RBCC Red Blood Cell Collection

PTGS2 (COX2) [Confidence: low (only semi-automatic identification from reviews)]
Prostaglandin G/H synthase 2; 1.14.99.1 (Cyclooxygenase-2; COX-2; PHS II; Prostaglandin H2 synthase 2; PGH synthase 2; PGHS-2; Prostaglandin-endoperoxide synthase 2; Flags: Precursor)

UniProt P35354
ID PGH2_HUMAN Reviewed; 604 AA.
AC P35354; A8K802; Q16876;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 15-DEC-1998, sequence version 2.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=Prostaglandin G/H synthase 2;
DE EC=1.14.99.1;
DE AltName: Full=Cyclooxygenase-2;
DE Short=COX-2;
DE AltName: Full=PHS II;
DE AltName: Full=Prostaglandin H2 synthase 2;
DE Short=PGH synthase 2;
DE Short=PGHS-2;
DE AltName: Full=Prostaglandin-endoperoxide synthase 2;
DE Flags: Precursor;
GN Name=PTGS2; Synonyms=COX2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Endothelial cell;
RX PubMed=8473346;
RA Jones D.A., Carlton D.P., McIntyre T.M., Zimmerman G.A.,
RA Prescott S.M.;
RT "Molecular cloning of human prostaglandin endoperoxide synthase type
RT II and demonstration of expression in response to cytokines.";
RL J. Biol. Chem. 268:9049-9054(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Endothelial cell;
RX PubMed=1380156; DOI=10.1073/pnas.89.16.7384;
RA Hla T., Neilson K.;
RT "Human cyclooxygenase-2 cDNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:7384-7388(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Peripheral blood;
RX PubMed=8181472; DOI=10.1111/j.1432-1033.1994.tb18804.x;
RA Kosaka T., Miyata A., Ihara H., Hara S., Sugimoto T., Takeda O.,
RA Takahashi E., Tanabe T.;
RT "Characterization of the human gene (PTGS2) encoding prostaglandin-
RT endoperoxide synthase 2.";
RL Eur. J. Biochem. 221:889-897(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=7945196;
RA Appleby S.B., Ristimaki A., Neilson K., Narko K., Hla T.;
RT "Structure of the human cyclo-oxygenase-2 gene.";
RL Biochem. J. 302:723-727(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RA Sharma S.V., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS HIS-228; ALA-428;
RP ALA-511 AND ARG-587.
RG NIEHS SNPs program;
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Synovium;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [12]
RP CHARACTERIZATION.
RX PubMed=7947975; DOI=10.1016/0167-4838(94)90148-1;
RA Barnett J., Chow J., Ives D., Chiou M., Mackenzie R., Osen E.,
RA Nguyen B., Tsing S., Bach C., Freire J.;
RT "Purification, characterization and selective inhibition of human
RT prostaglandin G/H synthase 1 and 2 expressed in the baculovirus
RT system.";
RL Biochim. Biophys. Acta 1209:130-139(1994).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP S-NITROSYLATION AT CYS-526, AND MUTAGENESIS OF CYS-526; CYS-555 AND
RP CYS-561.
RX PubMed=16373578; DOI=10.1126/science.1119407;
RA Kim S.F., Huri D.A., Snyder S.H.;
RT "Inducible nitric oxide synthase binds, S-nitrosylates, and activates
RT cyclooxygenase-2.";
RL Science 310:1966-1970(2005).
RN [14]
RP GLYCOSYLATION AT ASN-580.
RX PubMed=17113084; DOI=10.1016/j.febslet.2006.10.073;
RA Sevigny M.B., Li C.F., Alas M., Hughes-Fulford M.;
RT "Glycosylation regulates turnover of cyclooxygenase-2.";
RL FEBS Lett. 580:6533-6536(2006).
RN [15]
RP VARIANT ALA-511.
RX PubMed=15308583; DOI=10.1093/carcin/bgh260;
RA Goodman J.E., Bowman E.D., Chanock S.J., Alberg A.J., Harris C.C.;
RT "Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX)
RT polymorphisms and colon cancer risk.";
RL Carcinogenesis 25:2467-2472(2004).
CC -!- FUNCTION: Critical component of colonic mucosal wound repair (By
CC similarity). Mediates the formation of prostaglandins from
CC arachidonate. May have a role as a major mediator of inflammation
CC and/or a role for prostanoid signaling in activity-dependent
CC plasticity.
CC -!- CATALYTIC ACTIVITY: Arachidonate + AH(2) + 2 O(2) = prostaglandin
CC H(2) + A + H(2)O.
CC -!- COFACTOR: Binds 1 heme B (iron-protoporphyrin IX) group per
CC subunit (By similarity).
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=16.2 uM for arachidonate (in absence of sodium nitroprusside
CC NO donor);
CC KM=17.0 uM for arachidonate (in presence of sodium nitroprusside
CC NO donor);
CC Vmax=81.3 nmol/min/mg enzyme (in absence of sodium nitroprusside
CC NO donor);
CC Vmax=132 nmol/min/mg enzyme (in absence of sodium nitroprusside
CC NO donor);
CC -!- PATHWAY: Lipid metabolism; prostaglandin biosynthesis.
CC -!- SUBUNIT: Homodimer (By similarity).
CC -!- SUBCELLULAR LOCATION: Microsome membrane; Peripheral membrane
CC protein. Endoplasmic reticulum membrane; Peripheral membrane
CC protein.
CC -!- INDUCTION: By cytokines and mitogens.
CC -!- PTM: S-nitrosylation by NOS2 (iNOS) activates enzyme activity. S-
CC nitrosylation may take place on different Cys residues in addition
CC to Cys-561.
CC -!- MISCELLANEOUS: This enzyme acts both as a dioxygenase and as a
CC peroxidase.
CC -!- MISCELLANEOUS: This enzyme is the target of nonsteroidal anti-
CC inflammatory drugs such as aspirin.
CC -!- SIMILARITY: Belongs to the prostaglandin G/H synthase family.
CC -!- SIMILARITY: Contains 1 EGF-like domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PTGS2ID509ch1q31.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/ptgs2/";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/ptgs2/";
