PMID: 33550096 RLIMS-P 2 Check other iTextMine results Issue Report
Title
| 1. | Alternative regulation of HIF-1α stability through Phosphorylation on Ser451. |
Abstract
| 2. | The hypoxia-inducible factor (HIF-1α) functions as a master regulator of oxygen homeostasis. |
| 3. | Oxygen-dependent hydroxylation of HIF-1α is tightly regulated by prolyl hydroxylase domain containing proteins (PHD1, PHD2, and PHD3). |
| 4. | The prolyl hydroxylation facilitates the recruitment of the von Hippel-Lindau (VHL) protein, leading to ubiquitination and degradation of HIF-1α by the proteasomes. |
| 5. | Besides prolyl hydroxylation, phosphorylation of HIF-1α is another central post-translational modification, which regulates its stability under hypoxic conditions as well as normoxic conditions. |
| 6. | By use of LC/MS/MS-based analysis, we were able to identify a specific serine residue (Ser451) of HIF-1α phosphorylated under hypoxic conditions. |
| 7. | Using plasmids expressing wild type (WT), non-phosphorylatable mutant HIF-1α (S451A), and phosphomimetic mutant HIF-1α (S451E), we demonstrated that the phosphorylation at Ser451 is important in maintaining the HIF-1α protein stability. |
| 8. | Notably, phosphorylation at S451 interrupts the interaction of HIF-1α with PHD and pVHL. |
| 9. | A phosphomimetic construct of HIF-1α at Ser451 (S451E) is significantly more stable than WT HIF-1α under normoxic conditions. |
| 10. | Cells transfected with unphosphorylatable HIF-1α exhibited significantly lower HIF-1 transcriptional activity than WT cells and markedly reduced tumor cell migration. |
| 11. | Further, tumors derived from the phosphomimetic mutant cells grew faster, whereas the tumors derived from non-phosphorylatable mutant cells grew slower than the control tumors, suggesting that the phosphorylation of HIF-1α at the Ser451 site is critical to promote tumor growth in vivo. |
| 12. | Taken together, our data suggest an alternative mechanism responsible for the regulation of HIF-1α stability. |
Loading...
Loading data