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Cheng-Wei Wu, Andrew Deonarine, Aaron Przybysz, Kevin Strange, Keith P Choe
SKN-1/Nrf are the primary antioxidant/detoxification response transcription factors in animals and they promote health and longevity in many contexts. SKN-1/Nrf are activated by a remarkably broad-range of natural and synthetic compounds and physiological conditions. Defining the signaling mechanisms that regulate SKN-1/Nrf activation provides insights into how cells coordinate responses to stress. Nrf2 in mammals is regulated in part by the redox sensor repressor protein named Keap1. In C. elegans, the p38 MAPK cascade in the intestine activates SKN-1 during oxidative stress by promoting its nuclear accumulation...
October 2016: PLoS Genetics
John F Dankert, Gergely Rona, Linda Clijsters, Phillip Geter, Jeffrey R Skaar, Keria Bermudez-Hernandez, Elizabeth Sassani, David Fenyö, Beatrix Ueberheide, Robert Schneider, Michele Pagano
SLBP (stem-loop binding protein) is a highly conserved factor necessary for the processing, translation, and degradation of H2AFX and canonical histone mRNAs. We identified the F-box protein cyclin F, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the G2 ubiquitin ligase for SLBP. SLBP interacts with cyclin F via an atypical CY motif, and mutation of this motif prevents SLBP degradation in G2. Expression of an SLBP stable mutant results in increased loading of H2AFX mRNA onto polyribosomes, resulting in increased expression of H2A...
September 24, 2016: Molecular Cell
Meng Chen, Nathaniel Rothman, Yuanqing Ye, Jian Gu, Paul A Scheet, Maosheng Huang, David W Chang, Colin P Dinney, Debra T Silverman, Jonine D Figueroa, Stephen J Chanock, Xifeng Wu
Genome-wide association studies (GWAS) are designed to identify individual regions associated with cancer risk, but only explain a small fraction of the inherited variability. Alternative approach analyzing genetic variants within biological pathways has been proposed to discover networks of susceptibility genes with additional effects. The gene set enrichment analysis (GSEA) may complement and expand traditional GWAS analysis to identify novel genes and pathways associated with bladder cancer risk. We selected three GSEA methods: Gen-Gen, Aligator, and the SNP Ratio Test to evaluate cellular signaling pathways involved in bladder cancer susceptibility in a Texas GWAS population...
July 2016: Genes & Cancer
Shifeng Su, Xiaoyu Chen, Jiang Geng, John T Minges, Gail Grossman, Elizabeth M Wilson
Melanoma antigen-A11 (MAGE-A11) is a proto-oncogene involved in androgen receptor signaling and androgen-dependent cell growth. In this report we provide evidence that MAGE-A11 interacts with Skp2 (S phase kinase-associated protein), the substrate recognition protein of the Skp1-Cullin1-F-box E3 ubiquitin ligase, and with Skp2 binding protein, cyclin A. A similar cyclin A binding motif in MAGE-A11 and Skp2A was consistent with a competitive relationship between MAGE-A11 and Skp2 in binding cyclin A. Skp2 inhibited MAGE-A11 interaction with cyclin A...
October 6, 2016: Molecular and Cellular Endocrinology
Yan Ma, Meijuan Yan, Hua Huang, Li Zhang, Qian Wang, Yaqi Zhao, Jianmei Zhao
Non-Hodgkin lymphoma (NHL) is a primary tumor arising in lymph nodes and lymphoid tissue. The incidence of NHL is increasing at an annual rate of 3%. The human Jun activation domain-binding protein 1/COP9 signalosome subunit 5 (Jab1/CSN5) is a negative regulator of the cell cycle inhibitor p27(Kip1) and abnormal expression of Jab1 is correlated with reduced p27 expression and associated with advanced tumor stage and poor prognosis in several human cancers. F-box protein S-phase kinase-interacting protein-2 (Skp2), the substrate recognition subunit of the Skp1-Cul1-F-box protein ubiquitin protein ligase complex, is required for the ubiquitination and consequent degradation of p27...
October 2016: Molecular and Clinical Oncology
Justyna A Karolak, Tomasz Gambin, Jose A Pitarque, Andrea Molinari, Shalini Jhangiani, Pawel Stankiewicz, James R Lupski, Marzena Gajecka
Keratoconus (KTCN) is a protrusion and thinning of the cornea, resulting in impairment of visual function. The extreme genetic heterogeneity makes it difficult to discover factors unambiguously influencing the KTCN phenotype. In this study, we used whole-exome sequencing (WES) and Sanger sequencing to reduce the number of candidate genes at the 5q31.1-q35.3 locus and to prioritize other potentially relevant variants in an Ecuadorian family with KTCN. We applied WES in two affected KTCN individuals from the Ecuadorian family that showed a suggestive linkage between the KTCN phenotype and the 5q31...
