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https://www.readbyqxmd.com/read/27933373/outcomes-of-multiple-myeloma-patients-receiving-bortezomib-lenalidomide-and-carfilzomib
#1
Ariana Berenson, Suzie Vardanyan, Michael David, James Wang, Nika Manik Harutyunyan, Jillian Gottlieb, Ran Halleluyan, Tanya M Spektor, Kyle A Udd, Shahrooz Eshaghian, Youram Nassir, Benjamin Eades, Regina Swift, James R Berenson
New classes of drugs including the proteasome inhibitors (PI) bortezomib and, more recently, carfilzomib and the immunomodulatory agent lenalidomide have shown improved outcomes for multiple myeloma (MM) patients during the past decade. However, most of the studies reporting outcomes for patients receiving these drugs have relied on older data sets derived from large institutions that included patients not receiving their treatment at those facilities and represented only those eligible for clinical trials or were from sites where treatment options were limited...
December 8, 2016: Annals of Hematology
https://www.readbyqxmd.com/read/27932943/vacuolar-protein-sorting-genes-in-parkinson-s-disease-a-re-appraisal-of-mutations-detection-rate-and-neurobiology-of-disease
#2
REVIEW
Stefano Gambardella, Francesca Biagioni, Rosangela Ferese, Carla L Busceti, Alessandro Frati, Giuseppe Novelli, Stefano Ruggieri, Francesco Fornai
Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined...
2016: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/27932681/acute-intermittent-hypoxia-in-rats-activates-muscle-proteolytic-pathways-through-a-glucocorticoid-dependent-mechanism
#3
Franciele Przygodda, Leandro Henrique Manfredi, Juliano Machado, Dawit A P Gonçalves, Neusa Maria Zanon, Leni G H Bonagamba, Benedito H Machado, Isis do Carmo Kettelhut, Luiz C C Navegantes
Although it is well known that chronic hypoxia induces muscle wasting, the effects of intermit-tent hypoxia on skeletal muscle protein metabolism remains unclear. We hypothesized that acute intermittent hypoxia (AIH), a challenge that activates the hypothalamic-pituitary-adrenal axis, would alter muscle protein homeostasis through a glucocorticoid-dependent mechanism. Three-week-old rats were submitted to adrenalectomy (ADX) and exposed to 8 h of AIH (6% O2 for 40s at 9 min intervals). Animals were sacrificed and the soleus and extensor digitorum longus (EDL) muscles were harvested and incubated in vitro for measurements of protein turn-over...
December 8, 2016: Journal of Applied Physiology
https://www.readbyqxmd.com/read/27932574/ulk1-cycling-the-ups-and-downs-of-the-autophagy-response
#4
Yan G Zhao, Hong Zhang
The Ser/Thr kinase ULK1/Atg1 controls autophagy initiation under nutrient starvation conditions. In this issue, Nazio et al. (2016. J. Cell Biol. https://doi.org/10.1083/jcb.201605089) demonstrate that oscillatory modulation of NEDD4L-mediated proteasomal degradation and mTOR-dependent de novo protein synthesis of ULK1 ensures the proper amplitude and duration of the autophagy response during prolonged starvation, thus maintaining cellular homeostasis.
December 8, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27932573/fine-tuning-of-ulk1-mrna-and-protein-levels-is-required-for-autophagy-oscillation
#5
Francesca Nazio, Marianna Carinci, Cristina Valacca, Pamela Bielli, Flavie Strappazzon, Manuela Antonioli, Fabiola Ciccosanti, Carlo Rodolfo, Silvia Campello, Gian Maria Fimia, Claudio Sette, Paolo Bonaldo, Francesco Cecconi
Autophagy is an intracellular degradation pathway whose levels are tightly controlled to secure cell homeostasis. Unc-51-like kinase 1 (ULK1) is a conserved serine-threonine kinase that plays a central role in the initiation of autophagy. Here, we report that upon autophagy progression, ULK1 protein levels are specifically down-regulated by the E3 ligase NEDD4L, which ubiquitylates ULK1 for degradation by the proteasome. However, whereas ULK1 protein is degraded, ULK1 mRNA is actively transcribed. Upon reactivation of mTOR-dependent protein synthesis, basal levels of ULK1 are promptly restored, but the activity of newly synthesized ULK1 is inhibited by mTOR...