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DR EMBL; L15326; AAA35803.1; -; mRNA.
DR EMBL; M90100; AAA58433.1; -; mRNA.
DR EMBL; D28235; BAA05698.1; -; Genomic_DNA.
DR EMBL; U04636; AAA57317.1; -; Genomic_DNA.
DR EMBL; AY462100; AAR23927.1; -; mRNA.
DR EMBL; AY229989; AAO38056.1; -; Genomic_DNA.
DR EMBL; AY382629; AAQ75702.1; -; Genomic_DNA.
DR EMBL; AK292167; BAF84856.1; -; mRNA.
DR EMBL; AL033533; CAB41240.1; -; Genomic_DNA.
DR EMBL; CH471067; EAW91216.1; -; Genomic_DNA.
DR EMBL; BC013734; AAH13734.1; -; mRNA.
DR PIR; A46150; A46150.
DR RefSeq; NP_000954.1; NM_000963.2.
DR UniGene; Hs.196384; -.
DR PDB; 1V0X; Model; -; A=1-604.
DR PDBsum; 1V0X; -.
DR ProteinModelPortal; P35354; -.
DR SMR; P35354; 18-568.
DR DIP; DIP-28131N; -.
DR MINT; MINT-203337; -.
DR STRING; 9606.ENSP00000356438; -.
DR BindingDB; P35354; -.
DR ChEMBL; CHEMBL230; -.
DR DrugBank; DB00316; Acetaminophen.
DR DrugBank; DB00945; Aspirin.
DR DrugBank; DB01014; Balsalazide.
DR DrugBank; DB00963; Bromfenac.
DR DrugBank; DB00821; Carprofen.
DR DrugBank; DB00482; Celecoxib.
DR DrugBank; DB01188; Ciclopirox.
DR DrugBank; DB00586; Diclofenac.
DR DrugBank; DB00861; Diflunisal.
DR DrugBank; DB01240; Epoprostenol.
DR DrugBank; DB00749; Etodolac.
DR DrugBank; DB01628; Etoricoxib.
DR DrugBank; DB00573; Fenoprofen.
DR DrugBank; DB00712; Flurbiprofen.
DR DrugBank; DB00154; gamma-Homolinolenic acid.
DR DrugBank; DB01404; Ginseng.
DR DrugBank; DB01050; Ibuprofen.
DR DrugBank; DB00159; Icosapent.
DR DrugBank; DB00328; Indomethacin.
DR DrugBank; DB01009; Ketoprofen.
DR DrugBank; DB00465; Ketorolac.
DR DrugBank; DB00480; Lenalidomide.
DR DrugBank; DB01283; Lumiracoxib.
DR DrugBank; DB00939; Meclofenamic acid.
DR DrugBank; DB00784; Mefenamic acid.
DR DrugBank; DB00814; Meloxicam.
DR DrugBank; DB00244; Mesalazine.
DR DrugBank; DB00461; Nabumetone.
DR DrugBank; DB00788; Naproxen.
DR DrugBank; DB00991; Oxaprozin.
DR DrugBank; DB00812; Phenylbutazone.
DR DrugBank; DB00533; Rofecoxib.
DR DrugBank; DB00936; Salicyclic acid.
DR DrugBank; DB01399; Salsalate.
DR DrugBank; DB00605; Sulindac.
DR DrugBank; DB00870; Suprofen.
DR DrugBank; DB00469; Tenoxicam.
DR DrugBank; DB01041; Thalidomide.
DR DrugBank; DB01600; Tiaprofenic acid.
DR DrugBank; DB00500; Tolmetin.
DR DrugBank; DB00580; Valdecoxib.
DR GuidetoPHARMACOLOGY; 1376; -.
DR PeroxiBase; 3321; HsPGHS02.
DR PhosphoSite; P35354; -.
DR DMDM; 3915797; -.
DR PaxDb; P35354; -.
DR PRIDE; P35354; -.
DR DNASU; 5743; -.
DR Ensembl; ENST00000367468; ENSP00000356438; ENSG00000073756.
DR GeneID; 5743; -.
DR KEGG; hsa:5743; -.
DR UCSC; uc001gsb.3; human.
DR CTD; 5743; -.
DR GeneCards; GC01M186640; -.
DR HGNC; HGNC:9605; PTGS2.
DR HPA; CAB000113; -.
DR HPA; HPA001335; -.
DR MIM; 600262; gene.
DR neXtProt; NX_P35354; -.
DR PharmGKB; PA293; -.
DR eggNOG; NOG39991; -.
DR HOGENOM; HOG000013149; -.
DR HOVERGEN; HBG000366; -.
DR InParanoid; P35354; -.
DR KO; K11987; -.
DR OMA; ICNNVKG; -.
DR OrthoDB; EOG7RFTHC; -.
DR PhylomeDB; P35354; -.
DR BioCyc; MetaCyc:HS01115-MONOMER; -.
DR BRENDA; 1.14.99.1; 2681.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P35354; -.
DR UniPathway; UPA00662; -.
DR GeneWiki; Prostaglandin-endoperoxide_synthase_2; -.
DR GeneWiki; PTGS2; -.
DR GenomeRNAi; 5743; -.
DR NextBio; 22358; -.
DR PRO; PR:P35354; -.
DR ArrayExpress; P35354; -.
DR Bgee; P35354; -.
DR CleanEx; HS_PTGS2; -.
DR Genevestigator; P35354; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0043005; C:neuron projection; IDA:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0050473; F:arachidonate 15-lipoxygenase activity; TAS:Reactome.
DR GO; GO:0020037; F:heme binding; ISS:UniProtKB.
DR GO; GO:0008289; F:lipid binding; IEA:Ensembl.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004601; F:peroxidase activity; NAS:UniProtKB.
DR GO; GO:0004666; F:prostaglandin-endoperoxide synthase activity; IDA:UniProtKB.
DR GO; GO:0042640; P:anagen; IEA:Ensembl.
DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR GO; GO:0030282; P:bone mineralization; IEA:Ensembl.
DR GO; GO:0050873; P:brown fat cell differentiation; IEA:Ensembl.
DR GO; GO:0006928; P:cellular component movement; TAS:ProtInc.
DR GO; GO:0071318; P:cellular response to ATP; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; IEP:UniProtKB.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0034644; P:cellular response to UV; IEA:Ensembl.
DR GO; GO:0019371; P:cyclooxygenase pathway; IDA:BHF-UCL.
DR GO; GO:0046697; P:decidualization; IEA:Ensembl.
DR GO; GO:0007566; P:embryo implantation; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0007612; P:learning; IEA:Ensembl.
DR GO; GO:0019372; P:lipoxygenase pathway; TAS:Reactome.
DR GO; GO:0035633; P:maintenance of blood-brain barrier; IEA:Ensembl.
DR GO; GO:0007613; P:memory; IEA:Ensembl.
DR GO; GO:0051926; P:negative regulation of calcium ion transport; IEA:Ensembl.
DR GO; GO:0045786; P:negative regulation of cell cycle; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0045986; P:negative regulation of smooth muscle contraction; IEA:Ensembl.
DR GO; GO:0032227; P:negative regulation of synaptic transmission, dopaminergic; IEA:Ensembl.
