Topic
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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TL;DR: Data is presented to show that both 4-OH and 4'-OH are critical for the ability of 4, 4'-DHS to induce down-regulation of ER alpha and suggest that 4,4'- DHS provides a useful scaffold for development of novel ER alpha antagonists.
19 citations
TL;DR: It is shown that the presence of an intact p53 pathway significantly enhances cytotoxic activity, thus suggesting that this tumor suppressor is a critical downstream mediator of cell death following proteasomal inhibition.
Abstract: The 26S proteasome has emerged over the past decade as an attractive therapeutic target in the treatment of cancers. Here, we report new tripeptide aldehydes that are highly specific for the chymotrypsin-like catalytic activity of the proteasome. These new specific proteasome inhibitors demonstrated high potency and specificity for sarcoma cells, with therapeutic windows superior to those observed for benchmark proteasome inhibitors, MG132 and Bortezomib. Constraining the peptide backbone into the β-strand geometry, known to favor binding to a protease, resulted in decreased activity in vitro and reduced anticancer activity. Using these new proteasome inhibitors, we show that the presence of an intact p53 pathway significantly enhances cytotoxic activity, thus suggesting that this tumor suppressor is a critical downstream mediator of cell death following proteasomal inhibition.
19 citations
TL;DR: The characterization of HSF2 from an evolutionary ancient vertebrate, the fish rainbow trout, is reported and rtHSF2 appears closely related to its mammalian counterparts at structural and functional levels.
19 citations
TL;DR: Results indicated that the phosphorylation of TPH was a prerequisite for proteasome-driven TPH degradation, and was digested more rapidly in the cell-free prote asome system than was the nonphosphorylated enzyme.
Abstract: We previously demonstrated in mast cell lines RBL2H3 and FMA3 that tryptophan hydroxylase (TPH) undergoes very fast turnover driven by 26S-proteasomes [Kojima, M., Oguro, K., Sawabe, K., Iida, Y., Ikeda, R., Yamashita, A., Nakanishi, N. & Hasegawa, H. (2000) J.Biochem (Tokyo) 2000, 127, 121–127]. In the present study, we have examined an involvement of TPH phosphorylation in the rapid turnover, using non-neural TPH. The proteasome-driven degradation of TPH in living cells was accelerated by okadaic acid, a protein phosphatase inhibitor. Incorporation of 32 P into a 53-kDa protein, which was judged to be TPH based on autoradiography and Western blot analysis using anti-TPH serum and purified TPH as the size marker, was observed in FMA3 cells only in the presence of both okadaic acid and MG132, inhibitors of protein phosphatase and proteasome, respectively. In a cell-free proteasome system constituted mainly of RBL2H3 cell extracts, degradation of exogenous TPH isolated from mastocytoma P-815 cells was inhibited by protein kinase inhibitors KN-62 and K252a but not by H89. Consistent with the inhibitor specificity, the same TPH was phosphorylated by exogenous Ca 2+ /calmodulindependent protein kinase II in the presence of Ca 2+ and calmodulin but not by protein kinase A (catalytic subunit). TPH protein thus phosphorylated by Ca 2+ /calmodulindependent protein kinase II was digested more rapidly in the cell-free proteasome system than was the nonphosphorylated enzyme. These results indicated that the phosphorylation of TPH was a prerequisite for proteasome-driven TPH
19 citations
TL;DR: It is concluded that hypoxia induces PAI-1 expression, in EBC-1 cells, through the stabilization of HIF-1 complex and this may be related to cancer metastasis.
Abstract: Plasminogen activator inhibitor-1 (PAI-1) is one of the target genes of hypoxia inducible factor-1α (HIF-1α). Besides being an important physiological regulator of the fibrinolytic system PAI-1 is also involved in cancer invasiveness. HIF-1α is expressed in various types of pulmonary cells, but the relation of PAI-1 to HIF-1α under hypoxic condition in these cells are not fully elucidated. We, therefore, studied the effect of hypoxia on the expression of PAI-1 in a lung cancer cell line EBC-1. The expression of HIF-1α protein in EBC-1 cells was enhanced by hypoxia, and this was associated with increased secretion of PAI-1. Hypoxia did not affect the levels of HIF-1α mRNA but enhanced the PAI-1 mRNA. Pretreatment of the cells with MG132, which inhibits the proteasomal degradation of HIF-1α, increased the production of PAI-1 under both normoxia and hypoxia. We conclude that hypoxia induces PAI-1 expression, in EBC-1 cells, through the stabilization of HIF-1 complex and this may be related to cancer metastasis.
19 citations