December 8, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27932549/proteolytic-degradation-of-heat-shock-protein-a2-occurs-in-response-to-oxidative-stress-in-male-germ-cells-of-the-mouse
#6
Elizabeth G Bromfield, R John Aitken, Eileen A McLaughlin, Brett Nixon
STUDY QUESTION: Does oxidative stress compromise the protein expression of heat shock protein A2 (HSPA2) in the developing germ cells of the mouse testis? SUMMARY ANSWER: Oxidative stress leads to the modification of HSPA2 by the lipid aldehyde 4-hydroxynonenal (4HNE) and initiates its degradation via the ubiquitin-proteasome system. WHAT IS KNOWN ALREADY: Previous work has revealed a deficiency in HSPA2 protein expression within the spermatozoa of infertile men that have failed fertilization in a clinical setting...
December 8, 2016: Molecular Human Reproduction
https://www.readbyqxmd.com/read/27932072/a-case-for-sec61-channel-involvement-in-erad
#7
REVIEW
Karin Römisch
Proteins that misfold in the endoplasmic reticulum (ER) need to be transported back to the cytosol for degradation by proteasomes, a process known as ER-associated degradation (ERAD). The first candidate discussed as a retrograde protein transport conduit was the Sec61 channel which is responsible for secretory protein transport into the ER during biogenesis. The Sec61 channel binds the proteasome 19S regulatory particle which can extract an ERAD substrate from the ER. Nevertheless its role as a general export channel has been dismissed, and Hrd1 and Der1 have been proposed as alternatives...
December 5, 2016: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/27930845/isolation-and-characterization-of-rna-aptamers-against-a-proteasome-associated-deubiquitylating-enzyme-uch37
#8
Jung Hoon Lee, Min Jae Lee
Deubiquitylating (DUB) enzymes antagonize ubiquitin-dependent protein degradation both before and after the substrates are engaged with proteasomes. UCH37 is one of three proteasome-associated DUB enzymes in mammals and the only protease among them from the ubiquitin carboxyl-terminal hydrolase (UCH) family. Here, we report the identification of specific RNA aptamers for UCH37 through in vitro selection, and we describe their inhibitory effects on the DUB activity of UCH37. The RNA aptamers significantly delayed RPN13-mediated UCH37 activation and lowered total DUB activity of proteasomes, as measured by the hydrolysis of ubiquitin-rhodamine 110...
December 8, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27929429/the-regulation-of-tumor-suppressor-p63-by-the-ubiquitin-proteasome-system
#9
REVIEW
Stephen R Armstrong, Hong Wu, Benfan Wang, Yasser Abuetabh, Consolato Sergi, Roger P Leng
The protein p63 has been identified as a homolog of the tumor suppressor protein p53 and is capable of inducing apoptosis, cell cycle arrest, or senescence. p63 has at least six isoforms, which can be divided into two major groups: the TAp63 variants that contain the N-terminal transactivation domain and the ΔNp63 variants that lack the N-terminal transactivation domain. The TAp63 variants are generally considered to be tumor suppressors involved in activating apoptosis and suppressing metastasis. ΔNp63 variants cannot induce apoptosis but can act as dominant negative inhibitors to block the function of TAp53, TAp73, and TAp63...
December 6, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27929395/deficiency-in-the-ubiquitin-conjugating-enzyme-ube2a-in-alzheimer-s-disease-ad-is-linked-to-deficits-in-a-natural-circular-mirna-7-sponge-circrna-cirs-7
#10
Yuhai Zhao, Peter N Alexandrov, Vivian Jaber, Walter J Lukiw
Our understanding of the highly specialized functions for small non-coding single-stranded RNA (ssRNA) in the transcriptome of the human central nervous system (CNS) continues to evolve. Circular RNAs (circRNAs), a recently discovered class of ssRNA enriched in the brain and retina, are extremely stable and intrinsically resilient to degradation by exonuclease. Conventional methods of ssRNA, microRNA (miRNA), or messenger RNA (mRNA) detection and quantitation requiring free ribonucleotide ends may have considerably underestimated the quantity and significance of CNS circRNA in the CNS...
