DOCSLIB.ORG

Estrogen Receptor-Α Directly Regulates the Hypoxia- Inducible Factor 1 Pathway Associated with Antiestrogen Response in Breast Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Estrogen Receptor-Α Directly Regulates the Hypoxia- Inducible Factor 1 Pathway Associated with Antiestrogen Response in Breast Cancer Estrogen receptor-α directly regulates the hypoxia- inducible factor 1 pathway associated with antiestrogen response in breast cancer Jun Yanga,b,1, Alaa AlTahanb, Dylan T. Jonesa, Francesca M. Buffaa, Esther Bridgesa, Rodrigo B. Interianob, Chunxu Quc, Nathan Vogtb, Ji-Liang Lia, Dilair Baband, Jiannis Ragoussisd,2, Robert Nicholsone, Andrew M. Davidoffb, and Adrian L. Harrisa aGrowth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom; bDepartment of Surgery, St. Jude Children’s Research Hospital, Memphis, TN 38105; cDepartment of Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN 38105; dGenomics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom; and eTenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3NB, United Kingdom Edited by Joan S. Brugge, Harvard Medical School, Boston, MA, and approved October 13, 2015 (received for review November 17, 2014) + A majority of breast cancers are driven by estrogen via estrogen resistance in neoadjuvant, primary therapy of ERα breast cancers receptor-α (ERα). Our previous studies indicate that hypoxia-induc- (12), as well as resistance to chemoendocrine therapy (13). ible factor 1α (HIF-1α) cooperates with ERα in breast cancer cells. HIF-1α is a master regulator of oxygen homeostasis, which is However, whether ERα is implicated in the direct regulation of rapidly degraded in normoxia by the tumor suppressor, von Hippel– HIF-1α and the role of HIF-1α in endocrine therapy response are un- Lindau protein (VHL), but is stabilized in hypoxia (14). This pro- known. In this study we found that a subpopulation of HIF-1α targets, cess is mainly determined by the hydroxylation of HIF-1α catalyzed many of them bearing both hypoxia response elements and estrogen by prolyl hydroxylases. HIF-1α has been associated with an ag- response elements, are regulated by ERα in normoxia and hypoxia. gressive phenotype of breast cancer: that is, large tumor size, high Interestingly, the HIF-1α gene itself also bears an estrogen response grade, high proliferation, and lymph node metastasis (15). In- element, and its expression is directly regulated by ERα.Clinicaldata creased HIF-1α is also associated with ERα-positivity (15), revealed that expression of the HIF-1α gene or a hypoxia metagene whereas HIF-1β, the partner of HIF-1α, has been shown to signature is associated with a poor outcome to endocrine treatment function as a potent coactivator of ER-dependent transcription + + in ERα breast cancer. HIF-1α was able to confer endocrine therapy (16). Further studies revealed that in ER T47D breast cancer + resistance to ERα breast cancer cells. Our findings define, for the first cells, combined hypoxia and E2 treatment had additive effects on time to our knowledge, a direct regulatory pathway between ERα expression of some genes (17), although the mechanism is not and HIF-1α, which might modulate hormone response in treatment. clear. We have previously shown that HIF-1α and ERα can co- ordinate expression of genes, such as lysine-specific demethylase ERα | HIF-1α | tamoxifen 4B/Jumonji domain-containing 2B (KDM4B/JMJD2B), an H3K9me3/me2 histone demethylase, which is targeted by both strogen receptor-α (ERα) is an estrogen-dependent nuclear ERα and HIF-1α and epigenetically regulates cell cycle progression Etranscription factor that is critical for mammary epithelial cell division and breast cancer progression (1, 2). ERα is Significance expressed in ∼70% of breast tumors (3), the majority of which depend on estrogen signaling, thereby providing the rationale for About 1.7 million new cases of breast cancer occur every year, 70% using antiestrogens as adjuvant therapy to treat breast cancer (4). of which are estrogen receptor-α (ERα) positive. Antiestrogen Tamoxifen is a first generation selective ER modulator and has therapy to block ERα function is the most important approach in + been widely used in breast cancer prevention and treatment (4). treatmentofERα patients. However, resistance eventually will Although now replaced by aromatase inhibitors as first-line develop for various reasons. Here we demonstrate that hypoxia- treatment in postmenopausal women, it still remains important inducible factor 1α (HIF-1α) is a direct transcriptional target of ERα, α in premenopausal breast cancer and after failure of aromatase which may compensate for ER function loss because many other α α α inhibitors. Tamoxifen acts as an antagonist in breast cancer cells ER targets are also HIF-1 targets. We further show that HIF-1 α by competing with estrogen for the ER. Tamoxifen-bound ER is able to confer cancer cell resistance to ER antagonists tamox- ifen and fulvestrant, and the expression of HIF-1α is associated recruits the nuclear receptor corepressor and histone deacetylase + with poor survival to endocrine therapy in ERα patients. Our (HDAC), as opposed to coactivators, leading to transcriptional findings thus have revealed a previously unidentified mechanism repression (5). Although hundreds of thousands of patients have for antiestrogen resistance. benefited from tamoxifen treatment, its efficacy is limited to an average time of 15 mo in patients with metastatic disease (6), as Author contributions: J.Y., A.M.D., and A.L.H. designed research; J.Y., A.A., D.T.J., E.B., R.B.I., resistance often develops (7). Many mechanisms have been proposed to N.V., D.B., and J.R. performed research; J.Y., J.-L.L., and R.N. contributed new reagents/ account for tamoxifen resistance (8), including loss of ERα ex- analytic tools; J.Y., A.A., F.M.B., and C.Q. analyzed data; and J.Y., A.M.D., and A.L.H. wrote the paper. pression or expression of truncated ER isoforms, posttranslational The authors declare no conflict of interest. modification of ERα, deregulation of ERα coactivators, and in- creased receptor tyrosine kinase signaling. Recent studies further This article is a PNAS Direct Submission. α Data deposition: The data reported in this paper have been deposited in the Gene Ex- indicate that somatic ER mutation (9, 10), as well as genomic pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE61799). amplification of distant ER response elements (11), could con- 1To whom correspondence should be addressed. Email: [email protected]. tribute to hormone therapy resistance. 2Present address: McGill University and Genome Quebec Innovation Centre, McGill Uni- Our clinical studies suggest that the in vivo tumor environment versity, Montreal, QC, Canada. may play a role in tamoxifen resistance, as hypoxia-inducible factor This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1α (HIF-1α) protein expression was associated with tamoxifen 1073/pnas.1422015112/-/DCSupplemental. 15172–15177 | PNAS | December 8, 2015 | vol. 112 | no. 49 www.pnas.org/cgi/doi/10.1073/pnas.1422015112 Downloaded by guest on September 29, 2021 (18). The genomic locus of KDM4B bears both HIF-1α and ERα directly regulate their expression. The top hits were ERα and binding elements (18, 19). These data collectively suggest that HIF-1α (Fig. 1C). Thus, these data indicate that a subgroup of HIF-1α and ERα are functionally associated. However, how these genes that are targeted by hypoxia/HIF-1α is also regulated by two important oncogenic pathways interact has not yet been de- ERα signaling, which is dual responsive to hormone and oxygen. fined. In addition, whether HIF-1α plays an autonomous role in Interestingly, some of these genes can be bound by p53 in murine modulating endocrine therapy efficacy, such as tamoxifen re- embryonic stem cells although the biological function is unclear sistance, is unknown. In this study, we investigated the role of ERα (20). Cancer genomic sequencing reveals that p53 is more com- + in the regulation of HIF-1 signaling and how HIF-1 signaling is monly mutated in triple-negative breast cancers than ERα involved in endocrine drug response. patients (21), whereas MCF7 is p53 wild-type. ZNF263 is a tran- scription factor that regulates FoxA1 expression (22). FoxA1 is a Results pioneer factor that facilitates ERα for genomic binding (23), ERα Signaling Regulates Hypoxia/HIF-1α Pathway. We have previously which further suggests that the estrogen-ER signaling pathway