Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.21.69 (
APC
)
16,337
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The F-box protein
FBXO31
is a tumor suppressor that is encoded in 16q24.3, for which there is loss of heterozygosity in various solid tumors.
FBXO31
serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2.
FBXO31
levels are normally low but increase substantially following genotoxic stress through a mechanism that remains to be determined. Here we show that the low levels of
FBXO31
are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (
APC
/C). We find that the
APC
/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in
FBXO31
to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of
FBXO31
on serine-33 by the prosurvival kinase AKT. Following genotoxic stress, phosphorylation of
FBXO31
on serine-278 by another kinase, the DNA damage kinase ATM, results in disruption of its interaction with CDH1 and CDC20, thereby preventing
FBXO31
degradation. Collectively, our results reveal how alterations in
FBXO31
phosphorylation, mediated by AKT and ATM, underlie physiological regulation of
FBXO31
levels in unstressed and genotoxically stressed cells.
...
PMID:Degradation of FBXO31 by APC/C is regulated by AKT- and ATM-mediated phosphorylation. 2934 41
