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Supporting Information Bettayeb et al. 10.1073/pnas.1604176113 Fig. S1 provides additional images related to amyloid plaque the human genetic SNP association study and Table S4 provides analysis in vivo. Tables S1–S3 provide further information about further information about the variant association study. A AD/ -COP WT AD/ -COP mut AD/ -COP WT AD/ -COP mut B AD/ -COP WT AD/ -COP mut AD/ -COP WT AD/ -COP mut Fig. S1. Replicates of amyloid plaque immunostaining in 9-mo-old AD/δ-COP WT vs. AD/δ-COP mice. Representative images showing amyloid plaques in the brain. Amyloid plaque development was studied in both (A) the hippocampus and (B) the piriform cortex. (Scale bar, 500 μm.) Bettayeb et al. www.pnas.org/cgi/content/short/1604176113 1of3 Table S1. Breakdown of the number of independent tag SNPs from each of the eight candidate coatomer protein complex genes Gene symbol Gene name Chr Start End Gene length, bp Total SNPs Initial filter Tag SNPs COPA Coatomer protein complex, subunit alpha 1 160,258,377 160,313,354 54,977 100 92 16 COPG1 Coatomer protein complex, subunit gamma 1 3 128,968,453 128,996,616 28,163 43 43 4 COPB2 Coatomer protein complex, subunit beta 2 3 139,076,433 139,108,522 32,089 73 68 9 COPB1 Coatomer protein complex, subunit beta 1 11 14,479,049 14,521,441 42,392 73 68 18 COPD Coatomer protein complex, subunit delta 11 118,443,102 118,473,748 30,646 57 53 13 COPZ1 Coatomer protein complex, subunit zeta 1 12 54,718,911 54,745,633 26,722 30 27 8 COPZ2 Coatomer protein complex, subunit zeta 2 17 46,103,533 46,115,152 11,619 110 104 18 COPE Coatomer protein complex, subunit epsilon 19 19,010,323 19,030,199 19,876 44 41 10 Totals 530 496 96 Base pair positions from the UCSC February 2009 (GRCh37/hg19) genome build. The total SNPs column contains the total number of SNPs in the gene region imputed plus observed on the Affymetrix 6.0 SNP panel. The initial filter column contains the number of SNPs remaining after removal of SNPs with MAF <0.01 in probands or that deviated from Hardy–Weinberg equilibrium (P < 0.0001) or imputed SNPs with information score <0.40. Table S2. Most-significant meta-analysis association results from the six datasets for the eight candidate COPI genes Overall Effect Case-control Family NIMH NCRAD NIMH NCRAD GenADA TGEN2 NIA-LOAD ADNI SNP Gene meta-P direction meta-P meta-P Info. Fam. Info. Fam. FBAT-P FBAT-P P value P value P value P value rs7531886 COPA 0.02 −+++++ 0.02 0.37 156 128 −0.87 0.13 0.16 0.51 0.08 0.46 rs12033011 COPA 0.0015 +++++− 0.10 0.005 141 136 0.015 0.12 0.76 0.40 0.03 0.80 rs72868007 COPB1 0.03 ++++++ 0.26 0.40 25 23 0.47 0.64 0.19 0.25 0.69 0.09 rs73022058 COPD/IFT46 0.02 ++−+++ 0.87 0.04 62 75 0.04 0.40 0.29 0.47 0.05 0.06 rs3132828 COPD/IFT46 0.002 ++++++ 0.22 0.11 69 76 0.37 0.17 0.43 0.20 0.11 0.012 rs498872 COPD/PHLDB1 0.002 ++++++ 0.16 0.11 153 120 0.49 0.11 0.15 0.57 0.10 0.05 rs34280607 COPZ1 0.008 ++++++ 0.02 0.33 20 27 0.16 0.94 0.52 0.02 0.35 0.24 rs61614746 COPZ1 0.04 ++++++ 0.81 0.08 50 38 0.03 0.84 0.58 0.42 0.89 0.12 rs757352 COPZ2 7.E-04 ++++++ 0.04 0.09 112 99 0.17 0.30 0.13 0.10 0.14 0.14 rs9898218 COPZ2 0.0010 ++++++ 0.0011 0.31 208 154 0.58 0.37 0.19 0.0006 0.33 0.56 rs7216504 COPZ2 0.03 −+++++ 0.02 0.75 155 109 −0.19 0.04 0.78 0.09 0.07 0.31 rs11650615 COPZ2/NFE2L1 7.E-04 −+++++ 0.0007 0.39 179 129 −0.50 0.03 0.16 0.003 0.32 0.11 The effect direction column indicates a positive sign for each study that confers a risk effect and a negative sign for the study that confers a protective effect. The positive or negative sign represents the following studies in this order: NIMH, NCRAD, GenADA, TGEN2, NIA-LOAD, and ADNI. The Info. Fam. columns indicate the number of informative families from the FBAT analysis for each family-based study. A negative FBAT P value indicates an undertransmission of the minor allele in affected offspring, whereas a positive FBAT P value indicates an overtransmission of the minor allele in affected offspring. Table S3. Study cohort sample size Study cohort Cases Controls Subjects Platform NIMH, 387 families 857 329 1,186 Affymetrix 6.0 NCRAD, 354 families 884 70 954 Affymetrix 6.0 GenADA 783 755 1,538 Affymetrix 500 TGEN2 953 556 1,509 Affymetrix 1M NIA-LOAD 371 875 1,246 Illumina 370 ADNI 170 192 362 Illumina Human610 Total study sample 4,018 2,777 6,795 Two family-based study samples and four case-control cohorts were used. Bettayeb et al. www.pnas.org/cgi/content/short/1604176113 2of3 Table S4. Variants from WGS analyses of the COPI complex genes No. of No. of affected No. of unaffected Gene Identifier Alt. Ex Variant families carriers Med. AAO carriers MAF (dbSNP) MAF (WGS) COPA ENST00000368069 nEx 33 nAA 1,233 rs57425682 6 T146A 14 20/29 73 2/6 0.003 0.007 1:160278885 5 5′ splice 1 2/2 72.5 0/0 N/A 0.0007 rs75190422 8 5′ splice 6 8/10 65.5 0/1 0.001 0.003 1:160303386 28 5′ splice 1 3/4 75 0/0 N/A 0.001 1:160283843 9 R260C 1 2/3 68 0/1 N/A 0.0007 COPB1 ENST00000249923 nEx 22 nAA 953 11:14521151 1 3′ splice 6 9/16 77 1/12 N/A 0.003 rs201467424 18 V789I 1 3/3 76 0/0 N/A 0.001 rs375670951 8 5′ splice 1 3/3 76 0/0 N/A 0.001 11:14520389 2 D29Y 1 2/2 76.5 0/0 N/A 0.0007 11:14502548 9 R351K 1 2/3 78.5 0/2 N/A 0.0007 rs144780995 15 P625S 1 3/3 70.5 0/0 N/A 0.0007 COPG1 ENST00000314797 nEx 24 nAA 874 3:128968592 1 5′ splice 1 2/2 70.5 0/0 N/A 0.0007 COPG2 ENST00000445977 nEx 9 nAA 246 rs143820112 4 3′ splice 1 2/2 64 0/0 N/A 0.0007 COPD ENST00000264028 nEx 10 nAA 511 rs78730658 3 5′ splice 4 7/11 78 0/0 0.001 0.002 rs188303468 1 3′ splice 2 3/5 70 0/2 0.005 0.001 rs138863361 2 A6S 2 3/5 70 0/2 0.005 0.001 COPE ENST00000262812 nEx 10 nAA 308 rs2231987 1 S13C 18 27/40 74 4/13 0.07 0.01 rs199731661 10 5′ splice 6 6/11 72 2/7 0.003 0.02 rs141039416 3 R96Q 1 2/2 79 0/0 N/A 0.0007 rs34510432 3 R85H 1 2/3 66 0/0 0.005 0.0007 COPZ1 ENST00000262061 nEx 9 nAA 177 12:54741793 7 E136Q 1 2/2 69 0/0 N/A 0.0007 COPZ2 ENST00000006101 nEx 10 nAA 208 rs115870363 6 3′ splice 9 13/17 75 2/3 0.004 0.005 17:46115120 2 6, frameshift 1 2/2 87.5 0/0 N/A 0.001 17:46115121 2 W6R 1 2/2 87.5 0/0 N/A 0.001 The variants resulting from the analyses of the nine COPI genes are listed above. Identifier: dbSNP (The Single Nucleotide Polymorphism Database) ID when available or the physical location of the variant in the genome (hg19 reference panel). Alt. Ex: exon affected by the variation. Variant: impact of the mutation. No. of families: number of families where at least one subject is a carrier. No. of affected carriers: ratio of the number of subjects showing the presence of the alternate allele/total number of affected patients in the carrier families. Med. AAO: median onset age of the AD patients. No. of unaffected carriers: ratio of the number of unaffected family members carrying the alternate allele/total number of unaffected in the carrier families. MAF (dbSNP) and MAF (WGS): frequency of the minor alternate allele in the reported study population. ENST, Ensembl Canonical Transcript ID for the gene of interest; N/A, not available; nAA, number of amino acids in the transcribed protein; nEx, number of exons in the gene transcript. Bettayeb et al. www.pnas.org/cgi/content/short/1604176113 3of3.
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  • The Role of ARF Family Proteins and Their Regulators and Effectors in Cancer Progression: a Therapeutic Perspective

    The Role of ARF Family Proteins and Their Regulators and Effectors in Cancer Progression: a Therapeutic Perspective

    fcell-08-00217 April 17, 2020 Time: 19:19 # 1 REVIEW published: 21 April 2020 doi: 10.3389/fcell.2020.00217 The Role of ARF Family Proteins and Their Regulators and Effectors in Cancer Progression: A Therapeutic Perspective Cristina Casalou†, Andreia Ferreira† and Duarte C. Barral* CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal The Adenosine diphosphate-Ribosylation Factor (ARF) family belongs to the RAS superfamily of small GTPases and is involved in a wide variety of physiological processes, such as cell proliferation, motility and differentiation by regulating membrane Edited by: traffic and associating with the cytoskeleton. Like other members of the RAS Sunil Kumar Verma, superfamily, ARF family proteins are activated by Guanine nucleotide Exchange Factors Centre for Cellular & Molecular (GEFs) and inactivated by GTPase-Activating Proteins (GAPs). When active, they bind Biology (CCMB), India effectors, which mediate downstream functions. Several studies have reported that Reviewed by: Wei-Hsiung Yang, cancer cells are able to subvert membrane traffic regulators to enhance migration and Mercer University, United States invasion. Indeed, members of the ARF family, including ARF-Like (ARL) proteins have Ira Daar, National Cancer Institute (NCI), been implicated in tumorigenesis and progression of several types of cancer. Here, we United States review the role of ARF family members, their GEFs/GAPs and effectors in tumorigenesis *Correspondence: and cancer progression, highlighting the ones that can have a pro-oncogenic behavior Duarte C. Barral or function as tumor suppressors. Moreover, we propose possible mechanisms and [email protected] approaches to target these proteins, toward the development of novel therapeutic †These authors have contributed equally to this work strategies to impair tumor progression.