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Aurora Kinase a in Gastrointestinal Cancers: Time to Target Ahmed Katsha1, Abbes Belkhiri1, Laura Goff3 and Wael El-Rifai1,2,4*
Katsha et al. Molecular Cancer (2015) 14:106 DOI 10.1186/s12943-015-0375-4 REVIEW Open Access Aurora kinase A in gastrointestinal cancers: time to target Ahmed Katsha1, Abbes Belkhiri1, Laura Goff3 and Wael El-Rifai1,2,4* Abstract Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. During the last two decades, several studies have shown amplification and overexpression of Aurora kinase A (AURKA) in several GI malignancies. These studies demonstrated that AURKA not only plays a role in regulating cell cycle and mitosis, but also regulates a number of key oncogenic signaling pathways. Although AURKA inhibitors have moved to phase III clinical trials in lymphomas, there has been slower progress in GI cancers and solid tumors. Ongoing clinical trials testing AURKA inhibitors as a single agent or in combination with conventional chemotherapies are expected to provide important clinical information for targeting AURKA in GI cancers. It is, therefore, imperative to consider investigations of molecular determinants of response and resistance to this class of inhibitors. This will improve evaluation of the efficacy of these drugs and establish biomarker based strategies for enrollment into clinical trials, which hold the future direction for personalized cancer therapy. In this review, we will discuss the available data on AURKA in GI cancers. We will also summarize the major AURKA inhibitors that have been developed and tested in pre-clinical and clinical settings. Keywords: Aurora kinases, Therapy, AURKA inhibitors, MNL8237, Alisertib, Gastrointestinal, Cancer, Signaling pathways Introduction stage [9-11]. Furthermore, AURKA is critical for Mitotic kinases are the main proteins that coordinate ac- bipolar-spindle assembly where it interacts with Ran- curate mitotic processing [1]. -
Gene Symbol Gene Description ACVR1B Activin a Receptor, Type IB
Table S1. Kinase clones included in human kinase cDNA library for yeast two-hybrid screening Gene Symbol Gene Description ACVR1B activin A receptor, type IB ADCK2 aarF domain containing kinase 2 ADCK4 aarF domain containing kinase 4 AGK multiple substrate lipid kinase;MULK AK1 adenylate kinase 1 AK3 adenylate kinase 3 like 1 AK3L1 adenylate kinase 3 ALDH18A1 aldehyde dehydrogenase 18 family, member A1;ALDH18A1 ALK anaplastic lymphoma kinase (Ki-1) ALPK1 alpha-kinase 1 ALPK2 alpha-kinase 2 AMHR2 anti-Mullerian hormone receptor, type II ARAF v-raf murine sarcoma 3611 viral oncogene homolog 1 ARSG arylsulfatase G;ARSG AURKB aurora kinase B AURKC aurora kinase C BCKDK branched chain alpha-ketoacid dehydrogenase kinase BMPR1A bone morphogenetic protein receptor, type IA BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) BRAF v-raf murine sarcoma viral oncogene homolog B1 BRD3 bromodomain containing 3 BRD4 bromodomain containing 4 BTK Bruton agammaglobulinemia tyrosine kinase BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) C9orf98 chromosome 9 open reading frame 98;C9orf98 CABC1 chaperone, ABC1 activity of bc1 complex like (S. pombe) CALM1 calmodulin 1 (phosphorylase kinase, delta) CALM2 calmodulin 2 (phosphorylase kinase, delta) CALM3 calmodulin 3 (phosphorylase kinase, delta) CAMK1 calcium/calmodulin-dependent protein kinase I CAMK2A calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha CAMK2B calcium/calmodulin-dependent -
Association Analyses of Known Genetic Variants with Gene