DR GO; GO:0030728; P:ovulation; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0090336; P:positive regulation of brown fat cell differentiation; ISS:BHF-UCL.
DR GO; GO:0090050; P:positive regulation of cell migration involved in sprouting angiogenesis; ISS:BHF-UCL.
DR GO; GO:0031622; P:positive regulation of fever generation; ISS:BHF-UCL.
DR GO; GO:0090271; P:positive regulation of fibroblast growth factor production; ISS:BHF-UCL.
DR GO; GO:0042346; P:positive regulation of NF-kappaB import into nucleus; IEA:Ensembl.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; ISS:BHF-UCL.
DR GO; GO:0090362; P:positive regulation of platelet-derived growth factor production; ISS:BHF-UCL.
DR GO; GO:0031394; P:positive regulation of prostaglandin biosynthetic process; NAS:BHF-UCL.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0045987; P:positive regulation of smooth muscle contraction; IEA:Ensembl.
DR GO; GO:0031915; P:positive regulation of synaptic plasticity; IEA:Ensembl.
DR GO; GO:0051968; P:positive regulation of synaptic transmission, glutamatergic; IEA:Ensembl.
DR GO; GO:0071636; P:positive regulation of transforming growth factor beta production; ISS:BHF-UCL.
DR GO; GO:0045907; P:positive regulation of vasoconstriction; IEA:Ensembl.
DR GO; GO:0010575; P:positive regulation vascular endothelial growth factor production; ISS:BHF-UCL.
DR GO; GO:0008217; P:regulation of blood pressure; ISS:UniProtKB.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0032355; P:response to estradiol stimulus; IEA:Ensembl.
DR GO; GO:0070542; P:response to fatty acid; IEA:Ensembl.
DR GO; GO:0009750; P:response to fructose stimulus; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0010226; P:response to lithium ion; IEA:Ensembl.
DR GO; GO:0010042; P:response to manganese ion; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; IEA:InterPro.
DR GO; GO:0034612; P:response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0033280; P:response to vitamin D; IEA:Ensembl.
DR GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl.
DR Gene3D; 1.10.640.10; -; 1.
DR InterPro; IPR000742; EG-like_dom.
DR InterPro; IPR010255; Haem_peroxidase.
DR InterPro; IPR002007; Haem_peroxidase_animal.
DR InterPro; IPR019791; Haem_peroxidase_animal_subgr.
DR Pfam; PF03098; An_peroxidase; 1.
DR PRINTS; PR00457; ANPEROXIDASE.
DR SMART; SM00181; EGF; 1.
DR SUPFAM; SSF48113; SSF48113; 1.
DR PROSITE; PS00022; EGF_1; FALSE_NEG.
DR PROSITE; PS01186; EGF_2; FALSE_NEG.
DR PROSITE; PS50026; EGF_3; 1.
DR PROSITE; PS50292; PEROXIDASE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Dioxygenase; Disulfide bond;
KW Endoplasmic reticulum; Fatty acid biosynthesis; Fatty acid metabolism;
KW Glycoprotein; Heme; Iron; Lipid biosynthesis; Lipid metabolism;
KW Membrane; Metal-binding; Microsome; Oxidoreductase; Peroxidase;
KW Polymorphism; Prostaglandin biosynthesis; Prostaglandin metabolism;
KW Reference proteome; S-nitrosylation; Signal.
FT SIGNAL 1 17 Potential.
FT CHAIN 18 604 Prostaglandin G/H synthase 2.
FT /FTId=PRO_0000023875.
FT DOMAIN 18 55 EGF-like.
FT ACT_SITE 193 193 Proton acceptor (By similarity).
FT ACT_SITE 371 371 For cyclooxygenase activity (By
FT similarity).
FT METAL 374 374 Iron (heme axial ligand) (By similarity).
FT BINDING 106 106 Substrate (By similarity).
FT BINDING 341 341 Substrate (By similarity).
FT BINDING 371 371 Substrate (By similarity).
FT SITE 516 516 Aspirin-acetylated serine (By
FT similarity).
FT MOD_RES 561 561 S-nitrosocysteine (Probable).
FT CARBOHYD 53 53 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 130 130 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 396 396 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 580 580 N-linked (GlcNAc...).
FT DISULFID 21 32 By similarity.
FT DISULFID 22 145 By similarity.
FT DISULFID 26 42 By similarity.
FT DISULFID 44 54 By similarity.
FT DISULFID 555 561 By similarity.
FT VARIANT 228 228 R -> H (in dbSNP:rs3218622).
FT /FTId=VAR_016262.
FT VARIANT 428 428 P -> A (in dbSNP:rs4648279).
FT /FTId=VAR_016263.
FT VARIANT 488 488 E -> G (in dbSNP:rs5272).
FT /FTId=VAR_011980.
FT VARIANT 511 511 V -> A (in dbSNP:rs5273).
FT /FTId=VAR_011981.
FT VARIANT 587 587 G -> R (in dbSNP:rs3218625).
FT /FTId=VAR_016264.
FT MUTAGEN 526 526 C->S: Prevents activation by nitric oxid
FT (NO).
FT MUTAGEN 555 555 C->S: Abolishes enzyme activity.
FT MUTAGEN 561 561 C->S: Does not affect activation by
FT nitric oxid (NO).
FT CONFLICT 165 165 E -> G (in Ref. 2; AAA58433).
FT CONFLICT 438 438 I -> T (in Ref. 1; AAA35803).
SQ SEQUENCE 604 AA; 68996 MW; 72FBD699F6128519 CRC64;
MLARALLLCA VLALSHTANP CCSHPCQNRG VCMSVGFDQY KCDCTRTGFY GENCSTPEFL
TRIKLFLKPT PNTVHYILTH FKGFWNVVNN IPFLRNAIMS YVLTSRSHLI DSPPTYNADY
GYKSWEAFSN LSYYTRALPP VPDDCPTPLG VKGKKQLPDS NEIVEKLLLR RKFIPDPQGS
NMMFAFFAQH FTHQFFKTDH KRGPAFTNGL GHGVDLNHIY GETLARQRKL RLFKDGKMKY
QIIDGEMYPP TVKDTQAEMI YPPQVPEHLR FAVGQEVFGL VPGLMMYATI WLREHNRVCD
VLKQEHPEWG DEQLFQTSRL ILIGETIKIV IEDYVQHLSG YHFKLKFDPE LLFNKQFQYQ
NRIAAEFNTL YHWHPLLPDT FQIHDQKYNY QQFIYNNSIL LEHGITQFVE SFTRQIAGRV
AGGRNVPPAV QKVSQASIDQ SRQMKYQSFN EYRKRFMLKP YESFEELTGE KEMSAELEAL
YGDIDAVELY PALLVEKPRP DAIFGETMVE VGAPFSLKGL MGNVICSPAY WKPSTFGGEV
GFQIINTASI QSLICNNVKG CPFTSFSVPD PELIKTVTIN ASSSRSGLDD INPTVLLKER
STEL
//