October 5, 2016: European Journal of Human Genetics: EJHG
Risa Mukai, Takayuki Ohshima
Human T-cell leukemia virus type1 (HTLV-1) is an oncogenic retrovirus that is the etiological agent of adult T-cell leukemia (ATL). The HTLV-1 basic leucine-zipper factor (HBZ), which is encoded by the minus strand of the provirus, is constitutively expressed in all ATL patient cells and likely contributes to the development and maintenance of ATL. Furthermore, the overexpression of myeloid cell leukemia-1 (MCL1) is frequently observed in hematological cancers as well as several other types of cancers. Here, we found that the expression of HBZ in cells stabilized MCL1 protein expression and suppressed MCL-mediated release of cytochrome c from the mitochondria...
October 3, 2016: Molecular and Cellular Biology
Marta Delgado-Camprubi, Noemi Esteras, Marc Pm Soutar, Helene Plun-Favreau, Andrey Y Abramov
The Parkinson's disease (PD)-related protein F-box only protein 7 (Fbxo7) is the substrate-recognition component of the Skp1-Cullin-F-box protein E3 ubiquitin ligase complex. We have recently shown that PD-associated mutations in Fbxo7 disrupt mitochondrial autophagy (mitophagy), suggesting a role for Fbxo7 in modulating mitochondrial homeostasis. Here we report that Fbxo7 deficiency is associated with reduced cellular NAD(+) levels, which results in increased mitochondrial NADH redox index and impaired activity of complex I in the electron transport chain...
September 30, 2016: Cell Death and Differentiation
E Malek, M A Y Abdel-Malek, S Jagannathan, N Vad, R Karns, A G Jegga, A Broyl, M van Duin, P Sonneveld, F Cottini, K C Anderson, J J Driscoll
While clinical benefit of the proteasome inhibitor (PI) bortezomib for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin (Ub) ligase Skp1-Cullin-1-Skp2 (SCF(Skp2)) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCF(Skp2) activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B...
September 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Bastian Jöhnk, Özgür Bayram, Anja Abelmann, Thorsten Heinekamp, Derek J Mattern, Axel A Brakhage, Ilse D Jacobsen, Oliver Valerius, Gerhard H Braus
F-box proteins share the F-box domain to connect substrates of E3 SCF ubiquitin RING ligases through the adaptor Skp1/A to Cul1/A scaffolds. F-box protein Fbx15 is part of the general stress response of the human pathogenic mold Aspergillus fumigatus. Oxidative stress induces a transient peak of fbx15 expression, resulting in 3x elevated Fbx15 protein levels. During non-stress conditions Fbx15 is phosphorylated and F-box mediated interaction with SkpA preferentially happens in smaller subpopulations in the cytoplasm...
September 2016: PLoS Pathogens
Aldwin Suryo Rahmanto, Vasil Savov, Andrä Brunner, Sara Bolin, Holger Weishaupt, Alena Malyukova, Gabriela Rosén, Matko Čančer, Sonja Hutter, Anders Sundström, Daisuke Kawauchi, David Tw Jones, Charles Spruck, Michael D Taylor, Yoon-Jae Cho, Stefan M Pfister, Marcel Kool, Andrey Korshunov, Fredrik J Swartling, Olle Sangfelt
SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here, we show that SOX9 is a substrate of FBW7, a tumor suppressor, and a SCF (SKP1/CUL1/F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase and consequently degraded by SCF(FBW) (7α) Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma, one of the most common childhood brain tumors...
September 13, 2016: EMBO Journal
J M Jeffery, M Kalimutho, P Johansson, D G Cardenas, R Kumar, K K Khanna
F-box proteins in conjunction with Skp1, Cul1 and Rbx1 generate SCF complexes that are responsible for the ubiquitination of proteins, leading to their activation or degradation. Here we show that the F-box protein FBXO31 is required for normal mitotic progression and genome stability due to its role in regulating FOXM1 levels during the G2/M transition. FBXO31-depleted cells undergo a transient delay in mitosis due to an activated spindle checkpoint concomitant with an increase in lagging chromosomes and anaphase bridges...
August 29, 2016: Oncogene
Sarah J Wong, Micah D Gearhart, Alexander B Taylor, David R Nanyes, Daniel J Ha, Angela K Robinson, Jason A Artigas, Oliver J Lee, Borries Demeler, P John Hart, Vivian J Bardwell, Chongwoo A Kim
KDM2B recruits H2A-ubiquitinating activity of a non-canonical Polycomb Repression Complex 1 (PRC1.1) to CpG islands, facilitating gene repression. We investigated the molecular basis of recruitment using in vitro assembly assays to identify minimal components, subcomplexes, and domains required for recruitment. A minimal four-component PRC1.1 complex can be assembled by combining two separately isolated subcomplexes: the DNA-binding KDM2B/SKP1 heterodimer and the heterodimer of BCORL1 and PCGF1, a core component of PRC1...
October 4, 2016: Structure
Ken-Ichi Kubo, Mai Tsukahara, Sota Fujii, Kohji Murase, Yuko Wada, Tetsuyuki Entani, Megumi Iwano, Seiji Takayama
Self-incompatibility (SI) in flowering plants is a genetic reproductive barrier to distinguish self- and non-self pollen to promote outbreeding. In Solanaceae, self-pollen is rejected by the ribonucleases expressed in the styles (S-RNases), via its cytotoxic function. On the other side, male-determinant is the S-locus F-box proteins (SLFs) expressed in pollen. Multiple SLFs collaboratively detoxify non-self S-RNases; therefore non-self recognition is the mode of self-/non-self discrimination in Solanaceae. It is considered that SLFs function as a substrate-recognition module of Skp1-Cullin1-F-box (SCF) complex that inactivates non-self S-RNases via their polyubiquitination that leads to degradation by 26S proteasome...
