Constitutive Androstane Receptor induces Ribonucleotide Reductase-M2 expression and maintains hepatocyte ploidy in mice
Asokaumar, A.; Mathur, B.; Chou, A.; Cronologia, B.; Alencastro, F.; Wheeler, L.; Mathews, C. K.; Moore, D. D.; Duncan, A. W.; Anakk, S.
Show abstract
The nuclear receptor Constitutive Androstane Receptor (CAR/NR1i3) is known for regulating various liver functions, including detoxification, nutrient metabolism, and hepatocyte proliferation. While CAR activation has been previously linked to higher ploidy, the underlying mechanisms are not fully known. Here, we uncover a basal role for CAR in maintaining hepatocyte ploidy, such that CAR deletion increases the number of diploid (2c) hepatocytes with a concomitant reduction in tetraploid (4c) hepatocytes. We demonstrate that CAR controls the de novo dNTP synthesis by directly transactivating the Ribonucleotide reductase-M2 (RRM2) gene, which encodes the rate-limiting catalytic subunit of the enzyme, ribonucleotide reductase. Further, we find that the ligand-dependent CAR activation is sufficient to induce several genes involved in the de novo dNTP synthesis pathways, resulting in higher hepatic dATP and dTTP levels within the liver. Importantly, overexpressing RRM2 levels in CAR knockouts led to increased DNA synthesis and tetraploid (4c) hepatocytes compared to the control mice. Taken together, these findings reveal that the CAR-mediated RRM2 regulation contributes towards DNA synthesis and thereby maintains hepatocyte ploidy.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria 96%
- Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver 96%
- Endonucleosis mediates internalization of cytoplasm into the nucleus in senescent cells 96%
Similar papers in this journal
Similar papers in this journal
- The dynamic chromatin architecture of the regenerating liver 96%
- Patient induced pluripotent stem cell-derived hepatostellate organoids establish a basis for liver pathologies in telomeropathies 96%
- Activation of proneuronal transcription factor Ascl1 in maternal liver ensures a healthy pregnancy 94%
Similar papers in this journal
- The beta-catenin-target Fascin-1, altering hepatocyte differentiation, is a new marker of immature cells in hepatoblastomas 95%
- p53 and TIGAR promote redox control to protect against metabolic dysfunction-associated steatohepatitis 94%
- A single-cell fixed RNA profiling of liver fibrosis progression and regression reveals SEMA4D and LMCD1 as key mediators of fibrogenesis 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.