MIM 600262
*RECORD*
*FIELD* NO
600262
*FIELD* TI
*600262 PROSTAGLANDIN-ENDOPEROXIDE SYNTHASE 2; PTGS2
;;CYCLOOXYGENASE 2; COX2;;
PROSTAGLANDIN G/H SYNTHASE 2; PGHS2;;
read morePHS II;;
GLUCOCORTICOID-REGULATED INFLAMMATORY PROSTAGLANDIN G/H SYNTHASE;
GRIPGHS
*FIELD* TX

DESCRIPTION

A major mechanism for the regulation of prostaglandin synthesis occurs
at the level of cyclooxygenase, also known as prostaglandin-endoperoxide
synthase (PTGS; EC 1.14.99.1). The first rate-limiting step in the
conversion of arachidonic acid to prostaglandins is catalyzed by PTGS.
Two isoforms of PTGS have been identified: PTGS1 (COX1; 176805) and a
mitogen-inducible form, PTGS2. PTGS1 is involved in production of
prostaglandins for cellular housekeeping functions, whereas PTGS2 is
associated with biologic events such as injury, inflammation, and
proliferation (summary by Hla and Neilson (1992) and Tazawa et al.
(1994)).

CLONING

The antiinflammatory glucocorticoids are potent inhibitors of
cyclooxygenase, a key regulator of prostaglandin synthesis. To
investigate the mechanism of this inhibition, O'Banion et al. (1991,
1992) cloned a 4.1-kb mouse cDNA that conferred cyclooxygenase activity
to transfected cells. The mRNA of this cyclooxygenase, which O'Banion et
al. (1991, 1992) called Gripghs, was unique for its long 3-prime
untranslated region containing many AUUUA repeats. The 4.1-kb GRIPGHS
mRNA was rapidly increased by serum or interleukin-1-beta (IL1B; 147720)
in mouse fibroblasts and human monocytes, respectively, and decreased by
glucocorticoids, whereas levels of the 2.8-kb cyclooxygenase mRNA did
not change. O'Banion et al. (1991, 1992) concluded that the 2.8-kb
cyclooxygenase (PGHS1) is constitutive, whereas the 4.1-kb GRIPGHS is
regulated and is probably a major mediator of inflammation.

Hla and Neilson (1992) cloned COX2 from a human umbilical vein
endothelial cell (HUVEC) cDNA library. The deduced 604-amino acid
protein is 61% identical to human COX1 and 88% identical to mouse Cox2.
COX2 contains an N-terminal signal sequence, followed by a central
transmembrane region, a conserved active-site tyrosine, a conserved
aspirin acetylation site, and a C-terminal endoplasmic reticulum
retention signal. It also has several N-glycosylation sites, some of
which are conserved with COX1. In vitro translation of COX2 resulted in
a 70-kD protein. Northern blot analysis detected a 4.5-kb COX2
transcript in HUVECs. RT-PCR analysis revealed expression of COX2 and
COX1 in HUVECs, vascular smooth muscle cells, monocytes, and
fibroblasts.

Macchia et al. (1997) detected PGHS2 mRNA by Northern blot analysis of
term placenta. Western blot analysis using 3 highly specific antibodies
also found selective expression of PGHS2 immunoreactive protein in term
placenta. No PGHS1 was found in placenta.

Kirschenbaum et al. (2000) studied the immunohistochemical localization
of PTGS1 and PTGS2 in the human male fetal and adult reproductive
tracts. There was no PTGS1 expression in fetal samples (prostate,
seminal vesicles, or ejaculatory ducts), and only minimal expression in
adult tissues. There was no expression of PTGS2 in the fetal prostate.
In a prepubertal prostate there was some PTGS2 expression that localized
exclusively to the smooth muscle cells of the transition zone. In adult
hyperplastic prostates, PTGS2 was strongly expressed in smooth muscle
cells, with no expression in the luminal epithelial cells. PTGS2 was
strongly expressed in epithelial cells of both fetal and adult seminal
vesicles and ejaculatory ducts. The PTGS2 staining intensity in the
fetal ejaculatory ducts during various times of gestation correlated
with previously reported testosterone production rates by the fetal
testis. The authors concluded that PTGS2 is the predominant isoform
expressed in the fetal male reproductive tract, and its expression may
be regulated by androgens.

GENE FUNCTION

Hla and Neilson (1992) found that expression of human COX2 in COS-7
cells produced cyclooxygenase activity. COX2 mRNA was preferentially
induced by phorbol 12-myristate 13-acetate (PMA) and lipopolysaccharide
(LPS) in human endothelial cells and monocytes. This induction could be
partially inhibited by pretreatment with dexamethasone. In contrast,
COX1 showed minimal induction with LPS and PMA. Hla and Neilson (1992)
concluded that high-level induction of COX2 in mesenchymal-derived
inflammatory cells suggests a role for COX2 in inflammatory conditions.

Jones et al. (1993) found that stimulation of endothelial cells with TNF
(191160), PMA, LPS, or IL1 increased mRNA levels of PHS II, and this
change correlated with increased prostacyclin biosynthesis.
Cyclohexamide induced PHS II mRNA without a corresponding activity
increase, demonstrating that translation is required for enhanced
prostacyclin biosynthesis. Jones et al. (1993) concluded that expression
of PHS II may have important pathophysiologic effects in vasculature.

Tsujii and DuBois (1995) studied the effects of overexpressing COX2. Rat
intestinal epithelial (RIE) cells were stably transfected with a COX2
expression vector oriented in the sense (RIE-S) or antisense (RIE-AS)
direction. The RIE-S cells expressed elevated COX2 protein levels and
demonstrated increased adhesion to extracellular matrix proteins.
E-cadherin (192090) was undetectable in RIE-S cells, but was elevated in
parental RIE and RIE-AS cells. RIE-S cells were resistant to
butyrate-induced apoptosis, had elevated BCL2 (151430) protein
expression, and showed reduced transforming growth factor beta-2
receptor levels. The phenotypic changes involving both increased
adhesion to extracellular matrix and inhibition of apoptosis were
reversed by sulindac sulfide, a cyclooxygenase inhibitor. These studies
demonstrated that overexpression of COX2 leads to phenotypic changes in
intestinal epithelial cells that could enhance their tumorigenic
potential.

To explore the role of cyclooxygenase in endothelial cell migration and
angiogenesis, Tsujii et al. (1998) used 2 in vitro model systems
involving coculture of endothelial cells with colon carcinoma cells.
Cells overexpressing COX2 produced prostaglandins and proangiogenic
factors, and stimulated both endothelial migration and tube formation,
whereas control cells had little activity. The effect was inhibited by
antibodies to combinations of angiogenic factors, by NS-398 (a selective
COX2 inhibitor), and by aspirin. NS-398 did not inhibit production of
angiogenic factors or angiogenesis induced by COX2-negative cells.
Tsujii et al. (1998) also found that COX2 can modulate production of
angiogenic factors by colon cancer cells.

