p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis

Li, Le; Mao, Youxiang; Zhao, Lei; Li, Lijia; Wu, Jinjun; Zhao, Mingguo; Du, Wenjing; Liu, Yü; Jiang, Peng

doi:10.1038/s41586-019-0996-7

Cited by 117 publications

(93 citation statements)

References 25 publications

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“…The p53 mediated inhibition of the urea cycle effects tumor growth, increasing ammonia levels. Indeed, ammonia accumulation restrains polyamine biosynthesis, that is required for cell proliferation, by suppressing the translation of ODC1 mRNA, that codify for rate-limiting enzyme of polyamine biosynthesis [45].…”

Section: Regulation Of Metabolismmentioning

confidence: 99%

p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms

Pitolli

Wang

Candi

et al. 2019

Cancers

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The tumor suppressor p53 regulates different cellular pathways involved in cell survival, DNA repair, apoptosis, and senescence. However, according to an increasing number of studies, the p53-mediated canonical DNA damage response is dispensable for tumor suppression. p53 is involved in mechanisms regulating many other cellular processes, including metabolism, autophagy, and cell migration and invasion, and these pathways might crucially contribute to its tumor suppressor function. In this review we summarize the canonical and non-canonical functions of p53 in an attempt to provide an overview of the potentially crucial aspects related to its tumor suppressor activity.

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Section: Regulation Of Metabolismmentioning

confidence: 99%

p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms

Pitolli

Wang

Candi

et al. 2019

Cancers

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“…While p53-dependent apoptosis and cell cycle arrest are not required for p53-dependent tumor suppression (Janic et al, 2018), they could collaborate with DNA repair pathways to maintain genomic stability and tumor suppression (Janic et al, 2018). In addition, p53 plays complex roles in cellular metabolism, contributing to p53-dependent genomic stability and tumor suppression (Labuschagne et al, 2018;Kim et al, 2019;Li et al, 2019). In the absence of stresses, the activity of p53 is inhibited by MDM2 and MDMX, two transcriptional targets of p53, through protein-protein interaction (Hollstein et al, 1991;Kawamura et al, 2009;Marión et al, 2009;Lee et al, 2012).…”

Section: Tumor Suppressor P53mentioning

confidence: 99%

Functions of p53 in pluripotent stem cells

et al. 2019

Protein Cell

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Pluripotent stem cells (PSCs) are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body, and thus hold great promise for regenerative medicine. To achieve their clinical potential, it is critical for PSCs to maintain genomic stability during the extended proliferation. The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells. In response to DNA damage or oncogenic stress, p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest, apoptosis, and senescence to prevent the passage of genetic mutations to the daughter cells. p53 is also required to maintain the genomic stability of PSCs. However, in response to the genotoxic stresses, a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency, providing mechanisms to maintain the genomic stability of the self-renewing PSCs. In addition, the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress. In summary, the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.

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“…For example, p53 of humans and zebrafish are both transrepressor against hypoxia (Feng et al, 2011). Hence, our studies suggest a general mechanism for p53 transcriptional repression activity, which is not rare (Jiang et al, 2015;Li et al, 2019;Wang et al, 2016).…”

Section: Discussionmentioning

confidence: 62%

Mammalian-unique eIF4E2 maintains GSK3β proline kinase activity to resist senescence against hypoxia

Zhang

Sun

et al. 2020

Preprint

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Cellular senescence is a stable state of cell cycle arrest elicited by various stresses. Hypoxia modulates senescence, but its consequences and implications in living organisms remains unknown. Here we identified the eIF4E2-GSK3β pathway regulated by hypoxia to maintain p53 proline-directed phosphorylation (S/T-P) to prevent senescence. We previously knew that GSK3β activates p53 translation through phosphorylation of RBM38 Ser195 (-Pro196). Unexpectedly, eIF4E2 directly binds to GSK3β via a conserved motif, mediating Ser195 phosphorylation. Phosphoproteomics revealed that eIF4E2-GSK3β specifically regulates proline-directed phosphorylation. Peptide e2-I or G3-I that disrupts this pathway dephosphorylates p53 at multiple S/T-P, which accelerate senescence by transcriptional suppressing TOPBP1 and TRX1. Consistently, peptides induce liver senescence that is rescued by TOPBP1 expression, and mediate senescence-dependent tumor regression. Furthermore, hypoxia inhibits eIF4E2-GSK3β. Inspiringly, eIF4E2-GSK3β is unique to mammals, which maintains mice viability and prevents liver senescence against physiological hypoxia. Interestingly, this mammalian eIF4E2 protects heart of zebrafish against hypoxia. Together, we identified a mammalian -unique eIF4E2-GSK3β pathway preventing senescence and guarding against hypoxia in vivo.

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p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis

Cited by 117 publications

References 25 publications

p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms

p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms

Functions of p53 in pluripotent stem cells

Mammalian-unique eIF4E2 maintains GSK3β proline kinase activity to resist senescence against hypoxia

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