Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis

Carr, Michael I.; Roderick, Justine E.; Gannon, Hugh S.; Kelliher, Michelle A.; Jones, Stephen N.

doi:10.1016/j.celrep.2016.08.014

Cited by 26 publications

(32 citation statements)

References 69 publications

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“…Intriguingly, while Mdm2-S394 phosphorylation delays lymphomagenesis in E μ- myc transgenic mice, and preventing Mdm2-S394 phosphorylation obviates the need for p53 mutation in Myc-driven tumorigenesis, irradiated Mdm2 S394A mice display increased hematopoietic stem and progenitor cell functions, and decreased radiation-induced lymphomagenesis. These findings document contrasting effects of ATM-Mdm2 signaling on p53 tumor suppression (184). …”

Section: Phosphorylation Of Mdm Proteins By Atmmentioning

confidence: 87%

“…Therefore, ATM phosphorylation of the negative regulator of p53, Mdm2, can profoundly impact p53 stabilization and activation in response to stress in vivo . In a subsequent study using Mdm2 S394A mice we showed that phosphorylation of Mdm2-S394 regulates p53 activity and the DNA damage response in lymphatic tissues in vivo by modulating Mdm2 stability (184). Intriguingly, while Mdm2-S394 phosphorylation delays lymphomagenesis in E μ- myc transgenic mice, and preventing Mdm2-S394 phosphorylation obviates the need for p53 mutation in Myc-driven tumorigenesis, irradiated Mdm2 S394A mice display increased hematopoietic stem and progenitor cell functions, and decreased radiation-induced lymphomagenesis.…”

Section: Phosphorylation Of Mdm Proteins By Atmmentioning

confidence: 99%

“…We have shown Mdm2 phosphorylation to significantly impact the capacity to repopulate bone marrow following irradiation and (in the case of Ser394 phosphorylation) simultaneously protect against lymphomagenesis induced by repeated IR exposure (184). Similar effects have been observed in the absence of appropriate MdmX phosphorylation (176).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

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Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

Carr¹,

Jones²

2016

Transl. Cancer Res.

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The p53 tumor suppressor acts as a guardian of the genome in mammalian cells undergoing DNA double strand breaks induced by a various forms of cell stress, including inappropriate growth signals or ionizing radiation. Following damage, p53 protein levels become greatly elevated in cells and p53 functions primarily as a transcription factor to regulate the expression a wide variety of genes that coordinate this DNA damage response. In cells undergoing high amounts of DNA damage, p53 can promote apoptosis, whereas in cells undergoing less damage, p53 promotes senescence or transient cell growth arrest and the expression of genes involved in DNA repair, depending upon the cell type and level of damage. Failure of the damaged cell to undergo growth arrest or apoptosis, or to respond to the DNA damage by other p53-coordinated mechanisms, can lead to inappropriate cell growth and tumorigenesis. In cells that have successfully responded to genetic damage, the amount of p53 present in the cell must return to basal levels in order for the cell to resume normal growth and function. Although regulation of p53 levels and function is coordinated by many proteins, it is now widely accepted that the master regulator of p53 is Mdm2. In this review, we discuss the role(s) of p53 in the DNA damage response and in tumor suppression, and how post-translational modification of Mdm2 regulates the Mdm2-p53 signaling axis to govern p53 activities in the cell.

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Section: Phosphorylation Of Mdm Proteins By Atmmentioning

confidence: 87%

Section: Phosphorylation Of Mdm Proteins By Atmmentioning

confidence: 99%

Section: Therapeutic Implicationsmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

Carr¹,

Jones²

2016

Transl. Cancer Res.

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“…Since a minimum Mdm2 level is necessary for proper DNA replication, events that lower the amounts of intracellular Mdm2 might confer replication stress. For instance, Mdm2 levels drop in response to DNA damage, through phosphorylation and subsequent autoubiquitination of Mdm2 (45,46). This suggests that impaired DNA replication might occur in response to DNA damage, not only as a direct result of DNA lesions, but also as a consequence of Mdm2 degradation.…”

Section: Discussionmentioning

confidence: 99%

Chromatin modifiers Mdm2 and RNF2 prevent RNA:DNA hybrids that impair DNA replication