Zhou et al. (1999) found that culturing cells with highly purified human
chorionic gonadotropin (hCG) resulted in a time- and dose-dependent
increase in steady state levels of COX2 mRNA and protein and the
secretion of prostaglandin E2 (PGE2). Although human luteinizing hormone
(LH; see 152780) could mimic hCG, follicle-stimulating hormone (see
136530), thyroid-stimulating hormone (see 188540), and the alpha (CGA;
118850) and beta (CGB; 118860) subunits of hCG had no effect on COX2
protein levels. The authors concluded that hCG and LH treatment can
increase expression of COX2 in human endometrial gland epithelial cells;
the effect is time and dose dependent, hormone specific, and mediated by
the cAMP/type I protein kinase A signaling pathway; the hCG actions
require a normal complement of its receptors in cells; and these hCG and
LH effects may be another action of these hormones in human endometrium
that is important for implantation of the blastocyst and continuation of
pregnancy.

In a randomized control study comparing the effect of COX2 inhibitors
with nonselective NSAIDS upon the renal function of elderly subjects,
Swan et al. (2000) found that both agents cause a significant decrease
in the glomerular filtration rate. They concluded that COX2 therefore
seems to play an important role in human renal function.

Erkinheimo et al. (2000) investigated the expression of COX2 in human
myometrium. Myometrial samples collected from women in labor during
lower segment cesarean section expressed 15-fold higher levels of COX2
mRNA compared to myometrial specimens collected from women not in labor,
as detected by Northern blot analysis. Immunohistochemical detection of
COX2 protein showed cytoplasmic staining in the smooth muscle cells of
the myometrium. Cultured myometrial cells expressed low levels of COX2
mRNA under baseline conditions, but IL1-beta caused a 17-fold induction
of expression of the PTGS2 transcript after incubation for 6 hours.
IL1-beta also induced expression of biologically active COX2 protein, as
detected by immunofluorescence, Western blot analysis, and measuring the
conversion of arachidonic acid to prostanoids in the presence and
absence of a COX2-selective inhibitor, NS-398. PGE2 receptor subtype EP2
(176804) mRNA was expressed in cultured myometrial smooth muscle cells,
whereas transcripts for EP1 (176802), EP3 (176806), EP4 (601586), FP
(601204), and IP (600022) were low or below the detection limit as
measured by Northern blot analysis. However, IL1-beta stimulated
expression of EP4 receptor mRNA. The authors concluded that expression
of COX2 transcript is elevated at the onset of labor in myometrial
smooth muscle cells. This increase in expression may depend on
cytokines. As, in addition to COX2, the expression of prostanoid
receptors is regulated, not only the production of prostanoids, but also
responsiveness to them, may be modulated.

Inflammation causes the induction of COX2, leading to the release of
prostanoids, which sensitize peripheral nociceptor terminals and produce
localized pain hypersensitivity. Peripheral inflammation also generates
pain hypersensitivity in neighboring uninjured tissue, because of the
increased neuronal excitability in the spinal cord, and a syndrome
comprising diffuse muscle and joint pain, fever, lethargy, and anorexia.
Samad et al. (2001) showed that COX2 may be involved in central nervous
system (CNS) responses, by finding a widespread induction of COX2
expression in spinal cord neurons and in other regions of the CNS,
elevating prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The
major inducer of central COX2 upregulation is IL1-beta in the CNS, and
as basal phospholipase A2 (see 600522) activity in the CNS does not
change with peripheral inflammation, COX2 levels must regulate central
prostanoid production. In the rat, intraspinal administration of an
interleukin-converting enzyme or COX2 inhibitor decreased
inflammation-induced central PGE2 levels and mechanical hyperalgesia.
Thus, Samad et al. (2001) concluded that preventing central prostanoid
production by inhibiting the IL1-beta-mediated induction of COX2 in
neurons or by inhibiting central COX2 activity reduces centrally
generated inflammatory pain hypersensitivity.

Epithelial tumors may be regulated by COX enzyme products. To determine
if COX2 expression and PGE2 synthesis are upregulated in cervical
cancers, Sales et al. (2001) used real-time quantitative PCR and Western
blot analysis to confirm COX2 RNA and protein expression in squamous
cell carcinomas and adenocarcinomas. In contrast, minimal expression of
COX2 was detected in histologically normal cervix. Immunohistochemical
analyses localized COX2 expression and PGE2 synthesis to neoplastic
epithelial cells of all squamous cell carcinomas and adenocarcinomas
studied. Immunoreactive COX2 and PGE2 were also colocalized to
endothelial cells lining the microvasculature. To establish whether PGE2
has an autocrine/paracrine effect in cervical carcinomas, the authors
investigated the expression of 2 subtypes of PGE2 receptors, namely EP2
and EP4 by real-time quantitative PCR. Expression of EP2 and EP4
receptors was significantly higher in carcinoma tissue than in
histologically normal cervix. The authors concluded that COX2, EP2, and
EP4 expression and PGE2 synthesis are upregulated in cervical cancer
tissue and that PGE2 may regulate neoplastic cell function in cervical
carcinoma in an autocrine/paracrine manner via the EP2/EP4 receptors.

Lassus et al. (2000) performed COX2 immunohistochemistry on lung tissues
from autopsies of fetuses (16 to 32 weeks), preterm infants, term
infants, and infants with bronchopulmonary dysplasia (BPD). COX2
staining was found exclusively in the epithelial cells resembling type
II pneumocytes in the alveoli, and in ciliated epithelial cells in the
bronchi. COX2 staining occurred in a changing pattern: moderate
intensity staining in 90 to 100% of cells lining the alveolar epithelium
of fetuses; high intensity but scattered staining in cells of preterm
infants; less intense and fewer positive cells in term infants; and no
staining in alveolar epithelial cells of infants with BPD. COX2
bronchial epithelial staining was found in almost all fetal cells, in
approximately half of cells from preterm infants and infants with BPD,
and in fewer cells from term infants. The authors suggested that COX2
may play a developmental role in perinatal lung.

COX2 has been associated with carcinogenesis, and it is overexpressed in
many human malignancies. Salmenkivi et al. (2001) investigated the
expression of COX2 in normal adrenal gland, in 92 primary
pheochromocytomas, and in 6 metastases using immunohistochemistry and
Northern blot and Western blot analyses. COX2 protein was expressed in
the adrenal cortex, whereas the medulla was negative as detected by
immunohistochemistry. Interestingly, all 8 malignant pheochromocytomas,
regardless of the primary location of the tumor, showed moderate or
strong COX2 immunoreactivity, whereas 75% of the 36 benign adrenal
tumors showed no or only weak immunopositivity. The authors concluded
that normal adrenal medulla does not express COX2 immunohistochemically.
However, strong COX2 protein expression was found in malignant
pheochromocytomas, whereas most benign tumors expressed COX2 only
weakly. These findings suggested that negative or weak COX2 expression
in pheochromocytomas favors benign diagnosis.

