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:3.6.3.44 (
P-glycoprotein
)
13,344
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
P-glycoprotein
(
P-gp
) is a critical determinant of multidrug resistance in cancer. We previously reported that MAPK inhibition downregulates
P-gp
expression and that
P-gp
undergoes ubiquitin-proteasomal degradation regulated by UBE2R1 and SCF
Fbx15
. Here, we investigated the crosstalk between MAPK inhibition and the ubiquitin-proteasomal degradation of
P-gp
. Proteasome inhibitors or knockdown of FBXO15 and/or UBE2R1 cancelled MEK inhibitor-induced
P-gp
downregulation.
RSK1
phosphorylated Thr162 on UBE2R1 but did not phosphorylate FBXO15. MEK and RSK inhibitors increased UBE2R1-WT but not UBE2R1-T162D and -T162A expression. UBE2R1-T162D showed higher self-ubiquitination and destabilisation than UBE2R1-WT and -T162A. Unlike UBE2R1-WT and -T162A, UBE2R1-T162D did not induce
P-gp
ubiquitination. UBE2R1-WT or -T162A downregulated
P-gp
expression and upregulated rhodamine 123 level and sensitivity to vincristine and doxorubicin. However, UBE2R1-T162D did not confer any change in
P-gp
expression, rhodamine 123 accumulation and sensitivity to the drugs. These results suggest that
RSK1
protects
P-gp
against ubiquitination by reducing UBE2R1 stability.
...
PMID:RSK1 protects P-glycoprotein/ABCB1 against ubiquitin-proteasomal degradation by downregulating the ubiquitin-conjugating enzyme E2 R1. 2778 5