December 5, 2016: Genes
https://www.readbyqxmd.com/read/27929086/the-e3-ubiquitin-ligase-trim31-attenuates-nlrp3-inflammasome-activation-by-promoting-proteasomal-degradation-of-nlrp3
#11
Hui Song, Bingyu Liu, Wanwan Huai, Zhongxia Yu, Wenwen Wang, Jing Zhao, Lihui Han, Guosheng Jiang, Lining Zhang, Chengjiang Gao, Wei Zhao
The NLRP3 inflammasome has a fundamental role in host defence against microbial pathogens and its deregulation may cause diverse inflammatory diseases. NLRP3 protein expression is a rate-limiting step for inflammasome activation, thus its expression must be tightly controlled to maintain immune homeostasis and avoid detrimental effects. However, how NLRP3 expression is regulated remains largely unknown. In this study, we identify E3 ubiquitin ligase TRIM31 as a feedback suppressor of NLRP3 inflammasome. TRIM31 directly binds to NLRP3, promotes K48-linked polyubiquitination and proteasomal degradation of NLRP3...
December 8, 2016: Nature Communications
https://www.readbyqxmd.com/read/27929047/caveolin-1-is-an-aggresome-inducing-protein
#12
Ajit Tiwari, Courtney A Copeland, Bing Han, Caroline A Hanson, Krishnan Raghunathan, Anne K Kenworthy
Caveolin-1 (Cav1) drives the formation of flask-shaped membrane invaginations known as caveolae that participate in signaling, clathrin-independent endocytosis and mechanotransduction. Overexpression or mutations of Cav1 can lead to its mistrafficking, including its accumulation in a perinuclear compartment previously identified as the Golgi complex. Here, we show that in the case of overexpressed Cav1-GFP, this perinuclear compartment consists of cytoplasmic inclusion bodies generated in response to the accumulation of aggregates of misfolded proteins, known as aggresomes...
December 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27926830/what-s-the-key-to-unlocking-the-proteasome-s-gate
#13
Andres H de la Peña, Gabriel C Lander
In this issue of Structure, Bolten et al. (2016) describe the organization of the mycobacterial proteasome in complex with the ATP-independent bacterial proteasome activator (Bpa, PafE). They confirm several activation motifs employed by archaea and eukaryotes and highlight differences that pose Bpa as a novel architectural class of proteasome activators.
December 6, 2016: Structure
https://www.readbyqxmd.com/read/27926485/axitinib-induces-senescence-associated-cell-death-and-necrosis-in-glioma-cell-lines-the-proteasome-inhibitor-bortezomib-potentiates-axitinib-induced-cytotoxicity-in-a-p21-waf-cip1-dependent-manner
#14
Maria Beatrice Morelli, Consuelo Amantini, Massimo Nabissi, Claudio Cardinali, Matteo Santoni, Giovanni Bernardini, Angela Santoni, Giorgio Santoni
Glioblastoma is associated with a poor overall survival despite new treatment advances. Antiangiogenic strategies targeting VEGF based on tyrosine kinase inhibitors (TKIs) are currently undergoing extensive research for the treatment of glioma.Herein we demonstrated that the TKI axitinib induces DNA damage response (DDR) characterized by γ-H2AX phosphorylation and Chk1 kinase activation leading to G2/M cell cycle arrest and mitotic catastrophe in U87, T98 and U251 glioma cell lines. Moreover, we found that p21(Waf1/Cip1) increased levels correlates with induction of ROS and senescence-associated cell death in U87 and T98 cell lines, which are reverted by N-acetyl cysteine pretreatment...
December 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27925369/conventional-and-unconventional-ubiquitination-in-plant-immunity
#15
REVIEW
Bangjun Zhou, Lirong Zeng
Ubiquitination is one of the most abundant types of protein post-translational modifications (PTMs) in plant cells. The importance of ubiquitination in the regulation of many aspects of plant immunity has been increasingly appreciated in recent years. Most of the studies linking ubiquitination to the plant immune system, however, have been focused on the E3 ubiquitin ligases and the conventional ubiquitination that leads to degradation of the substrate proteins by the 26S proteasome. By contrast, our knowledge about the role of unconventional ubiquitination that often plays non-degradative, regulatory role remains a significant gap...