Yokota et al. (2002) found that brown fat in normal human bone marrow
contains adiponectin (605441) and used marrow-derived preadipocyte lines
and long-term cultures to explore potential roles of adiponectin in
hematopoiesis. Recombinant adiponectin blocked fat cell formation in
long-term bone marrow cultures and inhibited the differentiation of
cloned stromal preadipocytes. Adiponectin also caused elevated
expression of COX2 by these stromal cells and induced release of
prostaglandin E2. A COX2 inhibitor prevented the inhibitory action of
adiponectin on preadipocyte differentiation, suggesting involvement of
stromal cell-derived prostanoids. Furthermore, adiponectin failed to
block fat cell generation when bone marrow cells were derived from COX2
heterozygous mice. Yokota et al. (2002) concluded that preadipocytes
represent direct targets for adiponectin action, establishing a
paracrine negative feedback loop for fat regulation. They also linked
adiponectin to the COX2-dependent prostaglandins that are critical in
this process.

Estrogen-induced responses in vascular cells have been shown to
influence prostaglandins and COX, a key enzyme in the production of
prostaglandins that has 2 isoforms, COX1 and COX2. Calkin et al. (2002)
investigated the effects of prostaglandins on the acute potentiation by
17-beta-estradiol of acetylcholine (ACh)-mediated vasodilation in the
cutaneous vasculature. Acute 17-beta-estradiol administration enhanced
the response to ACh after aspirin, diclofenac, and placebo; however,
this effect was completely abolished with treatment with celecoxib, a
specific COX2 inhibitor p less than 0.05). The authors concluded that
the COX2 pathway plays a specific role in the rapid
17-beta-estradiol-induced potentiation of cholinergic vasodilation in
postmenopausal women.

COX2 expression is translationally silenced in epithelial cells
undergoing radiation-induced apoptosis. Mukhopadhyay et al. (2003) found
that CUGBP2 (602538), a predominantly nuclear protein, is also rapidly
induced in response to radiation and translocates to the cytoplasm.
Antisense-mediated suppression of CUGBP2 rendered radioprotection
through a COX2-dependent prostaglandin pathway, providing an in vivo
demonstration of translation inhibition activity for CUGBP2. CUGBP2
bound to 2 sets of AU-rich sequences located within the first 60
nucleotides of the COX2 3-prime untranslated region (UTR). Upon binding,
CUGBP2 stabilized a chimeric luciferase-COX2 3-prime UTR mRNA but
inhibited its translation. These findings identified a novel paradigm
for RNA-binding proteins in facilitating opposing functions of mRNA
stability and translation inhibition and revealed a mechanism for
inhibiting COX2 expression in cancer cells.

Qin et al. (2003) found that expression of COX1 or COX2 in hamster and
human cells exogenously and endogenously expressing human amyloid
precursor protein (APP; 104760) induced production of the amyloid
peptides A-beta(1-40) and A-beta(1-42), as well as the
gamma-secretase-generated C-terminal fragment of APP. Peptide production
was coincident with the secretion of prostaglandin-E2 into the culture
medium. Treatment of APP-overexpressing cells with ibuprofen or with a
specific gamma-secretase inhibitor significantly attenuated COX1- and
COX2-mediated APP peptide production.

In rat hippocampal slices, Kim and Alger (2004) found evidence
suggesting that COX2 limits endocannabinoid action and signaling between
neurons.

Xu et al. (2004) demonstrated that activated T cells of patients with
systemic lupus erythematosus (SLE; 152700) resisted anergy and apoptosis
by markedly upregulating and sustaining COX2 expression. Inhibition of
COX2 caused apoptosis of the anergy-resistant lupus T cells by
augmenting FAS (134637) signaling and markedly decreasing the survival
molecule FLIP (603599), and this mechanism was found to involve
anergy-resistant lupus T cells selectively. Xu et al. (2004) noted that
the COX2 gene is located in a lupus susceptibility region on chromosome
1. They also found that only some COX2 inhibitors were able to suppress
the production of pathogenic autoantibodies to DNA by causing autoimmune
T-cell apoptosis, an effect that was independent of PGE2.

Egan et al. (2004) reported that estrogen acts on estrogen receptor
subtype alpha (133430) to upregulate the production of atheroprotective
prostacyclin (PGI2) by activation of COX2. This mechanism restrained
both oxidant stress and platelet activation that contribute to
atherogenesis in female mice. Deletion of the Pgi2 receptor removed the
atheroprotective effect of estrogen in ovariectomized female mice. Egan
et al. (2004) concluded that this suggested that chronic treatment of
patients with selective inhibitors of COX2 could undermine protection
from cardiovascular disease in premenopausal females.

Kothapalli et al. (2004) investigated the antimitogenic effect of high
density lipoprotein (HDL) on the inhibition of S-phase entry of murine
aortic smooth muscle cells, which they found to be mediated by
apolipoprotein E (APOE; 107741). They also demonstrated that specific
inhibition of Cox2 blocks the antimitogenic effects of HDL and Apoe,
that both HDL and Apoe induce Cox2 gene expression, and that the
prostacyclin receptor IP (600022) is required for the antimitogenic
effects of HDL and Apoe. Kothapalli et al. (2004) concluded that the
COX2 gene is a target of APOE signaling, linking HDL and APOE to IP
action, and suggested that this mechanism may contribute to the
cardioprotective effect of HDL and APOE.

By in vivo selection, transcriptomic analysis, functional verification,
and clinical validation, Minn et al. (2005) identified a set of genes
that marks and mediates breast cancer metastasis to the lungs. Some of
these genes serve dual functions, providing growth advantages both in
the primary tumor and in the lung microenvironment. Others contribute to
aggressive growth selectivity in the lung. Among the lung metastasis
signature genes identified, several, including PTGS2, were functionally
validated. Those subjects expressing the lung metastasis signature had a
significantly poorer lung metastasis-free survival, but not bone
metastasis-free survival, compared to subjects without the signature.

Liu et al. (2004) found that nitric oxide (NO) induced COX2 expression
in a human colorectal cell line and in nontransformed mouse colon
epithelial cells. NO-induced induction was due to PEA3 (ETV4;
600711)-p300 (EP300; 602700)-mediated activation of an ETS site and an
NFIL6 (CEBPB; 189965)-binding site in the COX2 promoter.

Kim et al. (2005) showed that inducible NO synthase (iNOS; 163730)
specifically binds to COX2 and S-nitrosylates it, enhancing COX2
catalytic activity. Selectively disrupting iNOS-COX2 binding prevented
NO-mediated activation of COX2. Kim et al. (2005) suggested that the
molecular synergism between iNOS and COX2 may represent a major
mechanism of inflammatory responses.

Metastasis entails numerous biologic functions that collectively enable
cancerous cells from a primary site to disseminate and overtake distant
organs. Using genetic and pharmacologic approaches, Gupta et al. (2007)
showed that the epidermal growth factor receptor ligand epiregulin
(602061), the cyclooxygenase COX2, and the matrix metalloproteinases
MMP1 (120353) and MMP2 (120360), when expressed in human breast cancer
cells, collectively facilitate the assembly of new tumor blood vessels,
the release of tumor cells into the circulation, and the breaching of
lung capillaries by circulating tumor cells to seed pulmonary
metastasis. Gupta et al. (2007) concluded that their findings revealed
how aggressive primary tumorigenic functions can be mechanistically
coupled to greater lung metastatic potential, and how such biologic
activities can be therapeutically targeted with specific drug
combinations.