ASSOCIATION ANALYSES OF KNOWN GENETIC VARIANTS WITH GENE EXPRESSION IN BRAIN by Viktoriya Strumba A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Bioinformatics) in The University of Michigan 2009 Doctoral Committee: Professor Margit Burmeister, Chair Professor Huda Akil Professor Brian D. Athey Assistant Professor Zhaohui S. Qin Research Statistician Thomas Blackwell To Sam and Valentina Dmitriy and Elizabeth ii ACKNOWLEDGEMENTS I would like to thank my advisor Professor Margit Burmeister, who tirelessly guided me though seemingly impassable corridors of graduate work. Throughout my thesis writing period she provided sound advice, encouragement and inspiration. Leading by example, her enthusiasm and dedication have been instrumental in my path to becoming a better scientist. I also would like to thank my co-advisor Tom Blackwell. His careful prodding always kept me on my toes and looking for answers, which taught me the depth of careful statistical analysis. His diligence and dedication have been irreplaceable in most difficult of projects. I also would like to thank my other committee members: Huda Akil, Brian Athey and Steve Qin as well as David States. You did not make it easy for me, but I thank you for believing and not giving up. Huda’s eloquence in every subject matter she explained have been particularly inspiring, while both Huda’s and Brian’s valuable advice made the completion of this dissertation possible. I would also like to thank all the members of the Burmeister lab, both past and present: Sandra Villafuerte, Kristine Ito, Cindy Schoen, Karen Majczenko, Ellen Schmidt, Randi Burns, Gang Su, Nan Xiang and Ana Progovac. -
Identification of a Novel CHN1 P.(Phe213val) Variant in a Large Han Chinese Family with Congenital Duane Retraction Syndrome
www.nature.com/scientificreports OPEN Identifcation of a novel CHN1 p.(Phe213Val) variant in a large Han Chinese family with congenital Duane retraction syndrome Tai‑Cheng Zhou1,3, Wen‑Hua Duan1,3, Xiao‑Lin Fu2,3, Qin Zhu1, Li‑Yun Guo1, Yuan Zhou1, Zhi‑Juan Hua1, Xue‑Jiao Li1, Dong‑Mei Yang1, Jie‑Ying Zhang1, Jie Yin1, Xiao‑Fan Zhang1, Guang‑Long Zhou1 & Min Hu1* Duane retraction syndrome (DRS) is a neuromuscular dysfunction of the eyes. Although many causative genes of DRS have been identifed in Europe and the United States, few reports have been published in regard to Chinese DRS. The aim of the present study was to explore the genetic defect of DRS in a Chinese family. Exome sequencing was used to identify the disease‑causing gene for the two afected family members. Ophthalmic and physical examinations, as well as genetic screenings for variants in chimerin 1 (CHN1), were performed for all family members. Functional analyses of a CHN1 variant in 293T cells included a Rac‑GTP activation assay, α2‑chimaerin translocation assay, and co‑immunoprecipitation assay. Genetic analysis revealed a NM_001822.7: c.637T > G variant in the CHN1 gene, which resulted in the substitution of a highly conserved C1 domain with valine at codon 213 (NP_001813.1: p.(Phe213Val)) (ClinVar Accession Number: SCV001335305). In-silico analysis revealed that the p.(Phe213Val) substitution afected the protein stability and connections among the amino acids of CHN1 in terms of its tertiary protein structure. Functional studies indicated that the p.(Phe213Val) substitution reduced Rac‑GTP activity and enhanced membrane translocation in response to phorbol‑myristoyl acetate (PMA). -
A Mutation in DNA Polymerase Α Rescues WEE1KO Sensitivity to HU
