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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
T Liu, J Xiong, S Yi, H Zhang, S Zhou, L Gu, M Zhou
The FK506-binding protein 12 (FKBP12) is a cytoplasmic protein and has been reported to possess multiple functions in signaling transduction based on its interaction with different cellular targets. Here, we report that FKBP12 interacts with oncoprotein MDM2 and induces MDM2 degradation. We demonstrate that FKBP12 degrades MDM2 through binding to MDM2 protein, disrupting MDM2/MDM4 interaction and inducing MDM2 self-ubiquitination. The FKBP12-mediated MDM2 degradation was significantly enhanced when the transfected MDM2 was localized in the cytoplasm...
September 12, 2016: Oncogene
Elena Maspero, Simona Polo
Ubiquitination of proteins in vitro has evolved as an indispensable tool for the functional analysis of this posttranslational modification. In vitro ubiquitination is particularly helpful to study conjugation mechanisms. The efficiency of the ubiquitination reaction depends in part on the quality of the enzymes utilized. Here we introduce the assay developed in our lab to study HECT E3 ligases. It involves bacterially expressed E1, His-tagged Ube2D3 (also called UbcH5c, the best E2 for Nedd4), untagged Nedd4, and untagged ubiquitin (Ub)...
2016: Methods in Molecular Biology
J Hou, Q Deng, J Zhou, J Zou, Y Zhang, P Tan, W Zhang, H Cui
CSN6, a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), has received attention as a regulator of the degradation of cancer-related proteins such as p53, c-myc and c-Jun, through the ubiquitin-proteasome system, suggesting its importance in cancerogenesis. However, the biological functions and molecular mechanisms of CSN6 in glioblastoma (GBM) remain poorly understood. Here, we report that GBM tumors overexpressed CSN6 compared with normal brain tissues and that CSN6 promoted GBM cell proliferation, migration, invasion and tumorigenesis...
August 22, 2016: Oncogene
Kamal Kumar Chaudhary, Sarvesh Kumar Gupta, Nidhi Mishra
NEDD-4 are closely related E3 ubiquitin-protein ligases that include a C2 domain, three or four WW domains and a catalytic HECT ubiquitin ligase domain. The WW domains of NEDD-4 proteins recognize substrates for ubiquitination by binding the sequence L/PPxY (the PY-motif) present in target proteins. NEDD-4 functions as a suppressor of the epithelial Na+ channel (ENaC), which interacts with NEDD-4 WW domains via PY-motifs located at its C-terminus. Fifty compounds, all of them flavanoids, were subjected to molecular docking studies...
March 30, 2016: Interdisciplinary Sciences, Computational Life Sciences
Lei Guo, Li Jiang, Ying Zhang, Xiu-Li Lu, Qi Xie, Dolf Weijers, Chun-Ming Liu
As the start of a new life cycle, activation of the first division of the zygote is a critical event in both plants and animals. Because the zygote in plants is difficult to access, our understanding of how this process is achieved remains poor. Here we report genetic and cell biological analyses of the zygote-arrest 1 (zyg1) mutant in Arabidopsis, which showed zygote-lethal and over-accumulation of cyclin B1 D-box-GUS in ovules. Map-based cloning showed that ZYG1 encodes the anaphase-promoting complex/cyclosome (APC/C) subunit 11 (APC11)...
April 2016: Plant Journal: for Cell and Molecular Biology
Yiwei Du, Wei He, Changwang Deng, Xi Chen, Lanming Gou, Fugui Zhu, Wei Guo, Jianfu Zhang, Tao Wang
Flowering time is a critical trait for crops cultivated under various temperature/photoperiod conditions around the world. To understand better the flowering time of rice, we used the vector pTCK303 to produce several lines of RNAi knockdown transgenic rice and investigated their flowering times and other agronomic traits. Among them, the heading date of FRRP1-RNAi knockdown transgenic rice was 23-26 days earlier than that of wild-type plants. FRRP1 is a novel rice gene that encodes a C3HC4-type Really Interesting Novel Gene (RING) finger domain protein...
2016: PloS One
Kun Gao, Chenji Wang, Xiaofeng Jin, Jiantao Xiao, Enceng Zhang, Xianmei Yang, Dejie Wang, Haojie Huang, Long Yu, Pingzhao Zhang
The oncoprotein MDM2 is an E3 ubiquitin ligase that targets tumor suppressor p53 for ubiquitination and proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. Dysregulation of MDM2-p53 axis was frequently observed in human cancers. Originally, it is proposed that MDM2 degradation was mainly achieved by destructive self-ubiquitination. However, recent study suggests that MDM2 may be targeted for degradation by an external E3 ubiquitin ligase(s) under physiological levels...
