the pathway are linked to ubiquitination events.

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Non-degradative ubiquitination of the Notch1 receptor by the E3 ligase MDM2 activates the Notch signalling pathway

Cited by 48 publications

References 39 publications

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding

Ubiquitinations in the Notch Signaling Pathway

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