International Journal of Molecular Sciences Article A Mutation in DNA Polymerase α Rescues WEE1KO Sensitivity to HU Thomas Eekhout 1,2 , José Antonio Pedroza-Garcia 1,2 , Pooneh Kalhorzadeh 1,2, Geert De Jaeger 1,2 and Lieven De Veylder 1,2,* 1 Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium; [email protected] (T.E.); [email protected] (J.A.P.-G.); [email protected] (P.K.); [email protected] (G.D.J.) 2 Center for Plant Systems Biology, VIB, 9052 Gent, Belgium * Correspondence: [email protected] Abstract: During DNA replication, the WEE1 kinase is responsible for safeguarding genomic integrity by phosphorylating and thus inhibiting cyclin-dependent kinases (CDKs), which are the driving force of the cell cycle. Consequentially, wee1 mutant plants fail to respond properly to problems arising during DNA replication and are hypersensitive to replication stress. Here, we report the identification of the pola-2 mutant, mutated in the catalytic subunit of DNA polymerase α, as a suppressor mutant of wee1. The mutated protein appears to be less stable, causing a loss of interaction with its subunits and resulting in a prolonged S-phase. Keywords: replication stress; DNA damage; cell cycle checkpoint Citation: Eekhout, T.; Pedroza- 1. Introduction Garcia, J.A.; Kalhorzadeh, P.; De Jaeger, G.; De Veylder, L. A Mutation DNA replication is a highly complex process that ensures the chromosomes are in DNA Polymerase α Rescues correctly replicated to be passed onto the daughter cells during mitosis. Replication starts WEE1KO Sensitivity to HU. Int. -
RASSF1A Interacts with and Activates the Mitotic Kinase Aurora-A
Oncogene (2008) 27, 6175–6186 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc ORIGINAL ARTICLE RASSF1A interacts with and activates the mitotic kinase Aurora-A L Liu1, C Guo1, R Dammann2, S Tommasi1 and GP Pfeifer1 1Division of Biology, Beckman Research Institute, City of Hope Cancer Center, Duarte, CA, USA and 2Institute of Genetics, University of Giessen, Giessen, Germany The RAS association domain family 1A (RASSF1A) gene tumorigenesis and carcinogen-induced tumorigenesis is located at chromosome 3p21.3 within a specific area of (Tommasi et al., 2005; van der Weyden et al., 2005), common heterozygous and homozygous deletions. RASS- supporting the notion that RASSF1A is a bona fide F1A frequently undergoes promoter methylation-asso- tumor suppressor. However, it is not fully understood ciated inactivation in human cancers. Rassf1aÀ/À mice how RASSF1A is involved in tumor suppression. are prone to both spontaneous and carcinogen-induced The biochemical function of the RASSF1A protein is tumorigenesis, supporting the notion that RASSF1A is a largely unknown. The homology of RASSF1A with the tumor suppressor. However, it is not fully understood how mammalian Ras effector novel Ras effector (NORE)1 RASSF1A is involved in tumor suppression pathways. suggests that the RASSF1A gene product may function Here we show that overexpression of RASSF1A inhibits in signal transduction pathways involving Ras-like centrosome separation. RASSF1A interacts with Aurora-A, proteins. However, recent data indicate that RASSF1A a mitotic kinase. Surprisingly, knockdown of RASS- itself binds to RAS only weakly and that binding to F1A by siRNA led to reduced activation of Aurora-A, RAS may require heterodimerization of RASSF1A and whereas overexpression of RASSF1A resulted in in- NORE1 (Ortiz-Vega et al., 2002). -
Enzymatic Encoding Methods for Efficient Synthesis Of