To identify new modulators of hematopoietic stem cell formation and
homeostasis, North et al. (2007) screened a panel of biologically active
compounds for effects on stem cell induction in the zebrafish
aorta-gonad-mesonephros region. The authors showed that chemicals that
enhance prostaglandin E2 synthesis increased hematopoietic stem cell
numbers, and those that blocked prostaglandin synthesis decreased stem
cell numbers. The cyclooxygenases responsible for PGE2 synthesis were
required for hematopoietic stem cell formation. A stable derivative of
PGE2 improved kidney marrow recovery following irradiation injury in
adult zebrafish. In murine embryonic stem cell differentiation assays,
PGE2 caused amplification of multipotent progenitors. Furthermore, in
vivo exposure to stabilized PGE2 enhanced spleen colony-forming units at
day 12 post transplant and increased the frequency of long-term
repopulating hematopoietic stem cells present in murine bone marrow
after limiting dilution competitive transplantation. The conserved role
for PGE2 in the regulation of vertebrate hematopoietic stem cell
homeostasis indicates that modulation of the prostaglandin pathway may
facilitate expansion of hematopoietic stem cell number for therapeutic
purposes.

Using RT-PCR, Pan et al. (2008) showed that both COX2 and CCR7 (600242)
were upregulated in a significant number of breast tumor samples
compared with adjacent normal tissue, and that this upregulation was
associated with enhanced lymph node metastasis. Overexpression and
knockdown studies in human breast cancer cell lines revealed that COX2
acted via the prostaglandin receptors EP2 (PTGER2; 176804) and EP4
(PTGER4; 601586), resulting in increased intracellular cAMP and
activation of the PKA (see 188830)-AKT (see 164730) signaling pathway,
which led to induction of CCR7 expression. Elevated CCR7 enhanced the
migration of breast cancer cells toward lymphatic endothelial cells,
suggesting that CCR7 upregulation ultimately mediates COX2-associated
lymph node metastasis.

Bos et al. (2009) isolated cells that preferentially infiltrate the
brain from patients with advanced breast cancer. Gene expression
analysis of these cells and of clinical samples, coupled with functional
analysis, identified the cyclooxygenase COX2, the epidermal growth
factor receptor (EGFR; 131550) ligand HBEGF (126150), and the
alpha-2,6-sialyltransferase ST6GALNAC5 (610134) as mediators of cancer
cell passage through the blood-brain barrier. EGFR ligands and COX2 had
been linked to breast cancer infiltration of the lungs, but not the
bones or liver, suggesting a sharing of these mediators in cerebral and
pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates
brain metastasis. Normally restricted to the brain, the expression of
ST6GALNAC5 in breast cancer cells enhances their adhesion to brain
endothelial cells and their passage through the blood-brain barrier.
This co-option of a brain sialyltransferase highlights the role of cell
surface glycosylation in organ-specific metastatic interactions. Bos et
al. (2009) demonstrated that breast cancer metastasis to the brain
involves mediators of extravasation through nonfenestrated capillaries,
complemented by specific enhancers of blood-brain barrier crossing and
brain colonization.

The acetylation of COX2 by aspirin enables the biosynthesis of
R-containing precursors of endogenous antiinflammatory mediators termed
resolvins (Serhan et al., 2002). Spite et al. (2009) established the
complete stereochemistry of endogenous resolvin-D2 and its potent
stereoselective actions facilitating resolution of inflammatory sepsis.

Coward et al. (2009) found that expression of COX2 mRNA and protein and
production of PGE2 was induced by TGF-beta-1 (TGFB1; 190180) and IL1B in
cultured normal lung fibroblasts, but not in fibroblasts cultured from
lung tissue of patients with idiopathic pulmonary fibrosis (IPF;
178500). They showed that defective histone acetylation was responsible
for diminished COX2 transcription in IPF.

Using mouse models, Vegiopoulos et al. (2010) showed that COX2, a
rate-limiting enzyme in prostaglandin synthesis, is a downstream
effector of beta-adrenergic signaling in white adipose tissue and is
required for the induction of brown adipose tissue in white adipose
tissue depots. Prostaglandin shifted the differentiation of defined
mesenchymal progenitors toward a brown adipocyte phenotype.
Overexpression of COX2 in white adipose tissue induced de novo brown
adipose tissue recruitment in white adipose tissue, increased systemic
energy expenditure, and protected mice against high fat diet-induced
obesity. Thus, Vegiopoulos et al. (2010) concluded that COX2 appears
integral to de novo brown adipose tissue recruitment, which suggests
that the prostaglandin pathway regulates systemic energy homeostasis.

GENE STRUCTURE

Tazawa et al. (1994) isolated the entire PGHS2 gene and its 5-prime
flanking region and showed that it contains 10 exons and spans 7.5 kb.
By comparison, the murine and human PGHS1 genes comprise 11 exons and 10
introns and are approximately 22 kb long (Kraemer et al., 1992).

Kosaka et al. (1994) determined that the PTGS2 gene contains 10 coding
exons and spans more than 8.3 kb. The upstream region and intron 1
contain a canonical TATA box and various transcriptional regulatory
elements, including a functional cAMP response element.

MAPPING

Jones et al. (1993) and Tazawa et al. (1994) mapped the PTGS2 gene to
chromosome 1. By fluorescence in situ hybridization, Tay et al. (1994)
mapped the PTGS2 gene to chromosome 1q25. Using FISH, Kosaka et al.
(1994) mapped the PTGS2 gene to chromosome 1q25.2-q25.3.

MOLECULAR GENETICS

Fritsche et al. (2001) sequenced the COX2 gene from 72 individuals and
identified no functionally important polymorphisms. They suggested that
there has been selective pressure against such SNPs because of the
critical role of COX2 in the maintenance of homeostasis.

CLINICAL MANAGEMENT

Xia et al. (2012) showed that prostaglandin E2 (PGE2) silences certain
tumor suppressor and DNA repair genes through DNA methylation to promote
tumor growth. Their findings uncovered a theretofore unrecognized role
for PGE2 in the promotion of tumor progression, and provided a rationale
for considering the development of a combination treatment using PTGS2
inhibitors and demethylating agents for the prevention or treatment of
colorectal cancer.

ANIMAL MODEL

Morham et al. (1995) noted that COX2 is induced at high levels in
migratory and other responding cells by proinflammatory stimuli. COX2 is
generally considered to be a mediator of inflammation. Its isoform,
COX1, is constitutively expressed in most tissues and is thought to
mediate housekeeping functions. These 2 enzymes are therapeutic targets
of the widely used nonsteroidal antiinflammatory drugs (NSAIDs). To
investigate further the different physiologic roles of these isoforms,
Morham et al. (1995) used homologous recombination to disrupt the mouse
gene encoding Cox2 (Ptgs2). Mice lacking Cox2 were found to have normal
inflammatory responses to treatments with tetradecanoyl phorbol acetate
or arachidonic acid. However, they developed severe nephropathy and were
susceptible to peritonitis.

