Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Molecular basis for nuclear accumulation and targeting of the inhibitor of apoptosis BIRC2

ABSTRACT: The inhibitor of apoptosis protein (IAP) BIRC2 regulates fundamental cell death and survival signaling pathways. Aberrant activity of BIRC2 is associated with immunological diseases, inflammation, and cancer. Unlike other IAPs, BIRC2 can localize to and function in the nucleus through unknown mechanisms. Here, we show that BIRC2 accumulates in the nucleus via binding of its second and third BIR domains, BIRC2BIR2 and BIRC2BIR3, to histone H3 tail and report the crystal structure of the BIRC2BIR3:H3 complex. RNA-seq analysis of cells in which the BIRC2 gene is knocked out by CRISPR/Cas9 reveals that the genes involved in the interferon and defense response signaling and the cell cycle regulation are most affected by depletion of BIRC2. Overexpression of BIRC2 delays DNA damage repair and recovery of the cell cycle progression and extends the etoposide-induced G2/M cell cycle arrest. We describe the structural mechanism for targeting of BIRC2BIR3 by a potent but biochemically uncharacterized small molecule inhibitor LCL161 and demonstrate that LCL161 disrupts the association of endogenous BIRC2 with H3 and readily stimulates cell death in cancer cells. We further show that LCL161 mediates degradation of BIRC2 in HIV-1 infected human CD4+ T cells. Our findings provide mechanistic insights into the nuclear accumulation of and blocking BIRC2.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230283 | GEO | 2023/04/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Cancer genes disfavoring T cell immunity identified via integrated systems approach

Project description:A375 melanoma cells were transduced with Cas9 and non-targeting (NT) or BIRC2-targeting sgRNAs. Cells were cultured for 20 days post gene-editing and cell pellets were collected for analysis. Separately, A375 melanoma cells were treated with LCL161 for 16 hours and cell pellets were collected for analysis.

2022-06-27 | MSV000089737 | MassIVE

Overlap of NatA and IAP substrates implicates N-terminal acetyltion in protein stabilization

Project description:SMAC/DIABLO and HTRA2 are mitochondrial proteins whose N-termina sequences, known as inhibitor of apoptosis binding motifs (IBMs), bind and activate ubiquitin ligases knwon as inhibitor of apoptosis proteins (IAPs), unleashing a cell´s poteintial.IBMs comprise a 4-residue, loose consensus sequence, and binding to IAPs requires an unmodified N-terminus. Closely related, IBM-like N-termini, are present in approximately 5% of human proteins. We show that suppression of the N-alpha-acetytransferase NatA truns these cryptic IBM-like sequences into very efficient IAP binders in cell lysates and in vitro, and ultimately also triggers apoptosis. Thus, N-terminal acetylation of IBM-like motifs in NatA substrates shields them from IAPs. This previously unrecognized relatonship suggests that N-terminal acetylation is generally protective against protein degradation in human cells. It also identifies IAPs as agents of a general quality control mechanism targeting unacetylated rogues in metazoans

2021-09-09 | PXD021815 | Pride

Mus musculus

Project description:The cell death inhibitor ARC relocates to the nucleus during diabetes to unleash elastase-dependent β-cell death

| PRJNA563773 | ENA

Transcriptome profile of melanoma cell lines A375 and A375-BIR (BIR-BRAF INHIBITOR RESISTANT) during dabrafenib treatment

Project description:Transcriptome profile of melanoma cell lines A375 and A375-BIR (BIR-BRAF INHIBITOR RESISTANT) during dabrafenib treatment

| PRJNA694123 | ENA

SmallRNAome profile of melanoma cell lines A375 and A375-BIR (BIR-BRAF INHIBITOR RESISTANT) during dabrafenib treatment

Project description:SmallRNAome profile of melanoma cell lines A375 and A375-BIR (BIR-BRAF INHIBITOR RESISTANT) during dabrafenib treatment

| PRJNA694124 | ENA

Direct Nucleosome Binding of Borealin Secures Chromosome Association of the Chromosomal Passenger Complex

Project description:CPC-NCP complexes were crosslinked using EDC and analysed by mass spectrometry. The results showed Borealin is critical for nucleosome binding made extensive contacts with NCPs, whereas Survivin interactions are mostly limited to the BIR domain and the H3 N-terminal tail as expected. Mapping the crosslinks onto the three dimensional structures of NCP and CPC suggests a model where the localisation module of the CPC together with a highly basic N-terminal tail of Borealin docks onto the acidic patch formed by H2A and H2B, a surface commonly involved in nucleosome recognition. This interaction may orient the Survivin BIR domain to facilitate binding of histone H3 tail phosphorylated at Thr3. Notably, Borealin loop residues trace along the DNA-histone interface implying its major contribution to nucleosome binding involves both protein-histone and possibly protein-DNA contacts.

2019-09-30 | PXD012882 | Pride

TCA cycle metabolomics of H3K27M Cell Nucleus Fraction and Cell Mitonchonrdial Fraction (Part-IV)

Project description:Testing TCA concentrations of Diffuse Intrinsic Pontine Gliomas (DIPG) cellines with H3K27M mutations. Preliminary studies show H3K27M tumor cells are addicted to Gln for survival. Removal of Gln from media resulted in tumor cell death which was rescued by the addition of α-KG. These data show that Gln is taken up and metabolized by H3K27M tumor cells and that Gln derived α-KG is critical for the survival of these tumors. Interestingly, tumor cell death with Gln deprivation was similar to the effect of the JMJD3 inhibitor GSKJ4. Therefore, Gln derived α-KG may be required for both anaplerosis and to drive JMJD3 demethylation. We hypothesize that H3K27M tumors are reliant on α-KG that is derived from Gln to drive the TCA cycle and further decrease H3K27 methylation levels. Furthermore, inhibition of Gln metabolism may represent a novel therapeutic approach for tumors with this mutation. In this study, TCA cycle metabolomics are analyzed of H3K27M cells grown in regular glutamine media, glutamine free media, and glutamine free media with alpha-ketoglutarate. Additionally, cell nucleus and cell mitochrondial fractions are run separately.

2018-07-18 | ST001026 | MetabolomicsWorkbench

Interactome of Arabidopsis BIR3 protein

Project description:Arabidopsis BAK1/SERK3, a co-receptor of leucine-rich repeat pattern recognition receptors (PRR), mediates pattern-triggered immunity (PTI). Genetic inactivation of BAK1 or BAK1-interacting receptors (BIR) causes cell death. We foundthat the TIR-NBS-LRR protein CONSTITUTIVE SHADE-AVOIDANCE 1 (CSA1) physically interacts with BIR3, but not with BAK1 and mediates ETI-type cell death in the absence of BAK1 and BIR3.

2022-11-29 | PXD036942 | Pride

Gene expression profiling of HDLM-2 Hodgkin lymphoma cell line after in vitro and in vivo treatment with Givinostat in combination with Sorafenib

Project description:Relapsed/refractory Hodgkin lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70- 80%) and a dramatic increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P < 0.0001), a 5- to 15-fold increase in BIM expression (P ≤.0001) and a 4-fold increase in tumor necrosis in Givinostat/Sorafenib-treated animals compared to mice that received the single agents. These results provide a rationale for exploring Givinostat/Sorafenib combination in relapsed/refractory HL.

2015-03-01 | GSE65479 | GEO

Gene expression profiling of L-540 Hodgkin lymphoma cell line after in vitro and in vivo treatment with Givinostat in combination with Sorafenib

2015-03-01 | GSE65483 | GEO