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MG132

About: MG132 is a research topic. Over the lifetime, 1499 publications have been published within this topic receiving 56589 citations. The topic is also known as: MG132 & Z-Leu-leu-leu-al.


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Journal ArticleDOI
TL;DR: Data indicate that JNK is critical for the cell death caused by proteasome inhibitors, and pretreatment with MG132 reduced JNK-dependent apoptosis caused by heat shock or ethanol, but it was unable to block J NK-independent apoptosis induced by TNFα.

312 citations

Journal ArticleDOI
TL;DR: It is shown that NADH quinone oxidoreductase 1 (NQO1) regulates p53 stability and plays an important role in regulating p53 functions by inhibiting its degradation.
Abstract: The tumor suppressor gene wild-type p53 encodes a labile protein that accumulates in cells after different stress signals and can cause either growth arrest or apoptosis One of the p53 target genes, p53-inducible gene 3 (PIG3), encodes a protein with significant homology to oxidoreductases, enzymes involved in cellular responses to oxidative stress and irradiation This fact raised the possibility that cellular oxidation-reduction events controlled by such enzymes also may regulate the level of p53 Here we show that NADH quinone oxidoreductase 1 (NQO1) regulates p53 stability The NQO1 inhibitor dicoumarol caused a reduction in the level of both endogenous and gamma-irradiation-induced p53 in HCT116 human colon carcinoma cells This reduction was prevented by the proteasome inhibitors MG132 and lactacystin, suggesting enhanced p53 degradation in the presence of dicoumarol Dicoumarol-induced degradation of p53 also was prevented in the presence of simian virus 40 large T antigen, which is known to bind and to stabilize p53 Cells overexpressing NQO1 were resistant to dicoumarol, and this finding indicates the direct involvement of NQO1 in p53 stabilization NQO1 inhibition induced p53 degradation and blocked wild-type p53-mediated apoptosis in gamma-irradiated normal thymocytes and in M1 myeloid leukemic cells that overexpress wild-type p53 Dicoumarol also reduced the level of p53 in its mutant form in M1 cells The results indicate that NQO1 plays an important role in regulating p53 functions by inhibiting its degradation

302 citations

Journal ArticleDOI
TL;DR: Inhibitory AhR-ERα cross talk is linked to a novel pathway for degradation of ERα in which TCDD initially induces formation of a nuclear AhR complex which coordinately recruits ERα and the proteasome complex, resulting in degradation of both receptors.
Abstract: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) ligands suppress 17beta-estradiol (E)-induced responses in the rodent uterus and mammary tumors and in human breast cancer cells. Treatment of ZR-75, T47D, and MCF-7 human breast cancer cells with TCDD induces proteasome-dependent degradation of endogenous estrogen receptor alpha (ERalpha). The proteasome inhibitors MG132, PSI, and PSII inhibit the proteasome-dependent effects induced by TCDD, whereas the protease inhibitors EST, calpain inhibitor II, and chloroquine do not affect this response. ERalpha levels in the mouse uterus and breast cancer cells were significantly lower after cotreatment with E plus TCDD than after treatment with E or TCDD alone, and our results indicate that AhR-mediated inhibition of E-induced transactivation is mainly due to limiting levels of ERalpha in cells cotreated with E plus TCDD. TCDD alone or in combination with E increases formation of ubiquitinated forms of ERalpha, and both coimmunoprecipitation and mammalian two-hybrid assays demonstrate that TCDD induces interaction of the AhR with ERalpha in the presence or absence of E. In contrast, E does not induce AhR-ERalpha interactions. Thus, inhibitory AhR-ERalpha cross talk is linked to a novel pathway for degradation of ERalpha in which TCDD initially induces formation of a nuclear AhR complex which coordinately recruits ERalpha and the proteasome complex, resulting in degradation of both receptors.

301 citations

Journal ArticleDOI
TL;DR: Evidence is provided that PKC theta is functionally coupled to CD28 costimulation by virtue of its selective ability to activate the CD28RE/activator protein-1 (AP-1) element in the IL-2 gene promoter, which identifies a unique PKCtheta-mediated pathway for the costimulatory action of CD28, which involves activation of the IkappaB-kinase beta/IkappaB/NF-kappa B-signaling cascade.
Abstract: Protein kinase C-theta (PKCtheta) is a Ca(2+)-independent member of the PKC family that is selectively expressed in skeletal muscle and T lymphocytes and plays an important role in T cell activation. However, the molecular basis for the important functions of PKCtheta in T cells and the manner in which it becomes coupled to the T cell receptor-signaling machinery are unknown. We addressed the functional relationship between PKCtheta and CD28 costimulation, which plays an essential role in T cell receptor-mediated IL-2 production. Here, we provide evidence that PKCtheta is functionally coupled to CD28 costimulation by virtue of its selective ability to activate the CD28RE/activator protein-1 (AP-1) element in the IL-2 gene promoter. First, CD28 costimulation enhanced the membrane translocation and catalytic activation of PKCtheta. Second, among several PKC isoforms, PKCtheta was the only one capable of activating NF-kappaB or CD28RE/AP-1 reporters in T cells (but not in 293T cells). Third, wild-type PKCtheta synergized with CD28/CD3 signals to activate CD28RE/AP-1. In addition, PKCtheta selectively synergized with Tat to activate a CD28RE/AP-1 reporter. Fourth, CD3/CD28-induced CD28RE/AP-1 activation and NF-kappaB nuclear translocation were blocked by a selective PKCtheta inhibitor. Last, PKCtheta-mediated activation of the same reporter was inhibited by the proteasome inhibitor MG132 (which blocks IkappaB degradation) and was found to involve IkappaB-kinase beta. These findings identify a unique PKCtheta-mediated pathway for the costimulatory action of CD28, which involves activation of the IkappaB-kinase beta/IkappaB/NF-kappaB-signaling cascade.

297 citations

Journal ArticleDOI
TL;DR: Inhibition of proteasomal degradation of AhR increases the amount of the nuclear AhR·Arnt complex and “superinduces” the expression of endogenous CYP1A1 gene by TCDD, indicating that the proteasome degradation ofAhR serves as a mechanism for controlling the activity of the activated receptor.

289 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202386
202270
202157
202059
201962
201848