Prolyl hydroxylase 3 stabilizes the p53 tumor suppressor by inhibiting the p53-MDM2 interaction in a hydroxylase-independent manner.

Prolyl hydroxylase 3 (PHD3) has initially been reported to hydroxylase hypoxia-inducible factor ? (HIF?) and mediate HIF? degradation. More recent studies have shown that, in addition to HIF?, PHD3 has also other substrates. Moreover, pHD3 is believed to act as a tumor suppressor, but the underlying mechanism remains to be ...
elucidated. Here, we demonstrate that PHD3 stabilizes p53 in a hydroxylase-independent manner. We found that PHD3 overexpression increases and PHD3 knockdown decreases p53 levels. Mechanistically, PHD3 bound MDM2 proto-oncogene (MDM2) and prevented MDM2 from interacting with p53, thereby inhibiting MDM2-mediated p53 degradation. Interestingly, we found that PHD3 overexpression could enhance p53 in the presence of the prolyl hydroxylase inhibitor dimethyloxalylglycine, and the prolyl hydroxylase activity-deficient variant PHD3-H196A also inhibited the p53-MDM2 interaction and stabilized p53. Genetic ablation of PHD3 decreased p53 protein levels in mice intestinal epithelial cells, but a genetic knockin of PHD3-H196A did not affect p53 protein levels in vivo These results suggest that the prolyl hydroxylase activity of PHD3 is dispensable for its ability to stabilize p53. We found that both PHD3 and PHD3-H196A suppress the expression of the stem cell-associated gene NANOG and inhibited the properties of colon cancer stem cells through p53. Our results reveal an additional critical mechanism underlying the regulation of p53 expression and highlight that PHD3 plays a role in the suppression of colon cancer cell stemness in a hydroxylase-independent manner.
Mesh Terms:
Animals, Colonic Neoplasms, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplastic Stem Cells, Procollagen-Proline Dioxygenase, Proto-Oncogene Proteins c-mdm2, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Ubiquitination
J. Biol. Chem.
Date: Dec. 21, 2018
Download 5 Interactions For This Publication
222173
Switch View:
  • Interactions 5