May 28, 2016: Cancer Letters
Jin-Mi Heo, Alban Ordureau, Joao A Paulo, Jesse Rinehart, J Wade Harper
Damaged mitochondria are detrimental to cellular homeostasis. One mechanism for removal of damaged mitochondria involves the PINK1-PARKIN pathway, which poly-ubiquitylates damaged mitochondria to promote mitophagy. We report that assembly of ubiquitin chains on mitochondria triggers autophagy adaptor recruitment concomitantly with activation of the TBK1 kinase, which physically associates with OPTN, NDP52, and SQSTM1. TBK1 activation in HeLa cells requires OPTN and NDP52 and OPTN ubiquitin chain binding. In addition to the known role of S177 phosphorylation in OPTN on ATG8 recruitment, TBK1-dependent phosphorylation on S473 and S513 promotes ubiquitin chain binding in vitro as well as TBK1 activation, OPTN mitochondrial retention, and efficient mitophagy in vivo...
October 1, 2015: Molecular Cell
K Mahajan
Genome integrity is vital to cellular homeostasis and its forfeiture is linked to deleterious consequences-cancer, immunodeficiency, genetic disorders and premature aging. The human ubiquitin ligase Pso4/Prp19 has emerged as a critical component of multiple DNA damage response (DDR) signaling networks. It not only senses DNA damage, binds double-stranded DNA in a sequence-independent manner, facilitates processing of damaged DNA, promotes DNA end joining, regulates replication protein A (RPA2) phosphorylation and ubiquitination at damaged DNA, but also regulates RNA splicing and mitotic spindle formation in its integral capacity as a scaffold for a multimeric core complex...
May 5, 2016: Oncogene
Emad Arafa, Philip A Bondzie, Kobra Rezazadeh, Rosana D Meyer, Edward Hartsough, Joel M Henderson, John H Schwartz, Vipul Chitalia, Nader Rahimi
Oxidative damage to renal tubular epithelial cells is a fundamental pathogenic mechanism implicated in both acute kidney injury and chronic kidney diseases. Because epithelial cell survival influences the outcome of acute kidney injury and chronic kidney diseases, identifying its molecular regulators could provide new insight into pathobiology and possible new therapeutic strategies for these diseases. We have identified transmembrane and immunoglobulin domain-containing 1 (TMIGD1) as a novel adhesion molecule, which is highly conserved in humans and other species...
October 2015: American Journal of Pathology
J Wang, Y Zhang, J Hou, X Qian, H Zhang, Z Zhang, M Li, R Wang, K Liao, Y Wang, Z Li, D Zhong, P Wan, L Dong, F Liu, X Wang, Y Wan, W Xiao, W W Zhang
Sox2 has a critical role in embryonic stem (ES) cell maintenance and differentiation. Interestingly, its activity is highly dosage-dependent. Although transcriptional regulation of Sox2 has been extensively studied, the mechanisms orchestrating its degradation remain unclear. In this study, we identified ubiquitin-conjugating enzyme E2S (Ube2s) as a novel effector for Sox2 protein degradation. Ube2s mediates K11-linked polyubiquitin chain formation at the Sox2-K123 residue, thus marking it for proteasome-mediated degradation...
March 2016: Cell Death and Differentiation
L Fan, G Peng, N Sahgal, L Fazli, M Gleave, Y Zhang, A Hussain, J Qi
The histone demethylase JMJD1A, which controls gene expression by epigenetic regulation of H3K9 methylation marks, functions in diverse activities, including spermatogenesis, metabolism and stem cell self-renewal and differentiation. Here, we found that JMJD1A knockdown in prostate cancer cells antagonizes their proliferation and survival. Profiling array analyses revealed that JMJD1A-dependent genes function in cellular growth, proliferation and survival, and implicated that the c-Myc transcriptional network is deregulated following JMJD1A inhibition...
