Human death effector domain-associated factor interacts with the viral apoptosis agonist Apoptin and exerts tumor-preferential cell killing

Oorschot, A. A. A. M. Danen-van; Voskamp, Patrick; Seelen, Maud C.M.J.; Miltenburg, M H A M van; Bolk, Marian W. J.; Tait, Stephen W.G.; Cock, Jeanine G.R. Boesen-de; Rohn, Jennifer L.; Borst, Jannie; Noteborn, Mathieu H. M.

doi:10.1038/sj.cdd.4401391

Cited by 74 publications

(72 citation statements)

References 32 publications

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“…Only one tumour-suppressor gene, RYBP, was present in this region. RYBP (RING1 and YY1 binding protein, also known as DEDAF) functions as a repressor of E4TF1 and induces apoptosis in tumour cells (Danen-van Oorschot et al 2004). The preferential tumour-killing activity of RYBP has made it a promising target for cancer therapy (Novak & Phillips 2008).…”

Section: Discussionmentioning

confidence: 99%

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

Andersson¹,

Swärd²,

Stenman³

et al. 2009

Endocrine-Related Cancer

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Ileal carcinoids are malignant neuroendocrine tumours of the small intestine. The aim of this study was to obtain a high-resolution genomic profile of ileal carcinoids in order to define genetic changes important for tumour initiation, progression and survival. Forty-three patients with ileal carcinoids were investigated by high-resolution array-based comparative genomic hybridization. The average number of copy number alterations (CNAs) per tumour was 7

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Section: Discussionmentioning

confidence: 99%

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

Andersson¹,

Swärd²,

Stenman³

et al. 2009

Endocrine-Related Cancer

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“…However, high levels of dRYBP expression induce apoptosis in all the imaginal discs studied (Figure 1). In transfection experiments, murine and human RYBP/DEDAF proteins have been shown to have the ability to specifically kill mammalian tumor cells while leaving normal cells unaffected [19,20]. We have shown that the induction of apoptosis in Drosophila does not require the apoptotic cell to be in the transformed state, indicating that this may be a useful system to study the mechanisms controlling the tumor-specific cell killing.…”

Section: High Levels Of Exogenous Drybp Induce Apoptosismentioning

confidence: 94%

“…Furthermore, the RYBP protein has been found to interact with Apoptin, a protein known to be active in killing tumor cells [20]. As induction of apoptosis is a common mechanism underlying cancer therapy, understanding the mechanisms controlling tumor cell-specific killing may facilitate the development of improved therapies.…”

Section: Introductionmentioning

confidence: 99%

High levels of dRYBP induce apoptosis in Drosophila imaginal cells through the activation of reaper and the requirement of trithorax, dredd and dFADD

González

Busturia

2009

Cell Res

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Drosophila RYBP (dRYBP; Ring1 and YY1 Binding Protein) is a Polycomb and trithorax interacting protein, whose homologous RYBP/DEDAF mammalian counterparts exhibit tumor cell-specific killing activity. Here we show that although endogenous dRYBP is not involved in developmental apoptosis, high levels of exogenous dRYBP induce apoptosis in all the imaginal discs of the fly, indicating that dRYBP apoptotic activity is not specific to tumor cells. We also show that dRYBP-induced apoptosis is inhibited by high levels of either p35 or DIAP1 (Drosophila Inhibitor of Apoptosis Protein 1), and requires the function of the pro-apoptotic REAPER, HID and GRIM proteins, the apical caspase DREDD, the adaptor dFADD protein as well as TRITHORAX (TRX), an epigenetic transcriptional regulator. Furthermore, we demonstrate that overexpression of TRX also induces apoptosis in the imaginal discs. Finally, we show that the expression of reaper-lacZ is upregulated both upon dRYBP-induced apoptosis and upon TRXinduced apoptosis in imaginal discs and that the reaper gene is a direct target of dRYBP in Drosophila embryos. Our results indicate that dRYBP triggers in a receptor-mediated apoptotic pathway that also includes TRX-dependent epigenetic regulation of gene expression.