(19) TZZ__T (11) EP 1 957 644 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 15/10 (2006.01) C12Q 1/68 (2006.01) 01.12.2010 Bulletin 2010/48 C40B 40/06 (2006.01) C40B 50/06 (2006.01) (21) Application number: 06818144.5 (86) International application number: PCT/DK2006/000685 (22) Date of filing: 01.12.2006 (87) International publication number: WO 2007/062664 (07.06.2007 Gazette 2007/23) (54) ENZYMATIC ENCODING METHODS FOR EFFICIENT SYNTHESIS OF LARGE LIBRARIES ENZYMVERMITTELNDE KODIERUNGSMETHODEN FÜR EINE EFFIZIENTE SYNTHESE VON GROSSEN BIBLIOTHEKEN PROCEDES DE CODAGE ENZYMATIQUE DESTINES A LA SYNTHESE EFFICACE DE BIBLIOTHEQUES IMPORTANTES (84) Designated Contracting States: • GOLDBECH, Anne AT BE BG CH CY CZ DE DK EE ES FI FR GB GR DK-2200 Copenhagen N (DK) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • DE LEON, Daen SK TR DK-2300 Copenhagen S (DK) Designated Extension States: • KALDOR, Ditte Kievsmose AL BA HR MK RS DK-2880 Bagsvaerd (DK) • SLØK, Frank Abilgaard (30) Priority: 01.12.2005 DK 200501704 DK-3450 Allerød (DK) 02.12.2005 US 741490 P • HUSEMOEN, Birgitte Nystrup DK-2500 Valby (DK) (43) Date of publication of application: • DOLBERG, Johannes 20.08.2008 Bulletin 2008/34 DK-1674 Copenhagen V (DK) • JENSEN, Kim Birkebæk (73) Proprietor: Nuevolution A/S DK-2610 Rødovre (DK) 2100 Copenhagen 0 (DK) • PETERSEN, Lene DK-2100 Copenhagen Ø (DK) (72) Inventors: • NØRREGAARD-MADSEN, Mads • FRANCH, Thomas DK-3460 Birkerød (DK) DK-3070 Snekkersten (DK) • GODSKESEN, -
Table 2. Significant
Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S. -
Contig Protein Description Symbol Anterior Posterior Ratio
Table S2. List of proteins detected in anterior and posterior intestine pooled samples. Data on protein expression are mean ± SEM of 4 pools fed the experimental diets. The number of the contig in the Sea Bream Database (http://nutrigroup-iats.org/seabreamdb) is indicated. Contig Protein Description Symbol Anterior Posterior Ratio Ant/Pos C2_6629 1,4-alpha-glucan-branching enzyme GBE1 0.88±0.1 0.91±0.03 0.98 C2_4764 116 kDa U5 small nuclear ribonucleoprotein component EFTUD2 0.74±0.09 0.71±0.05 1.03 C2_299 14-3-3 protein beta/alpha-1 YWHAB 1.45±0.23 2.18±0.09 0.67 C2_268 14-3-3 protein epsilon YWHAE 1.28±0.2 2.01±0.13 0.63 C2_2474 14-3-3 protein gamma-1 YWHAG 1.8±0.41 2.72±0.09 0.66 C2_1017 14-3-3 protein zeta YWHAZ 1.33±0.14 4.41±0.38 0.30 C2_34474 14-3-3-like protein 2 YWHAQ 1.3±0.11 1.85±0.13 0.70 C2_4902 17-beta-hydroxysteroid dehydrogenase 14 HSD17B14 0.93±0.05 2.33±0.09 0.40 C2_3100 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 ABHD5 0.85±0.07 0.78±0.13 1.10 C2_15440 1-phosphatidylinositol phosphodiesterase PLCD1 0.65±0.12 0.4±0.06 1.65 C2_12986 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-1 PLCD1 0.76±0.08 1.15±0.16 0.66 C2_4412 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 PLCG2 1.13±0.08 2.08±0.27 0.54 C2_3170 2,4-dienoyl-CoA reductase, mitochondrial DECR1 1.16±0.1 0.83±0.03 1.39 C2_1520 26S protease regulatory subunit 10B PSMC6 1.37±0.21 1.43±0.04 0.96 C2_4264 26S protease regulatory subunit 4 PSMC1 1.2±0.2 1.78±0.08 0.68 C2_1666 26S protease regulatory subunit 6A PSMC3 1.44±0.24 1.61±0.08 -
Supporting Information
Supporting Information Figure S1. The functionality of the tagged Arp6 and Swr1 was confirmed by monitoring cell growth and sensitivity to hydeoxyurea (HU). Five-fold serial dilutions of each strain were plated on YPD with or without 50 mM HU and incubated at 30°C or 37°C for 3 days. Figure S2. Localization of Arp6 and Swr1 on chromosome 3. The binding of Arp6-FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) are compared. The position of Tel 3L, Tel 3R, CEN3, and the RP gene are shown under the panels. Figure S3. Localization of Arp6 and Swr1 on chromosome 4. The binding of Arp6-FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) in the whole chromosome region are compared. The position of Tel 4L, Tel 4R, CEN4, SWR1, and RP genes are shown under the panels. Figure S4. Localization of Arp6 and Swr1 on the region including the SWR1 gene of chromosome 4. The binding of Arp6- FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) are compared. The position and orientation of the SWR1 gene is shown. Figure S5. Localization of Arp6 and Swr1 on chromosome 5. The binding of Arp6-FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) are compared. The position of Tel 5L, Tel 5R, CEN5, and the RP genes are shown under the panels. Figure S6. Preferential localization of Arp6 and Swr1 in the 5′ end of genes. Vertical bars represent the binding ratio of proteins in each locus. -
