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(12) Patent Application Publication (10) Pub. No.: US 2014/0018338A1 Chandran Et Al

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US 20140018338A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0018338A1 Chandran et al. (43) Pub. Date: Jan. 16, 2014 (54) METHODS AND ASSAYS FORTREATING CI2O 1/70 (2006.01) FLOVRIDAE INFECTIONS GOIN33/569 (2006.01) (52) U.S. Cl. (76) Inventors: Kartik Chandran, Brooklyn, NY (US); CPC .............. G0IN33/5035 (2013.01); C12O 1/70 Sean Whelan, Cambridge, MA (US); (2013.01); G0IN33/56983 (2013.01); A61 K Thijn Brummelkamp, Amsterdam 31/566 (2013.01); A61 K3I/55 (2013.01) (NL); Jan Carette, Palo Alto, CA (US); USPC ........... 514/178; 514/44. A 435/6.13:435/11; Matthijs Raaben, De Belt (NL) 435/7.92; 43.5/5: 514/217 (21) Appl. No.: 13/979,179 (57) ABSTRACT Methods and assays for treating a subject with a filovirus (22) PCT Filed: Jan. 24, 2012 infection using an agent that inhibits Niemann-Pick CI (NPCI), VPSII, VPSI6, VPSI8, VPS33A, VPS39, VPS41, (86) PCT NO.: PCT/US12A22349 BLOCISI, BLOCIS2, GNPTAB, PIKFYVE, ARHGAP23 or S371 (c)(1), FIG4. Methods for screening for an agent that treats and/or (2), (4) Date: Sep. 25, 2013 prevents infection of a subject with a filovirus, where the methods comprise determining whether the agent inhibits one Related U.S. Application Data or more of Niemann-Pick CI (NPCI), VPSII, VPSI6, VPSI8, VPS33A, VPS39, VPS41. BLOCISI, BLOCIS2, GNPTAB, (60) Provisional application No. 61/435,858, filed on Jan. PIKFYVE, ARHGAP23 or FIG4, wherein an agent that 25, 2011. inhibits one or more of NPCI, VPSII, VPSI6, VPSI8, VPS33A, VPS39, VPS41, BLOCISI, BLOCIS2, GNPTAB, Publication Classification PIKFYVE, ARHGAP23 or FIG4 is a candidate for treating and/or preventing an infection with a filovirus and wherein an (51) Int. C. agent that does not inhibit NPCI, VPSII, VPSI6, VPSI8, GOIN33/50 (2006.01) VPS33A. VPS39, VPS41, BLOCISI, BLOCIS2, GNPTAB, A6 IK3I/55 (2006.01) PIKFYVE, ARHGAP23 or FIG4 is not a candidate for treat A6 IK3I/566 (2006.01) ing and/or preventing an infection with a filovirus. Critical entry factors: & CTSB a HOPS complex NPC Patent Application Publication Jan. 16, 2014 Sheet 2 of 34 US 2014/0018338A1 b C 8 3.s s2 ------------------------------------AP CeS e 7 Control NPC 3 a Š VPS 116t g 5 VPS33AG VPS33A NPC167 4 : NPC1 GT2 ACTB is 3 WT VPS11GT VPS33A NPC G NPC GT2 . FIGURE 1 B-1D Patent Application Publication Jan. 16, 2014 Sheet 3 of 34 US 2014/0018338A1 Filipin Staining Virus infections rVSV-G rVSV-GP-EbOW Control FIGURE 2A Patent Application Publication Jan. 16, 2014 Sheet 4 of 34 US 2014/0018338A1 b s 7 2 Fibroblasts 5 WT 4 S NPC nut NPC2nut ... 3 S. 21. C 100 - - - s e- s ) rWSW-G sŠ rVSV-GP-Ebov i. "- O. O U18666A (uM) FIGURE 2B-2D Patent Application Publication Jan. 16, 2014 Sheet 5 of 34 US 2014/0018338A1 s 8 AP Cels a 7. Control S. 6 Š VRS1&T 5. $ WPS33AG NPC1&T 4 NPCGT2 $ 3. X t EBOV G cleaved) FIGURE 3A-3B Patent Application Publication Jan. 16, 2014 Sheet 6 of 34 US 2014/0018338A1 C ji" 3888& WSG WS33A'it NFO: Gi: 5 38 '' FIGURE 3C-3D Patent Application Publication Jan. 16, 2014 Sheet 7 of 34 US 2014/0018338A1 -- 234. 29 -o - - 24 as 72 96 i2O O 24 48 2 96 20 Hours post-infection Hours post-infection O. Ebow (Control) via:W (Control) O. Ebov (to drug) Marv (no drug) O Ebow (NPC) Marv (NPC1) O Ebov (U18666A) Marv (U18666A) FIGURE 4A-4B Patent Application Publication Jan. 16, 2014 Sheet 8 of 34 US 2014/0018338A1 Critical entry factors: CTSB HOPS complex NPC FIGURE 4C Patent Application Publication Jan. 16, 2014 Sheet 9 of 34 US 2014/0018338A1 FIGURE 5A Patent Application Publication Jan. 16, 2014 Sheet 10 of 34 US 2014/0018338A1 1a : 8 in '- 40 as 2 8, iOO S2 883 g 80 5 30 20 C. O s C O SO CO SO 100 virus concentration (MOI) FIGURE 5B-5C Patent Application Publication Jan. 16, 2014 Sheet 11 of 34 US 2014/0018338A1 HAP1 cells mutagenized with gene trap (complexity - 100x 106) unselected selected with Control - rWSW-GP-Ebola ( Y deep sequence deep sequence isolate insertion Sites insertion Sites cona derivatives l Count independent count independent functional insertions per gene insertions per gene Studies Control experimental dataSet dataSet -430,000 w -700 insertions insetors calculate per gene the significance of enrichment in