Trp53 regulates Notch 4 signaling through Mdm2

Sun, Youping; Klauzinska, Malgorzata; Lake, Robert J.; Lee, Joseph M.; Santopietro, Stefania; Raafat, Ahmed; Salomon, David; Callahan, Robert; Artavanis‐Tsakonas, Spyros

doi:10.1242/jcs.068965

Cited by 27 publications

(23 citation statements)

References 66 publications

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“…In keeping with this finding, Notch was recently shown to restore p53 in glioblastoma (43) and to enhance p53 protein levels in hepatocellular carcinoma (44). Activated Notch1 has been reported to directly bind p53 and inhibit its phosphorylation and transactivation (45), and a direct interaction between NICD4, p53, and murine double minute 2 (Mdm2) was recently shown to be important for Mdm2-mediated degradation of Notch (46). Conversely, modulation of p53 levels directly altered Notch levels in hepatocellular carcinoma, and p53 was required for Notch-induced growth and invasiveness (47).…”

Section: Discussionmentioning

confidence: 80%

Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms

Landor

Mutvei

Mamaeva

et al. 2011

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

112

109

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A switch from oxidative phosphorylation to glycolysis is frequently observed in cancer cells and is linked to tumor growth and invasion, but the underpinning molecular mechanisms controlling the switch are poorly understood. In this report we show that Notch signaling is a key regulator of cellular metabolism. Both hyper- and hypoactivated Notch induce a glycolytic phenotype in breast tumor cells, although by distinct mechanisms: hyperactivated Notch signaling leads to increased glycolysis through activation of the phosphatidylinositol 3-kinase/AKT serine/threonine kinase pathway, whereas hypoactivated Notch signaling attenuates mitochondrial activity and induces glycolysis in a p53-dependent manner. Despite the fact that cells with both hyper- and hypoactivated Notch signaling showed enhanced glycolysis, only cells with hyperactivated Notch promoted aggressive tumor growth in a xenograft mouse model. This phenomenon may be explained by that only Notch-hyperactivated, but not -hypoactivated, cells retained the capacity to switch back to oxidative phosphorylation. In conclusion, our data reveal a role for Notch in cellular energy homeostasis, and show that Notch signaling is required for metabolic flexibility.

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Section: Discussionmentioning

confidence: 80%

Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms

Landor

Mutvei

Mamaeva

et al. 2011

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

112

109

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“…Co-immunoprecipitation experiments in p53-null H1299 cells, which endogenously express NICD4 and Mdm2, reveal that NICD4 is a direct Mdm2 target and that this interaction is p53-independent. 109 Interestingly, Mdm2 also ubiquitinates Numb, an antagonist against Notch signaling, leading to its proteasomal degradation. 110 As discussed in the previous section on Mdm2 effectors, several ribosomal proteins (RPs) bind to Mdm2, inhibiting its binding to p53.…”

Section: Downstream Targets Of Mdm2mentioning

confidence: 99%

The Many Faces of MDM2 Binding Partners

Riley¹,

Lozano

2012

Genes & Cancer

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Mdm2 is an essential regulator of the p53 tumor suppressor. Mdm2 is modified at transcriptional, post-transcriptional, and post-translational levels to control p53 activity in normal versus stressed cells. Importantly, errors in these regulatory mechanisms can result in aberrant Mdm2 expression and failure to initiate programmed cell death in response to DNA damage. Such errors can have severe consequences as evidenced by tumor phenotypes resulting from amplification at the Mdm2 locus and changes in post-transcriptional and post-translational regulation of Mdm2. Although Mdm2 mediated inhibition of p53 is well characterized, Mdm2 interacts with many additional proteins and also targets many of these for proteosomal degradation. Mdm2 also has E3-ligase independent functions and p53-independent functions that have important implications for genome stability and cancer.

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“…Although p53 is considered the primary target of MDM2, there are other substrates for this E3-ligase; for example, MDM2 has been shown to promote the degradation of human telomerase reverse transcriptase (hTERT), PCNA, Notch4, and Slug. [39][40][41][42][43] For 2 of these substrates, Notch4 and Slug, p53 has been reported to be part of a trimeric complex (i.e., Notch4-MDM2-p53 or Slug-MDM2-p53), in which p53 plays a key role in regulating their degradation. [41][42][43] Thus, mutations that abrogate the interaction between p53 and MDM2 could presumably disrupt the formation of these trimeric complexes, resulting in the stabilization of Notch4 and Slug.…”

Section: Discussionmentioning

confidence: 99%

“…[39][40][41][42][43] For 2 of these substrates, Notch4 and Slug, p53 has been reported to be part of a trimeric complex (i.e., Notch4-MDM2-p53 or Slug-MDM2-p53), in which p53 plays a key role in regulating their degradation. [41][42][43] Thus, mutations that abrogate the interaction between p53 and MDM2 could presumably disrupt the formation of these trimeric complexes, resulting in the stabilization of Notch4 and Slug. In a similar manner, mutations in the MDM2 RING domain that disable its ubiquitin ligase activity would retain the capacity to form a trimeric complex between p53 and either Notch4 or Slug, but would be unable to promote their degradation.…”

Section: Discussionmentioning

confidence: 99%

Characterization of cancer-associated missense mutations in MDM2

Chauhan

Gopalakrishnan

Kollareddy

et al. 2015

Molecular & Cellular Oncology

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MDM2 is an E3 ubiquitin ligase that binds the N-terminus of p53 and promotes its ubiquitin-dependent degradation. Elevated levels of MDM2 due to overexpression or gene amplification can contribute to tumor development by suppressing p53 activity. Since MDM2 is an oncogene, we explored the possibility that other genetic lesions, namely missense mutations, might alter its activities. We selected mutations in MDM2 that reside in one of the 4 key regions of the protein: p53 binding domain, acidic domain, zinc finger domain, and the RING domain. Unexpectedly, we observed that individual mutations in several of these domains compromised the ability of MDM2 to degrade p53. Mutations in the N-terminal p53 binding domain prevented the formation of a p53-MDM2 complex, thereby protecting p53 from degradation. Additionally, as would be predicted, several cancer-associated mutations in the RING finger domain disrupted the ubiquitin ligase activity of MDM2 and prevented p53 degradation. Interestingly, we observed that amino acid substitutions at the same codon differentially affected MDM2 activity. Our data reveal that mutations in this oncogene can have the paradoxical effect of suppressing its activity. Further understanding of how these mutations perturb MDM2 function may yield novel approaches to inhibiting its activity.

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Trp53 regulates Notch 4 signaling through Mdm2

Cited by 27 publications

References 66 publications

Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms

Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms

The Many Faces of MDM2 Binding Partners

Characterization of cancer-associated missense mutations in MDM2

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