is shown that knockdown of ERα significantly down-regulated his- involved in hypoxia/HIF response. tone demethylase KDM4B expression (18), a HIF-1α transcrip- To further confirm that ERα and HIF-1α directly bind their tional target, suggesting that HIF-1α function is compromised by response elements in a subgroup of genes, we reanalyzed pub- loss of ERα even in hypoxia. To study whether ERα signaling is lished ChIP sequencing data (24, 25). We found that among the involved in the regulation of the hypoxia/HIF pathway, we used a 356 genes bound by HIF-1α, 202 (57%) of them were identified + chemical genetics approach in which the ERα breast cancer cell as the common genes bound by ERα as well (Fig. 1D and Table line MCF7 was treated with ICI182780 (fulvestrant) in normoxia S1). KDM4B was one of the targets of both ERα and HIF-1α and hypoxia to perform a global gene-expression profile analysis (Table S1), consistent with our previous studies (18, 26). Pathway (Fig. 1A). ICI182780 is an ER antagonist with no agonist effects, analysis reveals that these common genes
Load more

Recommended publications
  • Hypoxia and Hormone-Mediated Pathways Converge at the Histone Demethylase KDM4B in Cancer
    International Journal of Molecular Sciences Review Hypoxia and Hormone-Mediated Pathways Converge at the Histone Demethylase KDM4B in Cancer Jun Yang 1,* ID , Adrian L. Harris 2 and Andrew M. Davidoff 1 1 Department of Surgery, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; [email protected] 2 Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; [email protected] * Correspondence: [email protected] Received: 19 December 2017; Accepted: 9 January 2018; Published: 13 January 2018 Abstract: Hormones play an important role in pathophysiology. The hormone receptors, such as estrogen receptor alpha and androgen receptor in breast cancer and prostate cancer, are critical to cancer cell proliferation and tumor growth. In this review we focused on the cross-talk between hormone and hypoxia pathways, particularly in breast cancer. We delineated a novel signaling pathway from estrogen receptor to hypoxia-inducible factor 1, and discussed the role of this pathway in endocrine therapy resistance. Further, we discussed the estrogen and hypoxia pathways converging at histone demethylase KDM4B, an important epigenetic modifier in cancer. Keywords: estrogen receptor alpha; hypoxia-inducible factor 1; KDM4B; endocrine therapy resistance 1. Introduction A solid tumor is a heterogeneous mass that is comprised of not only genetically and epigenetically distinct clones, but also of areas with varying degree of hypoxia that result from rapid cancer cell proliferation that outgrows its blood supply. To survive in hostile hypoxic environments, cancer cells decelerate their proliferation rate, alter metabolism and cellular pH, and induce angiogenesis [1].
    [Show full text]
  • 2021 Western Medical Research Conference
    Abstracts J Investig Med: first published as 10.1136/jim-2021-WRMC on 21 December 2020. Downloaded from Genetics I Purpose of Study Genomic sequencing has identified a growing number of genes associated with developmental brain disorders Concurrent session and revealed the overlapping genetic architecture of autism spectrum disorder (ASD) and intellectual disability (ID). Chil- 8:10 AM dren with ASD are often identified first by psychologists or neurologists and the extent of genetic testing or genetics refer- Friday, January 29, 2021 ral is variable. Applying clinical whole genome sequencing (cWGS) early in the diagnostic process has the potential for timely molecular diagnosis and to circumvent the diagnostic 1 PROSPECTIVE STUDY OF EPILEPSY IN NGLY1 odyssey. Here we report a pilot study of cWGS in a clinical DEFICIENCY cohort of young children with ASD. RJ Levy*, CH Frater, WB Galentine, MR Ruzhnikov. Stanford University School of Medicine, Methods Used Children with ASD and cognitive delays/ID Stanford, CA were referred by neurologists or psychologists at a regional healthcare organization. Medical records were used to classify 10.1136/jim-2021-WRMC.1 probands as 1) ASD/ID or 2) complex ASD (defined as 1 or more major malformations, abnormal head circumference, or Purpose of Study To refine the electroclinical phenotype of dysmorphic features). cWGS was performed using either epilepsy in NGLY1 deficiency via prospective clinical and elec- parent-child trio (n=16) or parent-child-affected sibling (multi- troencephalogram (EEG) findings in an international cohort. plex families; n=3). Variants were classified according to Methods Used We performed prospective phenotyping of 28 ACMG guidelines.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • 1714 Gene Comprehensive Cancer Panel Enriched for Clinically Actionable Genes with Additional Biologically Relevant Genes 400-500X Average Coverage on Tumor