experimental dataset gene with multiple insertions and high significance of Expected Observed enrichment (based on control) Genes in experimental dataset FIGURE 6 Patent Application Publication Jan. 16, 2014 Sheet 12 of 34 US 2014/0018338A1 pose WS syS s WS33Ak SNossos orSeŠsessessssssssssssssSssssssssssssssssssssssssssssssssssssssssssss S WPS1 endogenous locus PS11 gene trap ocus PS33 endogenous locus PS33 gene trap locus FIGURE 7A-7B Patent Application Publication Jan. 16, 2014 Sheet 13 of 34 US 2014/0018338A1 FIGURE 7C Patent Application Publication Jan. 16, 2014 Sheet 14 of 34 US 2014/0018338A1 8 b ii iss c --&N x\\ S 8 f 8 : & Ko S 7 C CHO cells d 6 NC g 5 W s 4. NPC10 g " 3 st CKai. S 2 J FIGURE 8A-8B Patent Application Publication Jan. 16, 2014 Sheet 15 of 34 US 2014/0018338A1 7. 6 $ $ $ $ Fibroblasts 5 Control 4. NPC2 muta CS& CX& cSS S. is FIGURE 9 Patent Application Publication Jan. 16, 2014 Sheet 16 of 34 US 2014/0018338A1 a. CHO-NPC10/vec CHO-NPC10/NPC1-flag S FIGURE 10A-10B Patent Application Publication Jan. 16, 2014 Sheet 17 of 34 US 2014/0018338A1 a. b g s 200 S 2 50 se 3 No drug SD 100 . g E-64 se < 50 e O s O SN && cS CN Š C V S (S NY N Q SksS CN S3 C C. S. C. S. CCatB hCatB- - CCat SC hCat on CCat C Š- Contoloadin FIGURE 11 A-11C Patent Application Publication Jan. 16, 2014 Sheet 18 of 34 US 2014/0018338A1 nOck BafA NHC FIGURE 12 Patent Application Publication Jan. 16, 2014 Sheet 19 of 34 US 2014/0018338A1 NPC GT2 FIGURE 13 Patent Application Publication Jan. 16, 2014 Sheet 20 of 34 US 2014/0018338A1 OO ::::::::: 10 :::::::: 8O n 8 60 m 6 No drug : CD 40 k As a A aS2 4 U18666A S S 20 2 h pi: 48 72 96 48 72 96 48 E.OV MarV MarV HUWEC OC FIGURE 14A-14B Patent Application Publication Jan. 16, 2014 Sheet 21 of 34 US 2014/0018338A1 6 DMSO vehicle 5 S. a was Š U 8666A 3 3 2 O Time of pretreatment (h) OO O so to so Time of U18666A addition (min) FIGURE 15A-15B Patent Application Publication Jan. 16, 2014 Sheet 22 of 34 US 2014/0018338A1 S irriprattireUntreated (88. s in * : S s wa se cy. S 30 . - - - - - is as hrs fairs 38 is irs Niarburg Cit? Exia airs SS FIGURE 16 Patent Application Publication Jan. 16, 2014 Sheet 23 of 34 US 2014/0018338A1 {} so EbOW 80 or ... 8 O 8 S ({} 3. 28 O { 2 3 4 S 8 8 & 3 : S. Of 3. 80 7 S SO 48 38 { 3 & S S 8 {} 2 3 4 Days post-chaenge Wid-type mice (NPC -f- O Knockout mice (NPC -f--) FIGURE 17A-17B Patent Application Publication Jan. 16, 2014 Sheet 24 of 34 US 2014/0018338A1 100 90 80 f &s is 60 8 st s imipramine 25 mg/kg s 40 & 8 . s imipramine 15 mg/kg 30 2 * PBS in 8 innipramie (35 mgsg PBS to imipramine (25 mg/kg) kas S. s * imipramine (15 mg/kg) imipramine 35 mg/kg 2 i s 8 2 is S Days Post infection FIGURE 18 Patent Application Publication Jan. 16, 2014 Sheet 25 of 34 US 2014/0018338A1 Steroi-binding NPC2-binding Cysteine-rich dorrain dorai tioai Erics a M finger (yopias sterol-sensing Flag contain tag FIGURE 19 Patent Application Publication Jan. 16, 2014 Sheet 26 of 34 US 2014/0018338A1 Filipin GP-EBOV GP-MARV staining None NPC1-flag s ; : . NPC1 AA-flag NPC AC-flag 2% NPC -A-flag FIGURE 20A-2OC Patent Application Publication Jan. 16, 2014 Sheet 27 of 34 US 2014/0018338A1 3. NPC1-Flag lysate WSV: q s C. C. NPC -Flag P: kg &s B: is S&S NPC -Flag b O 2 4. 6 8 Lysate (1x10 celled./well) FIGURE 21 A-21B Patent Application Publication Jan. 16, 2014 Sheet 28 of 34 US 2014/0018338A1 d 3 sa Š Š-ŠŠ & Š 2 Š Š rVSV-GP S rVSV-GP O 20 40 60 80 OO NPC1-flag (ng/well) FIGURE 21 C-21D Patent Application Publication Jan. 16, 2014 Sheet 29 of 34 US 2014/0018338A1 al Side b ex do air C S Sibie 5 s -Š s ...-- s ce ser S t rVSV-GP SECa C 3. O.5 S rVSV-GP. i. Soluble O.O Domain C O O 2O 30 40 Soluble domain C (ig/mL) s s rVSV-GP E 50- Š rVSV-GP. S s y y O &c....access assoor-Š do so Soluble domain C-flag (ug/ml) FIGURE 22A-22C Patent Application Publication Jan. 16, 2014 Sheet 30 of 34 US 2014/0018338A1 FIGURE 23A-23B Patent Application Publication Jan. 16, 2014 Sheet 31 of 34 US 2014/0018338A1 Erdosora liter Cytoplasm FIGURE 24A-24B Patent Application Publication Jan. 16, 2014 Sheet 32 of 34 US 2014/0018338A1 Compound 3 FIGURE 24C-24D Patent Application Publication Jan. 16, 2014 Sheet 33 of 34 US 2014/0018338A1 TPA 2 Ru(bpy),3.
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  • MUTED Antibody - C-Terminal Region (ARP63301 P050) Data Sheet

