Comprehensive profiling and targeting of BCL-2 family members in nasopharyngeal carcinoma
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PROVIDER: PRJNA986493 | ENA |
REPOSITORIES: ENA
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Project description:Nasopharyngeal carcinoma (NPC) is among a small number of solid tumors that are caused by the Epstein-Barr virus (EBV). Recently, BH3 mimetics, a novel class of drugs that inhibit pro-survival proteins of the BCL-2 family, have demonstrated clinical anti-cancer efficacy in hematological malignancies and are being investigated for use in solid tumors. There is known dysregulation of pro-survival pathways, particularly, the intrinsic apoptotic pathway during EBV infection of B cells suggesting NPC may be driven by the same pathways, and thus sensitive to BH3 inhibition. Using immunohistochemistry, we examined the expression of BCL-2 family of proteins (BCL2, MCL1 and BCLxL) in 174 NPC from patients treated with curative intent as well as five NPC cell lines. We subsequently evaluated the anti-tumor efficacy of three BH3 mimetics (ABT-199, ABT-737 and S63845) in NPC cells alone or in combination with cisplatin, a commonly used cytotoxic agent in NPC treatment. BCL-2 was highly expressed in NPC tumors and cells. Despite this, BCL2 inhibition, or BH3 monotherapy was not effective. However, marked sensitivity was observed with the combination S63845 (targeting MCL-1) and cisplatin in NPC43, which had high expression of MCL-1. This combination resulted in upregulation of pro-apoptotic tBID suggesting a priming role of cisplatin and apoptotic potentiation through MCL-1 inhibition. Flow cytometry studies and RNA sequencing of NPC43 cells treated with the combination of cisplatin with S63845 and untreated cells showed death by apoptosis and upregulation in stress response and DNA damage pathways. Our study suggests that combining BH3 mimetics with cisplatin could be an effective treatment strategy for NPC and warrants further investigation
2024-10-01 | GSE235574 | GEO
Project description:To evaluate the effect on lincRNA expression by p53 family members, we overexpressed p53 family members in H1299 cells and evaluated the lincRNA expression by microarray analysis.
2014-02-05 | GSE52739 | GEO
Project description:Members of the GATA protein family play important roles in lineage specification and transdifferentiation. Previous reports show that some members of GATA protein family also can induce pluripotency in somatic cells by substituting for the key pluripotency-associated factor Oct4. However, the mechanism that links the lineage specifying cues and activation of pluripotency remains elusive. Here, we report that all GATA family members can substitute for Oct4 to induce pluripotency. We found that all members of the GATA family can inhibit elevated ectodermal-lineage genes, which is consistent with previous reports that a balance of different lineage-specifying forces is important for restoration of pluripotency. A conserved DNA-binding domain in the C-terminal zinc finger is critical for the GATA family to induce pluripotency. Using RNA-seq and ChIP-seq we identified that the pluripotency-related gene Sall4 is a direct target of GATA family members during reprogramming, serving as a bridge linking the lineage-specific GATA family to the pluripotency circuit. Thus, the GATA family is the first family of proteins wherein all members can function as inducers of the reprogramming process that can substitute for Oct4. Our results suggest that the roles of the GATA family in reprogramming have been greatly underestimated, and that the GATA family may serve as a general mediator for cell fate conversion.
2014-12-02 | GSE57849 | GEO
Project description:To evaluate the effect on lincRNA expression by p53 family members, we overexpressed p53 family members in H1299 cells and evaluated the lincRNA expression by microarray analysis. lincRNA expression was measured in H1299 cells infected with adenovirus expressing LacZ, p53, p63a, p63g, p73a and p73b.
2014-02-05 | E-GEOD-52739 | biostudies-arrayexpress
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Project description:Cytokines of the interleukin 12 (IL-12) family are assembled combinatorially from shared alpha and beta subunits. A common theme is that human IL-12 family alpha subunits remain incompletely structured in isolation until they pair with a designate beta subunit. Accordingly, chaperones need to support and control specific assembly processes. Here, we site-specifically introduce photo-crosslinking amino acids into the IL-12 and IL-23 alpha subunits (IL-12alpha and IL-23alpha). This allows to stabilize transient chaperone:client complexes for mass spectrometry and reveals a large set of ER chaperones to interact with IL-12alpha and IL-23alpha. Among those, we focus on protein disulfide isomerase (PDI) family members and reveal IL-12 family subunits to be clients of several ill-characterized PDIs. We find that different PDIs show selectivity for different cysteines in IL-12alpha and IL-23alpha. Despite this, PDI binding generally stabilizes unassembled IL-12alpha and IL-23alpha against degradation. In contrast, alpha:beta assembly appears robust and only multiple simultaneous PDI depletions reduce IL-12 secretion. Our comprehensive analysis of the IL-12/IL-23 chaperone machinery reveals a hitherto uncharacterized role for several PDIs in this process. This extends our understanding of how cells accomplish the task of specific protein assembly reactions for signaling processes. Furthermore, our findings show that cytokine secretion can be modulated by targeting specific ER chaperones.
2022-11-28 | PXD036463 | Pride
Project description:The p53 family comprises the tumor suppressor p53 and the structural homologs p63 and p73. How the three family members cooperate in tumor suppression remains unclear. Here, we report different but complementary functions of the individual members for regulating retinoblastoma protein (RB) function during myogenic differentiation. Whereas p53 transactivates the retinoblastoma gene, p63 and p73 induce the cyclin-dependent kinase inhibitor p57 to maintain RB in an active, hypophosphorylated state. DeltaNp73 inhibits these functions of the p53 family in differentiation control, prevents myogenic differentiation, and enables cooperating oncogenes to transform myoblasts to tumorigenicity. DeltaNp73 is frequently overexpressed in rhabdomyosarcoma and essential for tumor progression in vivo. These findings establish differentiation control as a key tumor suppressor activity of the p53 family. Keywords: oligonucleotide
2006-10-16 | GSE5447 | GEO
Project description:Survival rates for children diagnosed with acute lymphoblastic leukemia (ALL) have drastically improved, but those carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in ALL is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we showed that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. We went on to show that MLL leukemias are particularly sensitive to treatment with the BCL-2 inhibitor venetoclax which synergizes with both standard chemotherapeutic agents as well as DOT1L inhibitors. Altered expression of other BCL-2 family members is a major cause of resistance to ventoclax, so here we perform a detalied analysis of MLL-AF4 regulation of the entire BCL-2 family. By measuring nascent RNA production, we find that of all the BCL-2 family genes, MLL-AF4 directly controls the transcription of both BCL-2 and MCL-1, but only BCL-2 shows a significant loss of steady state RNA levels. Interestingly however, both MCL-1 and BCL-XL protein levels are dependent on MLL-AF4 activity through an unknown and likely indirect mechanism. Finally, we analyze MLL-AF4 regulation of the BCL-2 gene in greater detail and using Capture C we identify a major BCL-2 specific enhancer consisting of two clusters of H3K27Ac. Loss of MLL-AF4 activity results in a reduction of H2K27Ac levels at the major BCL-2 enhancer, revealing a novel regulatory dependence on MLL-AF4 function at BCL-2.
2016-11-23 | GSE85988 | GEO