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KPC1-Mediated Ubiquitination and Proteasomal Processing of NF-κB1 p105 to p50 Restricts Tumor Growth
Kravtsova-Ivantsiv, Y.,Shomer, I.,Cohen-Kaplan, V.,Snijder, B.,Superti-Furga, G.,Gonen, H.,Sommer, T.,Ziv, T.,Admon, A.,Naroditsky, I.,Jbara, M.,Brik, A.,Pikarsky, E.,Kwon, Y.,Doweck, I.,Ciechanover, Cell Press ; MIT Press 2015 Cell Vol.161 No.2
NF-κB is a key transcriptional regulator involved in inflammation and cell proliferation, survival, and transformation. Several key steps in its activation are mediated by the ubiquitin (Ub) system. One uncharacterized step is limited proteasomal processing of the NF-κB1 precursor p105 to the p50 active subunit. Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. Overexpression of KPC1 inhibits tumor growth likely mediated via excessive generation of p50. Also, overabundance of p50 downregulates p65, suggesting that a p50-p50 homodimer may modulate transcription in place of the tumorigenic p50-p65. Transcript analysis reveals increased expression of genes associated with tumor-suppressive signals. Overall, KPC1 regulation of NF-κB1 processing appears to constitute an important balancing step among the stimulatory and inhibitory activities of the transcription factor in cell growth control.
Kim, Ok‐,Hwa,Park, Hyunwoong,Seong, Moon‐,Woo,Cho, Tae‐,Joon,Nishimura, Gen,Superti‐,Furga, Andrea,Unger, Sheila,Ikegawa, Shiro,Choi, In Ho,Song, Hae‐,Ryong,Kim, Hyun Woo Wiley Subscription Services, Inc., A Wiley Company 2011 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Vol.a155 No.11
<P><B>Abstract</B></P><P>Multiple epiphyseal dysplasia (MED) is a genetically heterogeneous group of diseases characterized by variable degrees of epiphyseal abnormality primarily involving the hip and knee joints. The purpose of this study was to investigate the frequency of mutations in individuals with a clinical and radiographic diagnosis of MED and to test the hypothesis that characteristic radiological findings may be helpful in predicting the gene responsible. The radiographs of 74 Korean patients were evaluated by a panel of skeletal dysplasia experts. Six genes known to be associated with MED (<I>COMP</I>, <I>MATN3</I>, <I>COL9A1</I>, <I>COL9A2</I>, <I>COL9A3</I>, and <I>DTDST</I>) were screened by sequencing. Mutations were found in 55 of the 63 patients (87%). <I>MATN3</I> mutations were found in 30 patients (55%), followed by <I>COMP</I> mutations in 23 (41%), and <I>COL9A2</I> and <I>DTDST</I> mutations in one patient (2%) each. Comparisons of radiographic findings in patients with <I>COMP</I> and <I>MATN3</I> mutations showed that albeit marked abnormalities in hip and knee joints were observed in both groups, the degree of involvement and the morphology of dysplastic epiphyses differed markedly. The contour of the pelvic acetabulum, the presence of metaphyseal vertical striations, and/or the brachydactyly of the hand were also found to be highly correlated with the genotypes. The study confirms that <I>MATN3</I> and <I>COMP</I> are the genes most frequently responsible for MED and that subtle radiographic signs may give precious indications on which gene(s) should be prioritized for mutational screening in a given individual. © 2011 Wiley Periodicals, Inc.</P>
IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes
Michael Bonelli,Karolina Dalwigk,Alexander Platzer,Isabel Olmos Calvo,Silvia Hayer,Birgit Niederreiter,Johannes Holinka,Florian Sevelda,Thomas Pap,Günter Steiner,Giulio Superti-Furga,Josef S. Smolen,H 생화학분자생물학회 2019 Experimental and molecular medicine Vol.51 No.-
Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation. The major drivers of synovial inflammation are cytokines and chemokines. Among these molecules, TNF activates fibroblast-like synoviocytes (FLSs), which leads to the production of inflammatory mediators. Here, we show that TNF regulates the expression of the transcription factor interferon regulatory factor 1 (IRF1) in human FLSs as well as in a TNF transgenic arthritis mouse model. Transcriptomic analyses of IRF1-deficient, TNF-stimulated FLSs define the interferon (IFN) pathway as a major target of IRF1. IRF1 expression is associated with the expression of IFNβ, which leads to the activation of the JAK-STAT pathway. Blocking the JAK-STAT pathway with the Janus kinase inhibitor (JAKinib) baricitinib or tofacitinib reduces the expression of IFN-regulated genes (IRGs) in TNF-activated FLSs. Therefore, we conclude that TNF induces a distinct inflammatory cascade, in which IRGs are key elements, in FLSs. The IFN-signature might be a promising biomarker for the efficient and personalized use of new treatment strategies for RA, such as JAKinibs.
BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia
Cho, S.Y.,Bae, J.S.,Kim, N.K.D.,Forzano, F.,Girisha, K.M.,Baldo, C.,Faravelli, F.,Cho, T.J.,Kim, D.,Lee, K.Y.,Ikegawa, S.,Shim, J.S.,Ko, A.R.,Miyake, N.,Nishimura, G.,Superti-Furga, A.,Spranger, J.,Ki University of Chicago Press [etc.] 2016 American journal of human genetics Vol.98 No.6
<P>Spondyloepimetaphyseal dysplasias (SEMDs) comprise a heterogeneous group of autosomal-dominant and autosomal-recessive disorders. An apparent X-linked recessive (XLR) form of SEMD in a single Italian family was previously reported. We have been able to restudy this family together with a second family from Korea by segregating a severe SEMD in an X-linked pattern. Exome sequencing showed missense mutations in BGN c.439A>G (p.Lys147Glu) in the Korean family and c.776G>T (p.Gly259Val) in the Italian family; the c.439A>G (p.Lys147Glu) mutation was also identified in a further simplex SEMD case from India. Biglycan is an extracellular matrix proteoglycan that can bind transforming growth factor beta (TGF-beta) and thus regulate its free concentration. In 3-dimensional simulation, both altered residues localized to the concave arc of leucine-rich repeat domains of biglycan that interact with TGF-beta. The observation of recurrent BGN mutations in XLR SEMD individuals from different ethnic backgrounds allows us to define 'XLR SEMD, BGN type'' as a nosologic entity.</P>