    MUTED Antibody - C-Terminal Region (ARP63301 P050) Data Sheet

    MUTED antibody - C-terminal region (ARP63301_P050) Data Sheet Product Number ARP63301_P050 Product Name MUTED antibody - C-terminal region (ARP63301_P050) Size 50ug Gene Symbol BLOC1S5 Alias Symbols DKFZp686E2287; MU; MUTED Nucleotide Accession# NM_201280 Protein Size (# AA) 187 amino acids Molecular Weight 21kDa Product Format Lyophilized powder NCBI Gene Id 63915 Host Rabbit Clonality Polyclonal Official Gene Full Name Muted homolog (mouse) Gene Family BLOC1S This is a rabbit polyclonal antibody against MUTED. It was validated on Western Blot by Aviva Systems Biology. At Aviva Systems Biology we manufacture rabbit polyclonal antibodies on a large scale (200-1000 Description products/month) of high throughput manner. Our antibodies are peptide based and protein family oriented. We usually provide antibodies covering each member of a whole protein family of your interest. We also use our best efforts to provide you antibodies recognize various epitopes of a target protein. For availability of antibody needed for your experiment, please inquire (). Partner Proteins BLOC1S2,DTNBP1,BLOC1S1,BLOC1S2,CNO,DTNBP1,SNAPIN,BLOC1S2,BLOC1S3,DTNBP1,PLDN,SQS TM1,YOD1 This gene encodes a component of BLOC-1 (biogenesis of lysosome-related organelles complex 1). Components of this complex are involved in the biogenesis of organelles such as melanosomes and platelet- Description of Target dense granules. A mouse model for Hermansky-Pudlak Syndrome is mutated in the murine version of this gene. Alternative splicing results in multiple transcript variants. Read-through transcription exists between this gene and the upstream EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) gene, as well as with the downstream TXNDC5 (thioredoxin domain containing 5) gene.
  • S41467-019-09800-Y.Pdf

