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)
Expression of
P-glycoprotein
(
P-gp
)/ABCB1 on cancer cell surfaces is a critical determinant of anticancer drug resistance. Regulators of
P-gp
expression and function are key molecules controlling drug resistance. Here we report the mechanism underlying the ubiquitin-proteasome pathway-mediated degradation of
P-gp
. The proteasome inhibitor MG132 increased the
P-gp
level, enhanced its ubiquitination, and delayed the disappearance of the ubiquitinated
P-gp
. To search for regulators of
P-gp
ubiquitination, MALDI-time of flight mass spectrometry analyses were carried out, and 22 candidates were identified as
P-gp
binding partners. Among them,
FBXO15
/Fbx15 is known as an F-box protein in the ubiquitin E3 ligase complex, Skp1-Cullin1-
FBXO15
(SCF(Fbx15) ); therefore, we further studied the involvement of
FBXO15
on
P-gp
degradation. Coprecipitation assays revealed that
FBXO15
bound to
P-gp
. We screened ubiquitin-conjugating enzyme E2s that bind to
FBXO15
and
P-gp
; Ube2r1/Cdc34/Ubc3 was found to be a binding partner. Exogenous
FBXO15
expression enhanced
P-gp
ubiquitination, but
FBXO15
knockdown suppressed it.
FBXO15
knockdown increased
P-gp
expression without affecting its mRNA level. Ube2r1 knockdown decreased
P-gp
ubiquitination, and simultaneous knockdown of Ube2r1 with
FBXO15
further suppressed the ubiquitination. Ube2r1 knockdown increased
P-gp
expression, suggesting that Ube2r1 is a partner of
FBXO15
in
P-gp
ubiquitination.
FBXO15
knockdown enhanced vincristine resistance and lowered intracellular levels of rhodamine 123. These data suggest that
FBXO15
and Ube2r1 regulate
P-gp
expression through the ubiquitin-proteasome pathway.
...
PMID:FBXO15 regulates P-glycoprotein/ABCB1 expression through the ubiquitin--proteasome pathway in cancer cells. 2346 77
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
