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AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease

Conduit, SE; Davies, EM; Ooms, LM; Gurung, R; McGrath, MJ; Hakim, S; Cottle, DL; ... Mitchell, CA; + view all (2019) AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease. Human Molecular Genetics 10.1093/hmg/ddz232. (In press).

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Abstract

Polycystic kidney disease (PKD) results in the formation of renal cysts that can impair function leading to renal failure. DNA damage accumulates in renal epithelial cells in PKD but the molecular mechanisms are unclear and are investigated here. Phosphoinositide 3- kinase (PI3K)/AKT signaling activates mammalian target of rapamycin complex 1 (mTORC1) and hyperactivation of mTORC1 is a common event in PKD, however, mTORC1 inhibitors have yielded disappointing results in clinical trials. Here we demonstrate AKT and mTORC1 hyperactivation in two representative murine PKD models (renal epithelial-specific Inpp5e knockout and collecting duct-specific Pkd1 deletion) and identify a downstream signaling network that contributes to DNA damage accumulation. Inpp5e- and Pkd1-null renal epithelial cells showed DNA damage including double-stranded DNA breaks associated with increased replication fork numbers, multinucleation and centrosome amplification. mTORC1 activated CAD, which promotes de novo pyrimidine synthesis, to sustain cell proliferation. AKT, but not mTORC1, inhibited the DNA repair/replication fork origin firing regulator TOPBP1, which impacts on DNA damage and cell proliferation. Notably, Inpp5e- and Pkd1-null renal epithelial cell spheroid formation defects were rescued by AKT inhibition. These data reveal that AKT hyperactivation contributes to DNA damage accumulation in multiple forms of PKD and cooperates with mTORC1 to promote cell proliferation. Hyperactivation of AKT may play a causal role in PKD by regulating DNA damage and cell proliferation, independent of mTORC1, and AKT inhibition may be a novel therapeutic approach for PKD.

Type: Article
Title: AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease
DOI: 10.1093/hmg/ddz232
Publisher version: https://doi.org/10.1093/hmg/ddz232
Language: English
Additional information: This is an accepted, peer-reviewed version of the article published in Human Molecular Genetics by Oxford Academic before final editing. The final publisher-authenticated version: "Conduit SE, Davies EM, Ooms LM, Gurung R, McGrath MJ, Hakim S, Cottle DL, Smyth IM, Dyson JM, Mitchell CA. AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease. Human Molecular Genetics. Oct 18, 2019" is available online at: https://doi.org/10.1093/hmg/ddz232.
Keywords: signal transduction, cell proliferation, kidney failure, epithelium, 1-phosphatidylinositol 3-kinase, centrosome, dna damage, dna repair, mammals, phosphatidylinositols, phosphotransferases, polycystic kidney diseases, pyrimidines, kidney, micerenal cystepithelial cells, proto-oncogene proteins c-aktphosphoinositide 3-kinase, amplification, dna replication fork, double-stranded dna breaks, mechanistic target of rapamycin complex 1
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10085672
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