    xO GENE PANEL 1714 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes 400-500x average coverage on tumor Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11 IL6R KAT5 ACVR2A
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]
  • Electronic Supplementary Material (ESI) for Metallomics
    Electronic Supplementary Material (ESI) for Metallomics. This journal is © The Royal Society of Chemistry 2018 Uniprot Entry name Gene names Protein names Predicted Pattern Number of Iron role EC number Subcellular Membrane Involvement in disease Gene ontology (biological process) Id iron ions location associated 1 P46952 3HAO_HUMAN HAAO 3-hydroxyanthranilate 3,4- H47-E53-H91 1 Fe cation Catalytic 1.13.11.6 Cytoplasm No NAD biosynthetic process [GO:0009435]; neuron cellular homeostasis dioxygenase (EC 1.13.11.6) (3- [GO:0070050]; quinolinate biosynthetic process [GO:0019805]; response to hydroxyanthranilate oxygenase) cadmium ion [GO:0046686]; response to zinc ion [GO:0010043]; tryptophan (3-HAO) (3-hydroxyanthranilic catabolic process [GO:0006569] acid dioxygenase) (HAD) 2 O00767 ACOD_HUMAN SCD Acyl-CoA desaturase (EC H120-H125-H157-H161; 2 Fe cations Catalytic 1.14.19.1 Endoplasmic Yes long-chain fatty-acyl-CoA biosynthetic process [GO:0035338]; unsaturated fatty 1.14.19.1) (Delta(9)-desaturase) H160-H269-H298-H302 reticulum acid biosynthetic process [GO:0006636] (Delta-9 desaturase) (Fatty acid desaturase) (Stearoyl-CoA desaturase) (hSCD1) 3 Q6ZNF0 ACP7_HUMAN ACP7 PAPL PAPL1 Acid phosphatase type 7 (EC D141-D170-Y173-H335 1 Fe cation Catalytic 3.1.3.2 Extracellular No 3.1.3.2) (Purple acid space phosphatase long form) 4 Q96SZ5 AEDO_HUMAN ADO C10orf22 2-aminoethanethiol dioxygenase H112-H114-H193 1 Fe cation Catalytic 1.13.11.19 Unknown No oxidation-reduction process [GO:0055114]; sulfur amino acid catabolic process (EC 1.13.11.19) (Cysteamine
    [Show full text]
  • Estrogen Receptor Signaling in Cancer
    cancers Editorial Estrogen Receptor Signaling in Cancer Simon P. Langdon Cancer Research UK Edinburgh Centre and Edinburgh Pathology, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK; [email protected] Received: 21 September 2020; Accepted: 22 September 2020; Published: 24 September 2020 Simple Summary: Estrogen receptor signaling plays an important role not only in breast cancer but also in other cancers including ovarian cancer, prostate cancer and acute myeloid leukemia. This series of articles includes new findings of estrogen receptor co-regulators in breast and ovarian cancer with potential as novel targets for therapy. The major isoforms of estrogen receptor—namely estrogen receptor alpha and estrogen receptor beta—can have opposing functionality and these differing roles are described in reviews of estrogen signaling in prostate and ovarian cancers and acute myeloid leukemia. In breast cancer, mutated forms of the estrogen receptor can be selected for on endocrine treatment and frequently lead to treatment resistance while novel imaging techniques are being evaluated to monitor diagnosis and response to treatment. These developing research fields are overviewed. Keywords: estrogen receptor; breast cancer; ovarian cancer; prostate cancer; acute myeloid leukemia; imaging The series of seven articles (two original articles and five reviews) in this Special Issue address estrogen receptor (ER) signaling pathways in cancer and is presented by international experts engaged in research across a variety of cancer types. While estrogen signaling has long been known to have a major role in breast cancer, there is emerging evidence that it can regulate function in other cancer types also.
