Augmentation of drug-induced cell death by ER protein BRI3BP

Yamazaki, Tetsuo; Sasaki, Nozomi; Nishi, Miyuki; Yamazaki, Daiju; Ikeda, Atsushi; Okuno, Yasushi; Komazaki, Shinji; Takeshima, Hiroshi

doi:10.1016/j.bbrc.2007.08.082

Cited by 12 publications

(8 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, programmed cell death 1 ligand 1 (PDL1), a known to be a target of miR-17, , was upregulated, although its cell surface expression was not affected, as assessed by immunohistochemical staining and flow cytometry (Figure S12C–E). The BRI3 binding protein (BRI3BP), a pro-apoptotic protein that increases drug-induced apoptosis by increasing cytochrome c release and improving Caspase-3 activity, , was also upregulated. Please see the Supporting Information for a detailed discussion of this proteomics analysis (Figure S12).…”

Section: Resultsmentioning

confidence: 99%

Targeted Degradation of the Oncogenic MicroRNA 17-92 Cluster by Structure-Targeting Ligands

et al. 2020

View full text Add to dashboard Cite

Many RNAs are processed into biologically active transcripts, the aberrant expression of which can contribute to disease phenotypes. For example, the primary microRNA-17-92 (pri-miR-17-92) cluster contains six microRNAs (miRNAs) that collectively act in several disease settings. Herein, we used sequence-based design of structure-specific ligands to target a common structure in the Dicer processing sites of three miRNAs in the cluster, miR-17, miR-18a, and miR-20a, thereby inhibiting their biogenesis. The compound was optimized to afford a dimeric molecule that binds the Dicer processing site and an adjacent bulge, affording a 100-fold increase in potency. The dimer’s mode of action was then extended from simple binding to direct cleavage by conjugation to bleomycin A5 in a manner that imparts RNA-selective cleavage or to indirect cleavage by recruiting an endogenous nuclease, or a ribonuclease targeting chimera (RIBOTAC). Interestingly, the dimer-bleomycin conjugate cleaves the entire pri-miR-17-92 cluster and hence functionally inhibits all six miRNAs emanating from it. The compound selectively reduced levels of the cluster in three disease models: polycystic kidney disease, prostate cancer, and breast cancer, rescuing disease-associated phenotypes in the latter two. Further, the bleomycin conjugate exerted selective effects on the miRNome and proteome in prostate cancer cells. In contrast, the RIBOTAC only depleted levels of pre- and mature miR-17, -18a, and 20a, with no effect on the primary transcript, in accordance with the cocellular localization of RNase L, the pre-miRNA targets, and the compound. These studies demonstrate a strategy to tune RNA structure-targeting compounds to the cellular localization of the target.

show abstract

Section: Resultsmentioning

confidence: 99%

Targeted Degradation of the Oncogenic MicroRNA 17-92 Cluster by Structure-Targeting Ligands

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Among 30 genes, BRI3 appears to be overexpressed in BM-CD33+ cells. It seems to play a key role in TNF-induced cell death [57].…”

Section: Discussionmentioning

confidence: 99%

Chromosomal Minimal Critical Regions in Therapy-Related Leukemia Appear Different from Those of De Novo Leukemia by High-Resolution aCGH

et al. 2011

View full text Add to dashboard Cite

Therapy-related acute leukemia (t-AML), is a severe complication of cytotoxic therapy used for primary cancer treatment. The outcome of these patients is poor, compared to people who develop de novo acute leukemia (p-AML). Cytogenetic abnormalities in t-AML are similar to those found in p-AML but present more frequent unfavorable karyotypes depending on the inducting agent. Losses of chromosome 5 or 7 are observed after alkylating agents while balanced translocations are found after topoisomerase II inhibitors. This study compared t-AML to p-AML using high resolution array CGH in order to find copy number abnormalities (CNA) at a higher resolution than conventional cytogenetics. More CNAs were observed in 30 t-AML than in 36 p-AML: 104 CNAs were observed with 63 losses and 41 gains (mean number 3.46 per case) in t-AML, while in p-AML, 69 CNAs were observed with 32 losses and 37 gains (mean number of 1.9 per case). In primary leukemia with a previously “normal” karyotype, 18% exhibited a previously undetected CNA, whereas in the (few) t-AML with a normal karyotype, the rate was 50%. Several minimal critical regions (MCRs) were found in t-AML and p-AML. No common MCRs were found in the two groups. In t-AML a 40kb deleted MCR pointed to RUNX1 on 21q22, a gene coding for a transcription factor implicated in frequent rearrangements in leukemia and in familial thrombocytopenia. In de novo AML, a 1Mb MCR harboring ERG and ETS2 was observed from patients with complex aCGH profiles. High resolution cytogenomics obtained by aCGH and similar techniques already published allowed us to characterize numerous non random chromosome abnormalities. This work supports the hypothesis that they can be classified into several categories: abnormalities common to all AML; those more frequently found in t-AML and those specifically found in p-AML.