August 26, 2016: Plant & Cell Physiology
Siv Vingill, David Brockelt, Camille Lancelin, Lars Tatenhorst, Guergana Dontcheva, Christian Preisinger, Nicola Schwedhelm-Domeyer, Sabitha Joseph, Miso Mitkovski, Sandra Goebbels, Klaus-Armin Nave, Jörg B Schulz, Till Marquardt, Paul Lingor, Judith Stegmüller
Mutations in the FBXO7 (PARK15) gene have been implicated in a juvenile form of parkinsonism termed parkinsonian pyramidal syndrome (PPS), characterized by Parkinsonian symptoms and pyramidal tract signs. FBXO7 (F-box protein only 7) is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its relevance and function in neurons remain to be elucidated. Here, we report that the E3 ligase FBXO7-SCF binds to and ubiquitinates the proteasomal subunit PSMA2. In addition, we show that FBXO7 is a proteasome-associated protein involved in proteasome assembly...
September 15, 2016: EMBO Journal
Kazuya Nishio, Yukiko Yoshida, Keiji Tanaka, Tsunehiro Mizushima
The SCF ubiquitin ligase comprises four components: Skp1, Cul1, Rbx1 and a variable-subunit F-box protein. The F-box protein Fbs1, which recognizes the N-linked glycoproteins, is involved in the endoplasmic reticulum-associated degradation pathway. Although FBG3, another F-box protein, shares 51% sequence identity with Fbs1, FBG3 does not bind glycoproteins. To investigate the sequence-structure relationship of the substrate-binding pocket, the crystal structure of a mutant substrate-binding domain of Fbs1 in which the six nonconserved regions (β1, β2-β3, β3-β4, β5-β6, β7-β8 and β9-β10) of Fbs1 were substituted with those of FBG3 was determined...
August 2016: Acta Crystallographica. Section F, Structural Biology Communications
Hi-Jai R Shin, Hyunkyung Kim, Keun Il Kim, Sung Hee Baek
Macroautophagy (hereafter referred to as autophagy) is an essential self-digestion process to maintain homeostasis and promote survival in response to starvation. Although the components of autophagy in the cytoplasm have been well-studied, little has been known about the fine-tuning mechanism of autophagy through epigenetic regulations. Recently, we identified the histone arginine methyltransferase CARM1 as a new component and followed histone H3R17 dimethylation as a critical epigenetic mark in starvation-induced autophagy...
August 3, 2016: Autophagy
Ji-Gen Ping, Fei Wang, Jin-Xian Pu, Ping-Fu Hou, Yan-Su Chen, Jin Bai, Jun-Nian Zheng
Cullin1 (Cul1) is a scaffold protein of the ubiquitin E3 ligase Skp1/Cullin1/Rbx1/F-box protein complex, which ubiquitinates a broad range of proteins involved in cell-cycle progression, signal transduction, and transcription. To investigate the role of Cul1 in the development of renal cell carcinoma (RCC), we evaluated the Cul1 expression by immunohistochemistry using a tissue microarray (TMA) containing 307 cases of RCC tissues and 34 normal renal tissues. The Cul1 expression was increased significantly in RCC and was correlated with renal carcinoma histology grade (P = 0...
July 23, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Kalyani S Kulkarni, Harshvardhan N Zala, Tejas C Bosamia, Yogesh M Shukla, Sushil Kumar, Ranbir S Fougat, Mruduka S Patel, Subhash Narayanan, Chaitanya G Joshi
Understanding the plant-pathogen interactions is of utmost importance to design strategies for minimizing the economic deficits caused by pathogens in crops. With an aim to identify genes underlying resistance to downy mildew, a major disease responsible for productivity loss in pearl millet, transcriptome analysis was performed in downy mildew resistant and susceptible genotypes upon infection and control on 454 Roche NGS platform. A total of ~685 Mb data was obtained with 1 575 290 raw reads. The raw reads were pre-processed into high-quality (HQ) reads making to ~82% with an average of 427 bases...
2016: Frontiers in Plant Science
Yi He, Chong Wang, James D Higgins, Junping Yu, Jie Zong, Pingli Lu, Dabing Zhang, Wanqi Liang
F-box proteins constitute a large superfamily in plants and play important roles in controlling many biological processes, but the roles of F-box proteins in male meiosis in plants remain unclear. Here, we identify the rice (Oryza sativa) F-box gene MEIOTIC F-BOX (MOF), which is essential for male meiotic progression. MOF belongs to the FBX subfamily and is predominantly active during leptotene to pachytene of prophase I. mof meiocytes display disrupted telomere bouquet formation, impaired pairing and synapsis of homologous chromosomes, and arrested meiocytes at late prophase I, followed by apoptosis...
August 2016: Plant Cell
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