    [Show full text]
  • Evolution of the Tyrosinase Gene Family in Bivalve Molluscs: Independent Ex- Pansion of the Mantle Gene Repertoire
    Accepted Manuscript Evolution of the tyrosinase gene family in bivalve molluscs: independent ex- pansion of the mantle gene repertoire Felipe Aguilera, Carmel McDougall, Bernard M Degnan PII: S1742-7061(14)00151-2 DOI: http://dx.doi.org/10.1016/j.actbio.2014.03.031 Reference: ACTBIO 3182 To appear in: Acta Biomaterialia Please cite this article as: Aguilera, F., McDougall, C., Degnan, B.M., Evolution of the tyrosinase gene family in bivalve molluscs: independent expansion of the mantle gene repertoire, Acta Biomaterialia (2014), doi: http:// dx.doi.org/10.1016/j.actbio.2014.03.031 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Evolution of the tyrosinase gene family in bivalve molluscs: independent expansion of the mantle gene repertoire Authors: Felipe Aguilera, Carmel McDougall and Bernard M Degnan* Authors Affiliations: Centre for Marine Sciences, School of Biological Sciences, The University of Queensland, Brisbane, Australia, 4072. Corresponding author: Bernard M Degnan, Centre for Marine Sciences, School of Biological Sciences, The University of Queensland, Brisbane, Australia, 4072. Ph: (+61) 7 3365 2467 Fax: (+61+ 7 3365 1199. Email. [email protected] Page 1 Abstract Tyrosinase is a copper-containing enzyme that mediates the hydroxylation of monophenols and oxidation of o-diphenols to o-quinones.
    [Show full text]
  • WO 2015/048577 A2 April 2015 (02.04.2015) W P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/048577 A2 April 2015 (02.04.2015) W P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 48/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US20 14/057905 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 26 September 2014 (26.09.2014) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/883,925 27 September 2013 (27.09.2013) US (84) Designated States (unless otherwise indicated, for every 61/898,043 31 October 2013 (3 1. 10.2013) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: EDITAS MEDICINE, INC.
    [Show full text]
  • VIEW Open Access the Role of Ubiquitination and Deubiquitination in Cancer Metabolism Tianshui Sun1, Zhuonan Liu2 and Qing Yang1*
    Sun et al. Molecular Cancer (2020) 19:146 https://doi.org/10.1186/s12943-020-01262-x REVIEW Open Access The role of ubiquitination and deubiquitination in cancer metabolism Tianshui Sun1, Zhuonan Liu2 and Qing Yang1* Abstract Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment. Keywords: Ubiquitination, Deubiquitination, Cancer, Metabolic reprogramming Background cells have aroused increasing attention and interest [3]. Metabolic pathways are of vital importance in proliferat- Because of the generality of metabolic alterations in can- ing cells to meet their demands of various macromole- cer cells, metabolic reprogramming is thought as hall- cules and energy [1]. Compared with normal cells, mark of cancer, providing basis for tumor diagnosis and cancer cells own malignant properties, such as increased treatment [1]. For instance, the application of 18F- proliferation rate, and reside in environments short of deoxyglucose positron emission tomography is based on oxygen and nutrient.
    [Show full text]
  • Xo PANEL DNA GENE LIST
    xO PANEL DNA GENE LIST ~1700 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes (at 400 -500x average coverage on tumor) Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11
    [Show full text]
  • Oxidized Phospholipids Regulate Amino Acid Metabolism Through MTHFD2 to Facilitate Nucleotide Release in Endothelial Cells
    ARTICLE DOI: 10.1038/s41467-018-04602-0 OPEN Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells Juliane Hitzel1,2, Eunjee Lee3,4, Yi Zhang 3,5,Sofia Iris Bibli2,6, Xiaogang Li7, Sven Zukunft 2,6, Beatrice Pflüger1,2, Jiong Hu2,6, Christoph Schürmann1,2, Andrea Estefania Vasconez1,2, James A. Oo1,2, Adelheid Kratzer8,9, Sandeep Kumar 10, Flávia Rezende1,2, Ivana Josipovic1,2, Dominique Thomas11, Hector Giral8,9, Yannick Schreiber12, Gerd Geisslinger11,12, Christian Fork1,2, Xia Yang13, Fragiska Sigala14, Casey E. Romanoski15, Jens Kroll7, Hanjoong Jo 10, Ulf Landmesser8,9,16, Aldons J. Lusis17, 1234567890():,; Dmitry Namgaladze18, Ingrid Fleming2,6, Matthias S. Leisegang1,2, Jun Zhu 3,4 & Ralf P. Brandes1,2 Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a cau- sal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipo- proteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2- controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
    [Show full text]