Tubular β-catenin and FoxO3 interactions protect in chronic kidney disease

Khodo, Stellor Nlandu; Osaki, Yosuke; Scarfe, Lauren; Yang, Haichun; Phillips-Mignemi, Melanie; Tonello, Jane Marie; Saito-Diaz, Kenyi; Neelisetty, Surekha; Ivanova, Alla V.; Huffstater, Tessa; McMahon, Robert S.; Taketo, Makoto Mark; deCaestecker, Mark; Kasinath, Balakuntalam S.; Harris, Raymond C.; Lee, Ethan; Gewin, Leslie

doi:10.1172/jci.insight.135454

Cited by 23 publications

(15 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this context, Qiao and colleagues revealed in murine models of kidney fibrosis that the inhibition of β-catenin/TCF prevented the profibrotic effects of TGF-β while promoting its anti-inflammatory function via concomitant β-catenin/Foxo1-induction of regulatory T cells (Tregs) (Qiao et al, 2018 , Rao et al, 2019 , Rao et al, 2021 ; Figure 1 ). This has been confirmed by other labs; the β-catenin/Foxo complex induces Tregs (Sumida et al, 2018 ) and protects against kidney fibrosis (Nlandu-Khodo et al, 2020 ).…”

supporting

confidence: 59%

Editorial: TGF-β in Human Disease: Friend or Foe?

Zheng

Harris

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

supporting

confidence: 59%

Editorial: TGF-β in Human Disease: Friend or Foe?

Zheng

Harris

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

“…Before experiments, PT cells were moved to 37°C, and IFN-γ was removed. The PT-enriched primary cells (primary PT cells) were generated as previously described ( 55 ) and incubated using RPMI 1640 containing 5% FBS, PT supplements, and penicillin/streptomycin. To induce hypoxia, primary PT cells were exposed to 1% O 2 in an Invivo2 200 hypoxia chamber (Ruskinn Technologies) for 2, 3, or 7 days.…”

Section: Methodsmentioning

confidence: 99%

Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease

Osaki¹,

Manolopoulou²,

Ivanova³

et al. 2022

JCI Insight

Self Cite

View full text Add to dashboard Cite

and genome-wide association studies identified dachshund homolog 1 (DACH1), which suppresses tubular cell cycle progression, as having protective effects on CKD (7). Though suggestive that ongoing tubular cell cycling may be detrimental, few studies have directly manipulated cell cycle progression in the chronically injured kidney to determine how tubular cell cycle alters tubular injury and fibrosis.Most proximal tubules in the uninjured kidney are quiescent (G0) but, upon injury, reenter the cell cycle at G1, which is the first cell cycle checkpoint. Actively cycling cells progress from G1/S phase (DNA synthesis); then to the second checkpoint, G2; and finally to M (mitosis). Work has established that some tubule cells arrest at G2/M following injury, and these G2-arrested cells play an important role in CKD progression through production of profibrotic growth factors like TGF-β and CTGF (8). However, little is known about the role of cell cycle progression at the G1/S transition in chronically injured tubules. Cyclin dependent kinases 4 and 6 (CDK4/6) combine with cyclin D1 to phosphorylate retinoblastoma protein (Rb), leading to the liberation of E2F, a transcription factor that promotes expression of genes related to G1/S phase progression. The FDA-approved drug palbociclib is a highly selective inhibitor of CDK4/6 that is currently used to treat patients with breast cancer and provides an important tool to assess how G1/S cell cycle progression alters CKD progression.In this manuscript, we use a cell cycle reporter mouse to confirm that cell cycle is persistently altered in the chronically injured proximal tubules. Blocking CDK4/6 in mice after 2 different models of CKD significantly reduced tubular cell cycle progression, ameliorated tubular injury, preserved renal function, and decreased tubulointerstitial fibrosis. Surprisingly, selective tubular deletion of cyclin D1 worsened, rather than improved, tubular injury in murine CKD. Human expression quantitative trait loci (eQTLs) and genome-wide association study (GWAS) data are consistent with the murine studies showing that inhibiting CDK4/6, but not cyclin D1, protects against CKD. Mechanistically, CDK4/6 inhibition reduced proximal tubule cell death through a pathway involving STAT3/IL-1β.

show abstract

“…Interaction between β-catenin and FOXO proteins induces the transcription of genes involved in cell cycle arrest as well as genes that prevent tissue injury [58][59][60].…”

Section: Non-tcf/lef Transcription Partners Of β-Cateninmentioning

confidence: 99%

“…FOXO proteins translocate to the nucleus to facilitate transcription of target genes to directly compete with TCF/LEF for binding to β-catenin. Interaction between β-catenin and FOXO proteins induces the transcription of genes involved in cell cycle arrest as well as genes that prevent tissue injury [ 58 , 59 , 60 ].…”

Section: Nuclear Mediators Of Wnt Signalingmentioning

confidence: 99%

Nuclear Regulation of Wnt/β-Catenin Signaling: It’s a Complex Situation

Anthony

Robbins

Ahmed

et al. 2020

Genes

Self Cite

View full text Add to dashboard Cite

Wnt signaling is an evolutionarily conserved metazoan cell communication pathway required for proper animal development. Of the myriad of signaling events that have been ascribed to cellular activation by Wnt ligands, the canonical Wnt/β-catenin pathway has been the most studied and best understood. Misregulation of Wnt/β-catenin signaling has been implicated in developmental defects in the embryo and major diseases in the adult. Despite the latter, no drugs that inhibit the Wnt/β-catenin pathway have been approved by the FDA. In this review, we explore the least understood step in the Wnt/β-catenin pathway—nuclear regulation of Wnt target gene transcription. We initially describe our current understanding of the importation of β-catenin into the nucleus. We then focus on the mechanism of action of the major nuclear proteins implicated in driving gene transcription. Finally, we explore the concept of a nuclear Wnt enhanceosome and propose a modified model that describes the necessary components for the transcription of Wnt target genes.

show abstract

Tubular β-catenin and FoxO3 interactions protect in chronic kidney disease

Cited by 23 publications

References 74 publications

Editorial: TGF-β in Human Disease: Friend or Foe?

Editorial: TGF-β in Human Disease: Friend or Foe?

Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease

Nuclear Regulation of Wnt/β-Catenin Signaling: It’s a Complex Situation

Contact Info

Product

Resources

About