Ina

Wohlberedt

Magerhans

et al. 2018

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

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The p53–Mdm2 system is key to tumor suppression. We have recently reported that p53 as well as Mdm2 are capable of supporting DNA replication fork progression. On the other hand, we found that Mdm2 is a modifier of chromatin, modulating polycomb repressor complex (PRC)-driven histone modifications. Here we show that, similar to Mdm2 knockdown, the depletion of PRC members impairs DNA synthesis, as determined in fiber assays. In particular, the ubiquitin ligase and PRC1 component RNF2/Ring1B is required to support DNA replication, similar to Mdm2. Moreover, the Ring finger domain of Mdm2 is not only essential for its ubiquitin ligase activity, but also for proper DNA replication. Strikingly, Mdm2 overexpression can rescue RNF2 depletion with regard to DNA replication fork progression, and vice versa, strongly suggesting that the two ubiquitin ligases perform overlapping functions in this context. H2A overexpression also rescues fork progression upon depletion of Mdm2 or RNF2, but only when the ubiquitination sites K118/K119 are present. Depleting the H2A deubiquitinating enzyme BAP1 reduces the fork rate, suggesting that both ubiquitination and deubiquitination of H2A are required to support fork progression. The depletion of Mdm2 elicits the accumulation of RNA/DNA hybrids, suggesting R-loop formation as a mechanism of impaired DNA replication. Accordingly, RNase H overexpression or the inhibition of the transcription elongation kinase CDK9 each rescues DNA replication upon depletion of Mdm2 or RNF2. Taken together, our results suggest that chromatin modification by Mdm2 and PRC1 ensures smooth DNA replication through the avoidance of R-loop formation.

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“…To understand the role of p53-TIGAR-mediated glycolytic suppression in FA HSCs, we first determined p53 activation in Fanca −/− HSPCs. We observed increased phosphorylation of p53 at Serine 18 (p53 Ser18 ), an established marker for p53 activation [38,39], in Fanca −/− BM LSK cells compared with WT cells (Fig. 3A).…”

Section: P53-tigar Attenuates Ros Dna Damage and Chromosomal Instabmentioning

confidence: 96%

p53-TP53-Induced Glycolysis Regulator Mediated Glycolytic Suppression Attenuates DNA Damage and Genomic Instability in Fanconi Anemia Hematopoietic Stem Cells

Zopp

et al. 2019

Stem Cells

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Emerging evidence have shown that resting quiescent hematopoietic stem cells (HSCs) prefer to utilize anaerobic glycolysis rather than mitochondrial respiration for energy production. Compelling evidence has also revealed that altered metabolic energetics in HSC underlies the onset of certain blood diseases. However, the mechanisms responsible for energetic reprogramming remain elusive. We recently found that Fanconi anemia (FA) HSCs are more dependent on mitochondrial respiration relative to glycolysis in their resting state for energy metabolism. Here we have investigated the role of deficient glycolysis in FA HSC maintenance. We observed significantly reduced glucose consumption, lactate production and ATP production in HSCs but not less primitive multipotent progenitors or restricted hematopoietic progenitors of Fanca−/− and Fancc−/− mice compared to those of wild-type mice, which was associated with an over-activated p53-TIGAR metabolic axis. We have utilized Fanca−/− HSCs deficient for p53 to show that the p53-TIGAR axis suppressed glycolysis in FA HSCs, leading to enhanced pentose phosphate pathway and cellular antioxidant function, and consequently reduced DNA damage and attenuated HSC exhaustion. Furthermore, by using Fanca−/− HSCs carrying the separation-of-function mutant p53R172P transgene that selectively impairs the p53 function in apoptosis but not cell-cycle control, we demonstrated that the cell-cycle function of p53 was not required for glycolytic suppression in FA HSCs. Finally, ectopic expression of the glycolytic rate-limiting enzyme PFKFB3 specifically antagonized p53-TIGAR-mediated metabolic reprogramming in FA HSCs. Together, our results suggest that p53-TIGAR metabolic axis-mediated glycolytic suppression may play a compensatory role in attenuating DNA damage and proliferative exhaustion in FA HSCs.

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Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis

Cited by 26 publications

References 69 publications

Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

Chromatin modifiers Mdm2 and RNF2 prevent RNA:DNA hybrids that impair DNA replication

p53-TP53-Induced Glycolysis Regulator Mediated Glycolytic Suppression Attenuates DNA Damage and Genomic Instability in Fanconi Anemia Hematopoietic Stem Cells

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