AI Article Synopsis
- The study investigates the role of GREB1, an enzyme induced by ERα, in the O-GlcNAcylation of ERα, which affects its stability and transcriptional activity.
- It highlights that O-GlcNAcylation at specific residues prevents ERα from being targeted for degradation by ubiquitin ligase, leading to sustained levels of the reproductive hormone receptor.
- The research also suggests that increased GREB1 expression in ERα-positive breast cancer can improve treatment outcomes with tamoxifen and indicates that GREB1 is a significant player in the glycosylation process in mammalian cells.
Article Abstract
What covalent modifications control the temporal ubiquitination of ERα and hence the duration of its transcriptional activity remain poorly understood. We show that GREB1, an ERα-inducible enzyme, catalyzes O-GlcNAcylation of ERα at residues T553/S554, which stabilizes ERα protein by inhibiting association with the ubiquitin ligase ZNF598. Loss of GREB1-mediated glycosylation of ERα results in reduced cellular ERα levels and insensitivity to estrogen. Higher expression in ERα breast cancer is associated with greater survival in response to tamoxifen, an ERα agonist. Mice lacking exhibit growth and fertility defects reminiscent of phenotypes in ERα-null mice. In summary, this study identifies GREB1, a protein with an evolutionarily conserved domain related to DNA-modifying glycosyltransferases of bacteriophages and kinetoplastids, as the first inducible and the only other (apart from OGT) O-GlcNAc glycosyltransferase in mammalian cytoplasm and ERα as its first substrate.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968844 | PMC |
| http://dx.doi.org/10.1126/sciadv.abe2470 | DOI Listing |
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