December 7, 2016: Molecular Plant Pathology
https://www.readbyqxmd.com/read/27924301/data-on-the-identity-of-non-canonical-complexes-formed-from-proteasome-subunits-in-vivo
#16
Lindsay J Hammack, Andrew R Kusmierczyk
The dataset presented here represents analysis supplied by the local proteomics core facility on samples submitted to it in support of the article "Assembly of proteasome subunits into non-canonical complexes in vivo" Hammack and Kusmierczyk (2016) [1]. This article provides the detailed protein contents of gel slices, cut from non-denaturing polyacrylamide gels, containing distinct protein complexes visualized following gel staining. The identification of the protein contents of these complexes was carried out by liquid chromatography tandem mass-spectrometry (LC-MS/MS)...
December 2016: Data in Brief
https://www.readbyqxmd.com/read/27924158/lycorine-downregulates-hmgb1-to-inhibit-autophagy-and-enhances-bortezomib-activity-in-multiple-myeloma
#17
Mridul Roy, Long Liang, Xiaojuan Xiao, Yuanliang Peng, Yuhao Luo, Weihua Zhou, Ji Zhang, Lugui Qiu, Shuaishuai Zhang, Feng Liu, Mao Ye, Wen Zhou, Jing Liu
Multiple myeloma (MM) is largely incurable and drug-resistant. Novel therapeutic approaches such as inhibiting autophagy or rational drug combinations are aimed to overcome this issue. In this study, we found that lycorine exhibits a promising anti-proliferative activity against MM in vitro and in vivo by inhibiting autophagy. We identified High mobility group box 1 (HMGB1), an important regulator of autophagy, as the most aberrantly expressed protein after lycorine treatment and as a critical mediator of lycorine activity...
2016: Theranostics
https://www.readbyqxmd.com/read/27923917/metadherin-astrocyte-elevated-gene-1-positively-regulates-the-stability-and-function-of-forkhead-box-m1-during-tumorigenesis
#18
Lixuan Yang, Kejun He, Sheng Yan, Yibing Yang, Xinya Gao, Maolei Zhang, Zhibo Xia, Zhengsong Huang, Suyun Huang, Nu Zhang
BACKGROUND: Forkhead box M1 (FOXM1) is overexpressed and activates numerous oncoproteins in tumors. However, the mechanism by which the FOXM1 protein aberrantly accumulates in human cancer remains uncertain. This study was designed to clarify the upstream signaling pathway(s) that regulate FOXM1 protein stability and transcriptional activity. METHODS: Mass spectrometry and immunoprecipitation were performed to identify the FOXM-metadherin (MTDH) interaction. In vivo and in vitro ubiquitination assays were conducted to test the effect of MTDH on FOXM1 stability...
December 6, 2016: Neuro-oncology
https://www.readbyqxmd.com/read/27923823/bortezomib-relieves-immune-tolerance-in-nasopharyngeal-carcinoma-via-stat1-suppression-and-indoleamine-2-3-dioxygenase-downregulation
#19
Guan-Min Jiang, Jun Du, Wei-Feng Ma, Hui Wang, Yu Qiu, Qiu-Gui Zhang, Wei Xu, Hui-Fang Liu, Hong-Sheng Wang, Jian-Ping Liang
Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC). Patients with intermediate and advanced stage NPC receiving only radiotherapy have limited survival, so newer immunotherapeutic approaches are sought. The major impediment to better clinical outcomes is tumor immune tolerance. Indoleamine 2, 3-dioxygenase (IDO), an interferon-γ (IFNγ)-inducible enzyme, is a major inducer of immune tolerance during tumor development; therefore, inhibition of the IDO pathway is an important modality for cancer treatment...
December 6, 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27923278/ampk-serves-as-a-therapeutic-target-against-anemia-of-inflammation
#20
Minjun Wang, Hong Xin, Wenbo Tang, Yiming Li, Zhaoyun Zhang, Linling Fan, Lei Miao, Bo Tan, Xiling Wang, Yizhun Zhu
<b>Aims:</b> Anemia of inflammation (AI), the second prevalent anemia, is associated with worse prognosis and increased mortality in numerous chronic diseases. We recently reported that the gasotransmitter hydrogen sulfide (H<sub>2</sub>S) suppressed the inflammatory activation of signal transducer and activator of transcription 3 (STAT3) and hepcidin, the critical mediators of AI. Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a novel inflammatory regulator and might be activated by H<sub>2</sub>S...
December 6, 2016: Antioxidants & Redox Signaling
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