show abstract

“…(Fig 8; S10 and S11 Tables). In the absence of Bcrp/Pgp, hepatic genes upregulated included Caspase 12 (Casp12), an endoplasmic reticulum (ER) membrane cell death initiator [55]; proteome activator subunit 3 (Psme3), a subunit of a proteasome regulator that controls proteasome mediated death; Fam134b, involved in degradation of misfolded proteins; and Marveld1, a marvel domain containing 1 protein that may regulate decay of damaged mRNA; and in response to those changes, induction of Bri3 binding protein, Bri3bp, a protein that in the ER that can decrease apoptosis [56]. Kidneys of dKO rats also showed induction of several proteins in ER stress pathways including activating transcription factor 3, Atf3, a transcription factor involved in ER quality control/protein folding after ER stress; Psme3; Nr4a1/Nurr77, a gene induced by ER stress and that can promote kidney injury [57]; and Uncoupling protein 1, Fig 6 . Identification of metabolites with greater accumulation in CSF than in plasma of dKO rats, compared to WT rats.…”

Section: Plos Onementioning

confidence: 99%

Metabolomic and transcriptomic analysis reveals endogenous substrates and metabolic adaptation in rats lacking Abcg2 and Abcb1a transporters

et al. 2021

View full text Add to dashboard Cite

Abcg2/Bcrp and Abcb1a/Pgp are xenobiotic efflux transporters limiting substrate permeability in the gastrointestinal system and brain, and increasing renal and hepatic drug clearance. The systemic impact of Bcrp and Pgp ablation on metabolic homeostasis of endogenous substrates is incompletely understood. We performed untargeted metabolomics of cerebrospinal fluid (CSF) and plasma, transcriptomics of brain, liver and kidney from male Sprague Dawley rats (WT) and Bcrp/Pgp double knock-out (dKO) rats, and integrated metabolomic/transcriptomic analysis to identify putative substrates and perturbations in canonical metabolic pathways. A predictive Bayesian machine learning model was used to predict in silico those metabolites with greater substrate-like features for either transporters. The CSF and plasma levels of 169 metabolites, nutrients, signaling molecules, antioxidants and lipids were significantly altered in dKO rats, compared to WT rats. These metabolite changes suggested alterations in histidine, branched chain amino acid, purine and pyrimidine metabolism in the dKO rats. Levels of methylated and sulfated metabolites and some primary bile acids were increased in dKO CSF or plasma. Elevated uric acid levels appeared to be a primary driver of changes in purine and pyrimidine biosynthesis. Alterations in Bcrp/Pgp dKO CSF levels of antioxidants, precursors of neurotransmitters, and uric acid suggests the transporters may contribute to the regulation of a healthy central nervous system in rats. Microbiome-generated metabolites were found to be elevated in dKO rat plasma and CSF. The altered dKO metabolome appeared to cause compensatory transcriptional change in urate biosynthesis and response to lipopolysaccharide in brain, oxidation-reduction processes and response to oxidative stress and porphyrin biosynthesis in kidney, and circadian rhythm genes in liver. These findings present insight into endogenous functions of Bcrp and Pgp, the impact that transporter substrates, inhibitors or polymorphisms may have on metabolism, how transporter inhibition could rewire drug sensitivity indirectly through metabolic changes, and identify functional Bcrp biomarkers.

show abstract

Augmentation of drug-induced cell death by ER protein BRI3BP

Cited by 12 publications

References 23 publications

Targeted Degradation of the Oncogenic MicroRNA 17-92 Cluster by Structure-Targeting Ligands

Targeted Degradation of the Oncogenic MicroRNA 17-92 Cluster by Structure-Targeting Ligands

Chromosomal Minimal Critical Regions in Therapy-Related Leukemia Appear Different from Those of De Novo Leukemia by High-Resolution aCGH

Metabolomic and transcriptomic analysis reveals endogenous substrates and metabolic adaptation in rats lacking Abcg2 and Abcb1a transporters

Contact Info

Product

Resources

About