Bacitracin: An inhibitor of the insulin degrading activity of glutathione-insulin transhydrogenase

Roth, Richard A.

doi:10.1016/0006-291x(81)90858-5

Cited by 104 publications

(46 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Next, we treated the resistant cells with bacitracin, a pan inhibitor of PDIs, and observed an increase in the CDDP-induced loss of DCm, restoring almost completely CDDP sensitivity for the highest dose of PDI inhibitor (Figure 3d). 29 These results indicate that pharmacological PDI inhibition rescues MMP induction by CDDP and suggests that PDIs might have a direct role in CDDP resistance.…”

Section: Wt R2mentioning

confidence: 78%

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

et al. 2014

View full text Add to dashboard Cite

Intrinsic and acquired chemoresistance are frequent causes of cancer eradication failure. Thus, long-term cis-diaminedichloroplatine(II) (CDDP) or cisplatin treatment is known to promote tumor cell resistance to apoptosis induction via multiple mechanisms involving gene expression modulation of oncogenes, tumor suppressors and blockade of pro-apoptotic mitochondrial membrane permeabilization. Here, we demonstrate that CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (480 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6, without any alteration in ER-cytosol Ca 2 þ fluxes. Using pharmacological and genetic inhibition, we show that inactivation of both proteins directly stimulates CDDP-induced cell death by different cellular signaling pathways. PDIA4 inactivation restores a classical mitochondrial apoptosis pathway, while knockdown of PDIA6 favors a non-canonical cell death pathway sharing some necroptosis features. Overexpression of both proteins has also been found in lung adenocarcinoma patients, suggesting a clinical importance of these proteins in chemoresistance.

show abstract

Section: Wt R2mentioning

confidence: 78%

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Effect of PDI inhibition on LmPDI activity and L. major parasite growth. Specific inhibitors of PDI enzymatic activity have been previously described (29,32,39,40). Some of them were used in the present study to evaluate their inhibitory effect on the recombinant LmPDI.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Disulfide Isomerase Protein ofLeishmania majoras a Putative Virulence Factor

et al. 2002

View full text Add to dashboard Cite

Several approaches have been previously used to elucidate the genetic basis of Leishmania virulence. In general, they were based on laboratory Leishmania clones genetically modified or grown in the presence of selecting agents. In a previous study, we demonstrated that Leishmania major freshly isolated from human cutaneous lesions showed significant differences in the severity of the experimental disease induced in BALB/c mice. Here, using the mRNA differential display technique, we analyzed gene expression in L. major promastigotes showing different levels of virulence. We have identified a novel Leishmania gene encoding a 477-aminoacid protein exhibiting two distinct regions that are identical to the putative active-site sequence (CGHC) of the eukaryotic protein disulfide isomerase (PDI). The recombinant protein displayed a specific PDI enzymatic activity. This L. major disulfide isomerase protein (LmPDI) is predominantly expressed, at both the mRNA and protein levels, in highly virulent strains. Specific PDI inhibitors abolished the enzymatic activity of the recombinant protein and profoundly affected parasite growth. These findings suggest that LmPDI may play an important role in Leishmania natural pathogenicity and may constitute a new target for anti-Leishmania chemotherapy.

show abstract

“…[31][32][33] Platelet aggregation in the presence of 3 to 6 mM bacitracin mimicked the effect of the thiol blockers pCMPS and DTNB. In samples from 5 different donors, bacitracin inhibited agonist-induced aggregation, blocking the second but not the first wave of ADP-or thrombin-induced aggregation and not affecting shape change (Figure 2).…”

Section: Effect Of Inhibiting Enzymatic Catalysis Of Disulfide Isomermentioning

confidence: 90%

Sustained integrin ligation involves extracellular free sulfhydryls and enzymatically catalyzed disulfide exchange

Lahav

Jurk

Hess

et al. 2002

Blood

184

209

View full text Add to dashboard Cite

Studies have suggested a pivotal role for free sulfhydryls in platelet integrin function, and enzyme-mediated reduction of disulfide bonds on platelets has been implicated. The platelet fibrinogen receptor ␣ IIb ␤ 3 is the best-studied platelet integrin and serves as a model system for studying the structure-function relation in this family of adhesion receptors. The demonstration of free sulfhydryls on the exofacial domain of purified ␣ IIb ␤ 3 , specifically in its activated conformation, prompted us to explore the potential for activation-dependent, enzymatically catalyzed thiol expression on intact platelets and the possible role of surface-associated protein disulfide isomerase (PDI) in ␣ IIb ␤ 3 ligation. Using the membrane-impermeant sulfhydryl blocker para-chloromercuriphenyl sulfonate, the inhibitor of disulfide exchange bacitracin, and the monoclonal anti-PDI antibody RL90, we examined fibrinogen binding to ␣ IIb ␤ 3 as well as ligation-induced allosteric changes in the conformation of ␣ IIb ␤ 3 . We sought to distinguish the possible involvement of disulfide exchange in agonist-induced platelet stimulation from its role in integrin ligation. Analysis of the role of free thiols in platelet aggregation suggested a thiolindependent initial ligation followed by a thiol-dependent stabilization of binding. IntroductionThe affinity of integrins for their ligands is tightly regulated, both by cellular events and subsequent to ligand binding. [1][2][3][4][5] Such cellular control over the interaction of extracellular proteins implies the existence of a mechanism to propagate information back and forth between the extracellular head and the cytoplasmic tail of the integrin receptor. In recent years, the posited mechanism has been the allosteric conformational changes occurring in the integrin receptor, both in response to cellular events that switch the receptor from low to high affinity (inside-out signaling) and external events that relay information about occupancy of the receptor (outside-in signaling). [6][7][8][9] Although information about the nature of the changes in conformation is slowly emerging (for review, see Woodside et al 10 ) and consequent changes in intracellular interactions are widely documented, 10-13 the molecular mechanism regulating such changes, particularly on the exofacial domain, has not been elucidated. We previously reported that extracellular sulfhydryls participate in conformational changes triggered by interaction of the platelet integrin ␣ 2 ␤ 1 with its natural ligand collagen. 14 We also found that disulfide exchange is required for platelet adhesion mediated by integrins ␣ 5 ␤ 1 and ␣ IIb ␤ 3 as well as ␣ 2 ␤ 1 and that surface-expressed protein disulfide isomerase (PDI) is involved in this exchange. 15 Furthermore, involvement of disulfide exchange in receptor function is a feature specific to the integrin-receptor family (J. L. et al, submitted manuscript, 2002). We therefore proposed that conformational changes subsequent to ligand interaction with the integrin lead to ...

show abstract

Bacitracin: An inhibitor of the insulin degrading activity of glutathione-insulin transhydrogenase

Cited by 104 publications

References 23 publications

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

Identification of a Disulfide Isomerase Protein ofLeishmania majoras a Putative Virulence Factor

Sustained integrin ligation involves extracellular free sulfhydryls and enzymatically catalyzed disulfide exchange

Contact Info

Product

Resources

About