Elevated level of SUMOylated IRF-1 in tumor cells interferes with IRF-1-mediated apoptosis

Park, Junsoo; Kim, Kwangsoo; Lee, Eun‐Ju; Seo, Yun-Jee; Lim, Sinae; Park, Kyoungsook; Rho, Seung Bae; Lee, Seung‐Hoon; Lee, Je‐Ho

doi:10.1073/pnas.0609852104

Cited by 56 publications

(37 citation statements)

References 29 publications

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“…IRF-1 expression is under the control of both type I and II IFNs [44] and subjected to multiple mechanisms of regulation, including interaction with MyD88 [45] or SUMOylation [46]. IRF-1 is a bona-fine tumor suppressor gene controlling apoptosis, and inactivating mutations have been identified in tumors [47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Type I IFNs signaling and apoptosis resistance in glioblastoma cells

et al. 2011

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Deletion of type I IFN genes and resistance to apoptosis induced by type I IFNs are common in glioblastoma. Here we have investigated the importance of the constitutive weak IFN-signaling in the apoptotic response to IFN-α in glioblastoma cells. U87MG cells hold a deletion of type I IFN genes, whereas in T98G cells the spontaneous IFN signaling is intact. In response to IFN-α U87MG cells produce much less TRAIL, while other IFN-inducible genes were efficiently up-regulated. Alterations in TRAIL promoter sequence and activity were not observed. DNA methylation can influence TRAIL transcription but without overt differences between the two cell lines. We also discovered that TRAIL mRNA stability is influenced by IFN-α, but again no differences can be appreciated between the two cell lines. By silencing IFNAR1 we provide evidences that the spontaneous IFN signaling loop is required to sustain elevated levels of TRAIL expression, possibly through the regulation of IRF-1. Despite the presence/absence of the constitutive IFN signaling, both cell lines were resistant to IFN-α induced apoptosis. Targeting the deisgylase USP18 can overcome resistance to IFN-induced apoptosis only in T98G cells. Alterations in elements of the extrinsic apoptotic pathway, such as Bid and c-FLIP contribute to apoptotic resistance of U87MG cells. Down-regulation of USP18 expression together with the induction of ER-stress efficiently restored apoptosis in U87MG cells. Finally, we demonstrated that the BH3-only protein Noxa provides an important contribution in the apoptotic response to ER-stress in USP18 silenced cells.

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Section: Discussionmentioning

confidence: 99%

Type I IFNs signaling and apoptosis resistance in glioblastoma cells

et al. 2011

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“…IRFs control expression of cytokines, growth factors, cell adhesion molecules, chemokines and regulate a large number of genes in a variety of cells and tissues under diverse conditions (Ozato et al 2007). Dysregulation of IRFs by gene mutation (Nishio et al 2001), differential expression (Choo et al 2006), alternative splicing of the mRNAs (Maratheftis et al 2006), post-translational modifi cation and proteolytic processing (Park et al 2007) during various pathological conditions and diseases have been reported. IRF-1 and IRF-2, the two founding members of IRF family, provide examples of both positive and negative regulators of transcription of genes during immune response (Colonna 2007), cell growth (Masumi et al 2003), differentiation (Chung and Kawamoto 2004) and cancer (Wang et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Replacement of the C-terminal tetrapeptide (314PAPV317 to 314SSSM317) in interferon regulatory factor-2 alters its N-terminal DNA-binding activity

Prakash

Rath

2010

J Biosci

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Interferon regulatory factor-2 (IRF-2) is an important transcription factor involved in cell growth regulation, immune response and cancer. IRF-2 can function as a transcriptional repressor and activator depending on its DNA-binding activity and protein-protein interactions. We compared the amino acid sequences of IRF-2 and found a C-terminal tetrapeptide (314PAPV317) of mouse IRF-2 to be different (314SSSM317) from human IRF-2. Recombinant GST-IRF-2 with 314PAPV317 (wild type) and 314SSSM317 (mutant) expressed in Escherichia coli were assessed for DNA-binding activity with 32P-(GAAAGT) 4 by electrophoretic mobility shift assay (EMSA). Wild type- and mutant GST-IRF-2 showed similar expression patterns and immunoreactivities but different DNA-binding activities. Mutant (mt) IRF-2 formed higher-molecular-mass, more and stronger DNA-protein complexes in comparison to wild type (wt) IRF-2. Anti-IRF-2 antibody stabilized the DNA-protein complexes formed by both wt IRF-2 and mt IRF-2, resolving the differences. This suggests that PAPV and SSSM sequences at 314-317 in the C-terminal region of mouse and human IRF-2 contribute to conformation of IRF-2 and influence DNA-binding activity of the N-terminal region, indicating intramolecular interactions. Thus, evolution of IRF-2 from murine to human genome has resulted in subtle differences in C-terminal amino acid motifs, which may contribute to qualitative changes in IRF-2-dependent DNA-binding activity and gene expression.

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“…Despite the fact that existing evidence suggests that IRF-1 function is highly regulated by post-translational mechanisms (17)(18)(19)(20) and that it represents a network hub for radiosensitivity and various human diseases (21)(22)(23), the identification of regulatory factors that function through protein-protein interactions with IRF-1 is limited (24,25). Here we report the application of affinity chromatography using IRF-1-based peptide aptamers to identify proteins that interact with the Mf2 interface from within a major ID domain in the central portion of the IRF-1 protein.…”

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confidence: 99%

A Multiprotein Binding Interface in an Intrinsically Disordered Region of the Tumor Suppressor Protein Interferon Regulatory Factor-1

Narayan¹,

Halada

Hernychová

et al. 2011

Journal of Biological Chemistry

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The interferon-regulated transcription factor and tumor suppressor protein IRF-1 is predicted to be largely disordered outside of the DNA-binding domain. One of the advantages of intrinsically disordered protein domains is thought to be their ability to take part in multiple, specific but low affinity protein interactions; however, relatively few IRF-1-interacting proteins have been described. The recent identification of a functional binding interface for the E3-ubiquitin ligase CHIP within the major disordered domain of IRF-1 led us to ask whether this region might be employed more widely by regulators of IRF-1 function. Here we describe the use of peptide aptamer-based affinity chromatography coupled with mass spectrometry to define a multiprotein binding interface on IRF-1 (Mf2 domain; amino acids 106 -140) and to identify Mf2-binding proteins from A375 cells. Based on their function as known transcriptional regulators, a selection of the Mf2 domain-binding proteins (NPM1, TRIM28, and YB-1) have been validated using in vitro and cell-based assays. Interestingly, although NPM1, TRIM28, and YB-1 all bind to the Mf2 domain, they have differing amino acid specificities, demonstrating the degree of combinatorial diversity and specificity available through linear interaction motifs.

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Elevated level of SUMOylated IRF-1 in tumor cells interferes with IRF-1-mediated apoptosis

Cited by 56 publications

References 29 publications

Type I IFNs signaling and apoptosis resistance in glioblastoma cells

Type I IFNs signaling and apoptosis resistance in glioblastoma cells

Replacement of the C-terminal tetrapeptide (314PAPV317 to 314SSSM317) in interferon regulatory factor-2 alters its N-terminal DNA-binding activity

A Multiprotein Binding Interface in an Intrinsically Disordered Region of the Tumor Suppressor Protein Interferon Regulatory Factor-1

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