p53 enables metabolic fitness and self-renewal of nephron progenitor cells

Li, Yuwen; Liu, Jiao; Li, Wencheng; Brown, Aaron C.; Baddoo, Melody; Li, Marilyn; Carroll, Thomas J.; Oxburgh, Leif; Feng, Yi; Saifudeen, Zubaida

doi:10.1242/dev.111617

Cited by 32 publications

(32 citation statements)

References 92 publications

(90 reference statements)

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“…For kidney sections, YN1-treated kidneys were fixed in 10% formalin and processed for paraffin embedding and sectioning as previously described. 47 Antibodies against the following proteins were used: Lhx1 (4F2; Developmental Studies Hybridoma Bank), Pax2 (Invitrogen), Six2 (Proteintech), and phosphohistone 3 (Ser10) (Cell Signaling).…”

Section: Embryonic Kidneys and Metanephric Mesenchyme Culture And Immmentioning

confidence: 99%

“…ATPlite (Perkin Elmer) luminescence assay was performed as per the manufacturer's instructions as previously described. 47 This assay is on the basis of light produced by conversion of luciferin by luciferase to oxyluciferin in an ATP-dependent reaction. The emitted light is proportional to ATP concentration in the cell lysate.…”

Section: Measurement Of Atp Levelsmentioning

confidence: 99%

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Regulation of Nephron Progenitor Cell Self-Renewal by Intermediary Metabolism

Liu

Edgington-Giordano

Dugas

et al. 2017

JASN

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Nephron progenitor cells (NPCs) show an age-dependent capacity to balance self-renewal with differentiation. Older NPCs (postnatal day 0) exit the progenitor niche at a higher rate than younger (embryonic day 13.5) NPCs do. This behavior is reflected in the transcript profiles of young and old NPCs. Bioenergetic pathways have emerged as important regulators of stem cell fate. Here, we investigated the mechanisms underlying this regulation in murine NPCs. Upon isolation and culture in NPC renewal medium, younger NPCs displayed a higher glycolysis rate than older NPCs. Inhibition of glycolysis enhanced nephrogenesis in cultured embryonic kidneys, without increasing ureteric tree branching, and promoted mesenchymal-to-epithelial transition in cultured isolated metanephric mesenchyme. Cotreatment with a canonical Wnt signaling inhibitor attenuated but did not entirely block the increase in nephrogenesis observed after glycolysis inhibition. Furthermore, inhibition of the phosphatidylinositol 3-kinase/Akt self-renewal signaling pathway or stimulation of differentiation pathways in the NPC decreased glycolytic flux. Our findings suggest that glycolysis is a pivotal, cell-intrinsic determinant of NPC fate, with a high glycolytic flux supporting self-renewal and inhibition of glycolysis stimulating differentiation.

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Section: Embryonic Kidneys and Metanephric Mesenchyme Culture And Immmentioning

confidence: 99%

Section: Measurement Of Atp Levelsmentioning

confidence: 99%

Regulation of Nephron Progenitor Cell Self-Renewal by Intermediary Metabolism

Liu

Edgington-Giordano

Dugas

et al. 2017

JASN

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“…In support of this idea, p53 or p21 CIP inactivation results in loss of quiescence and exhaustion of long‐term stem cells at advanced ages (Cheng et al ., ; Kippin et al ., ; Meletis et al ., ). Moreover, p53 also maintains the self‐renewal of the nephron progenitor pool in the mouse kidney (Li et al ., ). With regard to the role of the p16 Ink4a , there is no clear conclusion.…”

Section: Increased Arf / P53 Activity In Stem Cellsmentioning

confidence: 97%

Increased Arf/p53 activity in stem cells, aging and cancer

et al. 2017

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SummaryArf/p53 pathway protects the cells against DNA damage induced by acute stress. This characteristic is the responsible for its tumor suppressor activity. Moreover, it regulates the chronic type of stress associated with aging. This is the basis of its anti‐aging activity. Indeed, increased gene dosage of Arf/p53 displays elongated longevity and delayed aging. At a cellular level, it has been recently shown that increased dosage of Arf/p53 delays age‐associated stem cell exhaustion and the subsequent decline in tissue homeostasis and regeneration. However, p53 can also promote aging if constitutively activated. In this context, p53 reduces tissue regeneration, which correlates with premature exhaustion of stem cells. We discuss here the current evidence linking the Arf/p53 pathway to the processes of aging and cancer through stem cell regulation.

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“…BrdU-labelling of proliferating cells in the CM shows decreased BrdU incorporation (green) in the p53-mutant CM. This is modified from Li et al (2015) .…”

Section: Lineage-specific Mdm2 Deletion From the Mmentioning

confidence: 99%

Regulation of kidney development by the Mdm2/Mdm4–p53 axis

El‐Dahr

Hilliard

Saifudeen

2017

Journal of Molecular Cell Biology

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While p53 activity is required for tumour suppression, unconstrained p53 activity on the other hand is detrimental to the organism, resulting in inappropriate cellular death or proliferation defects. Unimpeded p53 activity is lethal in the developing embryo, underlining the need for maintaining a tight control on p53 activity during this period. The critical role of the negative regulators of p53, Mdm2 and Mdm4, in vertebrate development came to light by fatal disruption of embryogenesis that was observed with Mdm2 and Mdm4 gene deletions in mice. Embryonic lethality was rescued only by superimposing p53 removal. Here we summarize the contribution of the Mdm2/Mdm4–p53 axis that occurs at multiple steps of kidney development. Conditional, cell type-specific deletions reveal distinct functions of these proteins in renal morphogenesis. The severe impact on the renal phenotype from targeted gene deletions underscores the critical role played by the Mdm2/Mdm4–p53 nexus on nephrogenesis, and emphasizes the need to monitor patients with aberrations in this pathway for kidney function defects and associated cardiovascular dysfunction.

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p53 enables metabolic fitness and self-renewal of nephron progenitor cells

Cited by 32 publications

References 92 publications

Regulation of Nephron Progenitor Cell Self-Renewal by Intermediary Metabolism

Regulation of Nephron Progenitor Cell Self-Renewal by Intermediary Metabolism

Increased Arf/p53 activity in stem cells, aging and cancer

Regulation of kidney development by the Mdm2/Mdm4–p53 axis

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