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Description

A cell-permeable oxo-imidazolidinyl-hydroxyurea that preferentially localizes to ER, where it interacts with AAA (ATPase associated with diverse cellular activities) ATPase p97 (Kd = 5 - 10 microM) via its nitrofuran-containing moiety, without exhibiting affinity toward Hsp70 or AAA ATPase NSF (N-methylmaleimide-sensitive factor). Evidence indicates that EerI cellular metabolite, but not EerI itself, is responsible for the inhibition of ER membrane translocon sec61 complex-mediated transfer of newly synthesized polypeptide, resulting in a blockage of ER-mediated posttranslational glycosylation and signal peptide removal (Effective conc. = 8 microM in HepG2 and HeLa cultures). Ether independent or as a consequence of the early effect on sec61 complex, EerI culture treatment also induces a selective dissociation of an 180 kDa protein from the atx3-containing p97/VCP (Valosin-containing protein) complex and a blockage of the complex-associated deubiquitination of ERAD (ER-associated protein degradation) substrates in a reversible manner, resulting in an accumulation of polyubiquitinated proteins (Effective conc. = 10 microM in A9 and 293T cultures). EerI culture treatment (10 microM) is also demonstrated to selectively induce cytotoxicity in lymphoid cell lines, BJAB, HBL-2, JEKO-1, Jurkat, KMS-12, MINO, as well as primary leukemia cells from CLL (chronic lymphocytic leukemia) patients, but not PBMC from healthy donors, by upregulating the BH3-only pro-apoptotic protein NOXA in cancer cells via ATF3/4 activation and a downregulation of H2A ubiquitination. Unlike DBeQ (Cat. No. 506190), EeRI does not inhibit p97 ATPase activity., A cell-permeable oxo-imidazolidinyl-hydroxyurea whose cellular metabolite is shown to effectively inhibit the ER membrane translocon sec61 complex-mediated transfer of newly synthesized polypeptide, resulting in a blockage of ER-mediated posttranslational glycosylation and signal peptide removal (Effective conc. = 8 microM in HepG2 and HeLa cultures). Ether independent or as a consequence of the early effect on sec61 complex, EerI culture treatment also induces a selective dissociation of an 180 kDa protein from the atx3-containing p97/VCP (Valosin-containing protein) ATPase complex and a blockage of the p97 complex-associated deubiquitination of ERAD (ER-associated protein degradation) substrates in a reversible manner, resulting in an accumulation of polyubiquitinated proteins (Effective conc. = 10 microM in A9 and 293T cultures). EerI culture treatment (10 microM) is also demonstrated to selectively induce cytotoxicity in lymphoid cell lines, BJAB, HBL-2, JEKO-1, Jurkat, KMS-12, MINO, as well as primary leukemia cells from CLL (chronic lymphocytic leukemia) patients, but not PBMC from healthy donors, by upregulating the BH3-only pro-apoptotic protein NOXA in cancer cells via ATF3/4 activation and a downregulation of H2A ubiquitination.