Table S2. Enriched GO Categories in Biological Process for the Shared Degs
Table S2. Enriched GO categories in biological process for the shared DEGs photosynthesis (GO ID:15979) Fold Change ProbeID AGI Col-0(R) pifQ(D) Name Description /Col-0(D) /Col-0(D) A_84_P19035 AT1G30380 17.07 4.9 PSAK; PSAK (PHOTOSYSTEM I SUBUNIT K) A_84_P21372 AT4G12800 8.55 3.57 PSAL; PSAL (photosystem I subunit L) PSBP-1; PSBP-1 (OXYGEN-EVOLVING A_84_P20343 AT1G06680 12.27 3.85 PSII-P; ENHANCER PROTEIN 2); poly(U) binding OEE2; LHCB6; LHCB6 (LIGHT HARVESTING COMPLEX A_84_P14174 AT1G15820 23.9 6.16 CP24; PSII); chlorophyll binding A_84_P11525 AT1G79040 16.02 4.42 PSBR; PSBR (photosystem II subunit R) FAD5; ADS3; FAD5 (FATTY ACID DESATURASE 5); A_84_P19290 AT3G15850 4.02 2.27 FADB; oxidoreductase JB67; GAPA (GLYCERALDEHYDE 3- GAPA; PHOSPHATE DEHYDROGENASE A A_84_P19306 AT3G26650 4.6 3.43 GAPA-1; SUBUNIT); glyceraldehyde-3-phosphate dehydrogenase A_84_P193234 AT2G06520 14.01 3.89 PSBX; PSBX (photosystem II subunit X) LHB1B1; LHB1B1 (Photosystem II light harvesting A_84_P160283 AT2G34430 89.44 32.95 LHCB1.4; complex gene 1.4); chlorophyll binding PSAN (photosystem I reaction center subunit A_84_P10324 AT5G64040 26.14 7.12 PSAN; PSI-N); calmodulin binding LHB1B2; LHB1B2 (Photosystem II light harvesting A_84_P207958 AT2G34420 41.71 12.26 LHCB1.5; complex gene 1.5); chlorophyll binding LHCA2 (Photosystem I light harvesting A_84_P19428 AT3G61470 10.91 5.36 LHCA2; complex gene 2); chlorophyll binding A_84_P22465 AT1G31330 32.37 6.58 PSAF; PSAF (photosystem I subunit F) chlorophyll A-B binding protein CP29 A_84_P190244 AT5G01530 16.45 5.27 LHCB4 -
A Comprehensive Analysis of the Expression of Crystallins in Mouse Retina Jinghua Xi Washington University School of Medicine in St
Washington University School of Medicine Digital Commons@Becker Open Access Publications 2003 A comprehensive analysis of the expression of crystallins in mouse retina Jinghua Xi Washington University School of Medicine in St. Louis Rafal Farjo University of Michigan - Ann Arbor Shigeo Yoshida University of Michigan - Ann Arbor Timothy S. Kern Case Western Reserve University Anand Swaroop University of Michigan - Ann Arbor See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Xi, Jinghua; Farjo, Rafal; Yoshida, Shigeo; Kern, Timothy S.; Swaroop, Anand; and Andley, Usha P., ,"A comprehensive analysis of the expression of crystallins in mouse retina." Molecular Vision.9,. 410-419. (2003). https://digitalcommons.wustl.edu/open_access_pubs/1801 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Jinghua Xi, Rafal Farjo, Shigeo Yoshida, Timothy S. Kern, Anand Swaroop, and Usha P. Andley This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/1801 Molecular Vision 2003; 9:410-9 <http://www.molvis.org/molvis/v9/a53> © 2003 Molecular Vision Received 28 May 2003 | Accepted 19 August 2003 | Published 28 August 2003 A comprehensive analysis of the expression of crystallins in mouse retina Jinghua Xi,1 Rafal Farjo,3 Shigeo Yoshida,3 Timothy S. Kern,5 Anand Swaroop,3,4 Usha P. Andley1,2 Departments of 1Ophthalmology and Visual Sciences and 2Biochemistry and Molecular Biophysics, Washington University School of Medicine, St.