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“…The X-ray structure of the monomers of C-RING1B resembles that of a ubiquitin module, and it serves to interact with CBX proteins (18). Furthermore, we have also shown that C-RING1B is capable of interacting with RING1 and YY1 binding protein (RYBP) (19,20), which is a highly basic, oligomeric, intrinsically disordered protein (IDP) that interacts with DNA (19) and other proteins involved in apoptosis (21)(22)(23). The CBX proteins binding to C-RING1B undergo a tightening in their structures (24), and their presence hampers RYBP binding (25).…”

mentioning

confidence: 85%

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

Santofimia‐Castaño

Rizzuti

Pey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Intrinsically disordered proteins (IDPs) are ubiquitous in eukaryotes, and they are often associated with diseases in humans. The protein NUPR1 is a multifunctional IDP involved in chromatin remodeling and in the development and progression of pancreatic cancer; however, the details of such functions are unknown. Polycomb proteins are involved in specific transcriptional cascades and gene silencing. One of the proteins of the Polycomb complex is the Ring finger protein 1 (RING1). RING1 is related to aggressive tumor features in multiple cancer types. In this work we characterized the interaction between NUPR1 and the paralogue RING1B in vitro, in silico, and in cellulo. The interaction occurred through the C-terminal region of RING1B (C-RING1B), with an affinity in the low micromolar range (∼10 μM). The binding region of NUPR1, mapped by NMR, was a hydrophobic polypeptide patch at the 30s region of its sequence, as pinpointed by computational results and site-directed mutagenesis at Ala33. The association between C-RING1B and wild-type NUPR1 also occurred in cellulo as tested by protein ligation assays; this interaction is inhibited by trifluoperazine, a drug known to hamper binding of wild-type NUPR1 with other proteins. Furthermore, the Thr68Gln and Ala33Gln/Thr68Gln mutants had a reduction in the binding toward C-RING1B as shown by in vitro, in silico, and in cellulo studies. This is an example of a well-folded partner of NUPR1, because its other interacting proteins are also unfolded. We hypothesize that NUPR1 plays an active role in chromatin remodeling and carcinogenesis, together with Polycomb proteins.G ene expression control occurs through the combined activities of transcription factors and chromatin regulators, considered as effectors of epigenetic mechanisms. Posttranslational modifications of nucleosomal histones, DNA methylation, local compaction, and long-range interactions determine a variety of chromatin structures that can affect the transcriptional output.A group of chromatin regulators are the Polycomb Repressive complexes (PRCs) (1, 2). These Polycomb group (PcG) proteins are encoded by genes initially discovered over 60 years ago as repressors of the Hox genes in Drosophila (3). The PcG proteins form two main silencing heteromeric complexes called PRC1 and PRC2; both are highly conserved in eukaryotes and either in isolation or synergistically can silence genes (4, 5). The catalytic functions of both complexes include ubiquitin-ligase (H3K119ub1) and methyltransferase activity (H3K27Me3), respectively. In mammals, the PRC2 core is formed by, at least, four heteromeric units, one of which is EZH2 (or its paralog, EZH1), the methyltransferase that catalyzes the trimethylation of histone H3 at Lys27 (5). This modification can act as an anchoring site of PRC1 complexes containing chromobox (CBX) proteins. These CBX proteins recruit PRC1 complex onto PRC2-enriched chromatin, facilitating the monoubiquitylation. The PRC1-dependent monoubiquitylation at Lys119 of histone H2A correlates with transc...

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Human death effector domain-associated factor interacts with the viral apoptosis agonist Apoptin and exerts tumor-preferential cell killing

Cited by 74 publications

References 32 publications

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

High levels of dRYBP induce apoptosis in Drosophila imaginal cells through the activation of reaper and the requirement of trithorax, dredd and dFADD

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

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