    S41467-019-09800-Y.Pdf

    ARTICLE https://doi.org/10.1038/s41467-019-09800-y OPEN Vps11 and Vps18 of Vps-C membrane traffic complexes are E3 ubiquitin ligases and fine-tune signalling Gregory Segala 1, Marcela A. Bennesch1, Nastaran Mohammadi Ghahhari1, Deo Prakash Pandey1,3, Pablo C. Echeverria 1, François Karch 2, Robert K. Maeda2 & Didier Picard 1 1234567890():,; In response to extracellular signals, many signalling proteins associated with the plasma membrane are sorted into endosomes. This involves endosomal fusion, which depends on the complexes HOPS and CORVET. Whether and how their subunits themselves modulate signal transduction is unknown. We show that Vps11 and Vps18 (Vps11/18), two common subunits of the HOPS/CORVET complexes, are E3 ubiquitin ligases. Upon overexpression of Vps11/ Vps18, we find perturbations of ubiquitination in signal transduction pathways. We specifi- cally demonstrate that Vps11/18 regulate several signalling factors and pathways, including Wnt, estrogen receptor α (ERα), and NFκB. For ERα, we demonstrate that the Vps11/18- mediated ubiquitination of the scaffold protein PELP1 impairs the activation of ERα by c-Src. Thus, proteins involved in membrane traffic, in addition to performing their well-described role in endosomal fusion, fine-tune signalling in several different ways, including through ubiquitination. 1 Département de Biologie Cellulaire, Université de Genève, Sciences III, 30 quai Ernest-Ansermet, 1211 Genève, Switzerland. 2 Département de Génétique et Évolution, Université de Genève, Sciences III, 30 quai Ernest-Ansermet,
  • The Impact of Transcription Factor Prospero Homeobox 1 on the Regulation of Thyroid Cancer Malignancy

    The Impact of Transcription Factor Prospero Homeobox 1 on the Regulation of Thyroid Cancer Malignancy

    International Journal of Molecular Sciences Review The Impact of Transcription Factor Prospero Homeobox 1 on the Regulation of Thyroid Cancer Malignancy Magdalena Rudzi ´nska 1,2 and Barbara Czarnocka 1,* 1 Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland; [email protected] 2 Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia * Correspondence: [email protected]; Tel.: +48-225693812; Fax: +48-225693712 Received: 7 April 2020; Accepted: 30 April 2020; Published: 2 May 2020 Abstract: Transcription factor Prospero homeobox 1 (PROX1) is continuously expressed in the lymphatic endothelial cells, playing an essential role in their differentiation. Many reports have shown that PROX1 is implicated in cancer development and acts as an oncoprotein or suppressor in a tissue-dependent manner. Additionally, the PROX1 expression in many types of tumors has prognostic significance and is associated with patient outcomes. In our previous experimental studies, we showed that PROX1 is present in the thyroid cancer (THC) cells of different origins and has a high impact on follicular thyroid cancer (FTC) phenotypes, regulating migration, invasion, focal adhesion, cytoskeleton reorganization, and angiogenesis. Herein, we discuss the PROX1 transcript and protein structures, the expression pattern of PROX1 in THC specimens, and its epigenetic regulation. Next, we emphasize the biological processes and genes regulated by PROX1 in CGTH-W-1 cells, derived from squamous cell carcinoma of the thyroid gland. Finally, we discuss the interaction of PROX1 with other lymphatic factors. In our review, we aimed to highlight the importance of vascular molecules in cancer development and provide an update on the functionality of PROX1 in THC biology regulation.