May 12, 2016: Oncogene
Hong Liu, Yan Ma, Hong-Wei He, Jia-Ping Wang, Jian-Dong Jiang, Rong-Guang Shao
Autophagy, a self-catabolic process, has been found to be involved in abrogating the proliferation and metastasis of breast cancer. SLC9A3R1 (solute carrier family 9, subfamily A [NHE3, cation proton antiporter 3], member 3 regulator 1), a multifunctional scaffold protein, is involved in suppressing breast cancer cells proliferation and the SLC9A3R1-related signaling pathway regulates the activation of autophagy processes. However, the precise regulatory mechanism and signaling pathway of SLC9A3R1 in the regulation of autophagy processes in breast cancer cells remains unknown...
2015: Autophagy
Shiuh-Rong Ho, Yu-Ju Lee, Weei-Chin Lin
RNF144A, an E3 ubiquitin ligase for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), can promote DNA damage-induced cell apoptosis. Here we characterize an important regulation of RNF144A through its transmembrane (TM) domain. The TM domain of RNF144A is highly conserved among species. Deletion of the TM domain abolishes its membrane localization and also significantly reduces its ubiquitin ligase activity. Further evidence shows that the TM domain is required for RNF144A self-association and that the self-association may be partially mediated through a classic GXXXG interaction motif...
September 18, 2015: Journal of Biological Chemistry
Wei-Yu Lu, Thomas G Bird, Luke Boulter, Atsunori Tsuchiya, Alicia M Cole, Trevor Hay, Rachel V Guest, Davina Wojtacha, Tak Yung Man, Alison Mackinnon, Rachel A Ridgway, Timothy Kendall, Michael J Williams, Thomas Jamieson, Alex Raven, David C Hay, John P Iredale, Alan R Clarke, Owen J Sansom, Stuart J Forbes
Hepatocytes and cholangiocytes self-renew following liver injury. Following severe injury hepatocytes are increasingly senescent, but whether hepatic progenitor cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where the E3 ubiquitin ligase Mdm2 is inducibly deleted in more than 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution...
August 2015: Nature Cell Biology
Xiaoxiao Li, Wei Wei, HoangDinh Huynh, Hao Zuo, Xueqian Wang, Yihong Wan
Osteoclasts are bone-resorbing cells essential for skeletal remodeling. However, over-active osteoclasts can cause bone-degenerative disorders. Therefore, the level of NFATc1, the master transcription factor of osteoclast, must be tightly controlled. Although the activation and amplification of NFATc1 have been extensively studied, how NFATc1 signaling is eventually resolved is unclear. Here, we uncover a novel and critical role of the orphan nuclear receptor Nur77 in mediating an NFATc1 self-limiting regulatory loop to prevent excessive osteoclastogenesis...
2015: ELife
Chanmi Park, Chae Woo Lim, Woonhee Baek, Sung Chul Lee
Several E3 ubiquitin ligases have been associated with the response to abiotic and biotic stresses in higher plants. Here, we report that the hot pepper (Capsicum annuum) ABA-Insensitive RING protein 1 gene (CaAIR1) is essential for a hypersensitive response to drought stress. CaAIR1 contains a C3HC4-type RING finger motif, which plays a role for attachment of ubiquitins to the target protein, and a putative transmembrane domain. The expression levels of CaAIR1 are up-regulated in pepper leaves by ABA treatments, drought and NaCl, suggesting its role in the response to abiotic stress...
September 2015: Plant & Cell Physiology
Charbel E-H Moussa
Parkin biology has emerged as an exciting area of pharmaceutical development for several human diseases, including cancer and neurodegeneration. Parkin's role is multifaceted in human health and disease and its function affecting major cellular quality control mechanisms, including the ubiquitin-proteasome and autophagy-lysosome systems, is critical in the maintenance of cellular homeostasis. Loss of Parkin function due to aging, protein instability and gene mutations is manifest in a number of human diseases, contributing to the validation of this protein as a therapeutic target...
2015: Neuro-degenerative Diseases
Lingling Fan, Guihong Peng, Arif Hussain, Ladan Fazli, Emma Guns, Martin Gleave, Jianfei Qi
Re-activation of androgen receptor (AR) activity is the main driver for development of castration-resistant prostate cancer. We previously reported that the ubiquitin ligase Siah2 enhanced AR transcriptional activity and prostate cancer cell growth. Among the genes we found to be regulated by Siah2 was AKR1C3, which encodes a key androgen biosynthetic enzyme implicated in castration-resistant prostate cancer development. Here, we found that Siah2 inhibition in CWR22Rv1 prostate cancer cells decreased AKR1C3 expression as well as intracellular androgen levels, concomitant with inhibition of cell growth in vitro and in orthotopic prostate tumors...
August 21, 2015: Journal of Biological Chemistry
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