Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
Gene/Protein
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Query: EC:2.3.1.177 (
BIS
)
957
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
B-cell lymphoma (BCL)-2-interacting cell death suppressor (
BIS
) has diverse cellular functions depending on its binding partners. However, little is known about the effects of biochemical modification of
BIS
on its various activities under oxidative stress conditions. In this study, we showed that H
2
O
2
reduced
BIS
mobility on SDS-polyacrylamide gels in a time-dependent manner via the activation of extracellular signaling-regulated kinase (ERK). The combined results of mass spectroscopy and computational prediction identified Thr285 and Ser289 in
BIS
as candidate residues for phosphorylation by ERK under oxidative stress conditions. Deletion of these sites resulted in a partial reduction in the H
2
O
2
-induced mobility shift relative to that of the wild-type
BIS
protein; overexpression of the deletion mutant sensitized A172 cells to H
2
O
2
-induced cell death without increasing the level of intracellular reactive oxygen species. Expression of the
BIS
deletion mutant decreased the level of heat shock protein (HSP) 70 mRNA following H
2
O
2
treatment, which was accompanied by impaired nuclear translocation of heat shock transcription factor (HSF) 1. Co-immunoprecipitation assays revealed that the binding of wild-type
BIS
to
HSF1
was decreased by oxidative stress, while the binding of the
BIS
deletion mutant to
HSF1
was not affected. These results indicate that ERK-dependent phosphorylation of
BIS
has a role in the regulation of nuclear translocation of
HSF1
likely through modulation of its interaction affinity with
HSF1
, which affects HSP70 expression and sensitivity to oxidative stress.
...
PMID:ERK-mediated phosphorylation of BIS regulates nuclear translocation of HSF1 under oxidative stress. 2765 16
The Bcl-2 family protein, Mcl-1 is known to have anti-apoptotic functions, and depletion of Mcl-1 by cellular stresses favors the apoptotic process. Moreover, Mcl-1 levels are frequently increased in various cancer cells, including non-small cell lung cancer (NSCLC), and is implicated in resistance to conventional chemotherapy and in cancer metastasis. In this study, we demonstrated that KRIBB11 accelerates the proteasomal degradation of Mcl-1 in the NSCLC cell line, A549. While KRIBB11 is an inhibitor of
HSF1
, we found that KRIBB11 induced Mcl-1 degradation in an
HSF1
-independent manner. Furthermore, this process was triggered via increase ubiquitination by the E3 ligase, Mule, rather than via de-ubiquitination by USP9X. Additionally, we found that Mcl-1 levels were only transiently reduced by KRIBB11: Mcl-1 levels were gradually restored as KRIBB11 activity diminished. However, we found that this effect was blocked in
BIS
(Bcl-2 interacting cell death suppressor, also called BAG3)-depleted cells, and that
BIS
prevents Mcl-1 from undergoing HSP70-driven proteasomal degradation, through an interaction with HSP70. Taken together, our results suggest that targeting Mcl-1 with KRIBB11 treatment, while simultaneously downregulating
BIS
, could be a therapeutic strategy in NSCLC.
...
PMID:KRIBB11 accelerates Mcl-1 degradation through an HSF1-independent, Mule-dependent pathway in A549 non-small cell lung cancer cells. 2885 86