Oshima et al. (1996) bred mice carrying an APC (611731) mutation (a
truncation at residue 716) that causes adenomatous polyposis coli
closely mimicking that in the human with mice with a disrupted Ptgs2
gene. All the animals were APC heterozygotes; if homozygous for wildtype
Ptgs2, they developed an average of 652 polyps at 10 weeks, while
heterozygotes had 224 polyps and homozygously deficient mice had only 93
polyps. This experiment provided definitive genetic evidence that
induction of Ptgs2 is an early rate-limiting step for adenoma formation.
They showed also that a drug which inhibits the COX2 isoform encoded by
Ptgs2, but not COX1, also markedly reduced the number of polyps. Thus,
Oshima et al. (1996) concluded that overexpression of COX2 is an early,
central event in carcinogenesis.

Lim et al. (1997) generated COX2-deficient mice by gene targeting. These
mice showed multiple failures in female reproductive processes that
included ovulation, fertilization, implantation, and decidualization.
The authors concluded that the defects in these mice were the direct
result of target organ-specific COX2 deficiency and not the result of
deficiency of pituitary gonadotropins or ovarian steroid hormones, or
reduced responsiveness of the target organs to their respective
hormones.

The transition to pulmonary respiration following birth requires rapid
alterations in the structure of the mammalian cardiovascular system. A
dramatic change that occurs is the closure and remodeling of the ductus
arteriosus (DA; see 607411), an arterial connection in the fetus that
directs blood flow away from the pulmonary circulation. A role of
prostaglandins in regulating the closure of this vessel is supported by
pharmacologic and genetic studies. The production of prostaglandins is
dependent on COX1 and COX2. Loftin et al. (2001) reported that the
absence of either or both COX isoforms in mice did not result in
premature closure of the DA in utero. However, 35% of COX2 -/- mice died
with a patent DA within 48 hours of birth. In contrast, the absence of
only the COX1 isoform did not affect closure of the DA. The mortality
and patent DA incidence due to absence of COX2 was, however, increased
to 79% when one copy of the gene encoding COX1 was also inactivated.
Furthermore, 100% of the mice deficient in both isoforms died with a
patent DA within 12 hours of birth, indicating that in COX2-deficient
mice, the contribution of COX1 to DA closure is gene dosage-dependent.
Together, these data established roles for COX1 and especially for COX2
in the transition of the cardiopulmonary circulation at birth.

See also 176805 for the work of Gavett et al. (1999) on allergen-induced
pulmonary inflammation and airway hyperresponsiveness in wildtype mice
and in Ptgs1 -/- and Ptgs2 -/- mice.

In mice and humans, deregulated expression of COX2, but not of COX1, is
characteristic of epithelial tumors, including squamous cell carcinomas
of skin. To explore the function of COX2 in epidermis, Neufang et al.
(2001) used a keratin-5 (148040) promoter to direct COX2 expression to
the basal cells of interfollicular epidermis and the pilosebaceous
appendage of transgenic mouse skin. Cox2 overexpression in the expected
locations, resulting in increased prostaglandin levels in epidermis and
plasma, correlated with a pronounced skin phenotype. Heterozygous
transgenic mice exhibited a reduced hair follicle density. Moreover,
postnatal hair follicle morphogenesis and thinning of interfollicular
dorsal epidermis were delayed. Adult transgenics showed a body
site-dependent sparse coat of greasy hair, the latter caused by
sebaceous gland hyperplasia and increased epicutaneous sebum levels. In
tail skin, hyperplasia of scale epidermis reflecting an increased number
of viable and cornified cell layers was observed. Hyperplasia was a
result of a disturbed program of epidermal differentiation rather than
an increased proliferation rate, as reflected by the strong suppression
of keratin-10 (148080), involucrin (147360), and loricrin (152445)
expression in suprabasal cells. Further pathologic signs were loss of
cell polarity, mainly of basal keratinocytes, epidermal invaginations
into the dermis, and formation of horn perls. Invaginating hyperplastic
lobes were surrounded by vessels testing positive for CD31,
platelet-endothelial cell adhesion molecule-1 (173445).

In a mouse model of retinopathy of prematurity (ROP), Wilkinson-Berka et
al. (2003) found that Cox2 was localized to sites associated with
retinal blood vessels. The selective Cox2 inhibitor rofecoxib attenuated
retinal angiogenesis that accompanied ROP. Normal retinal development
indicated that COX2 plays an important role in blood vessel formation in
the developing retina.

Brewer et al. (2003) generated healthy mice lacking glucocorticoid
receptor (GCCR; 138040) only in T cells and thymus. Gccr was dispensable
for T-cell development, but administration of a T-cell stimulus or
superantigen to mutant mice, but not control mice, resulted in high
mortality that could not be rescued by dexamethasone or anti-Ifng
(147570). Microarray and ribonuclease protection analyses suggested that
endogenous glucocorticoids are required for transcriptional suppression
of Ifng, but not Tnf or Il2 (147680), in T cells. Inhibition of Cox2
protected mice from lethality without affecting Ifng levels. Histologic
analysis revealed that T-cell stimulation in mutant mice caused
significant damage to the gastrointestinal tract, particularly the
cecum, but little or no damage in other tissues. Brewer et al. (2003)
concluded that Gccr function in T cells is essential for survival during
polyclonal T-cell activation. Furthermore, they suggested that Cox2
inhibition may be useful for treatment of glucocorticoid insufficiency
or resistance in patients with toxic shock syndrome (see 607395),
graft-versus-host disease (GVHD; see 614395), or other T-cell activating
processes.

Liu et al. (2001) generated transgenic mice that overexpressed the human
COX2 gene in the mammary glands using the murine mammary tumor virus
promoter. The human COX2 mRNA and protein were expressed in mammary
glands of female transgenic mice and were strongly induced during
pregnancy and lactation. Multiparous but not virgin females exhibited a
greatly exaggerated incidence of focal mammary gland hyperplasia,
dysplasia, and transformation into metastatic tumors. COX2-induced tumor
tissue expressed reduced levels of the pro-apoptotic proteins BAX
(600040) and BCLXL (600039) and an increase in the anti-apoptotic
protein BCL2, suggesting that decreased apoptosis of mammary epithelial
cells contributes to tumorigenesis. Liu et al. (2001) concluded that
enhanced COX2 expression is sufficient to induce mammary gland
tumorigenesis.

Using Cox1 -/- and Cox2 -/- mice, Zhang et al. (2002) demonstrated that
COX2 plays a role in both endochondral and intramembranous bone
formation during skeletal repair. Healing of stabilized tibia fractures
was significantly delayed in Cox2 -/- mice compared with Cox1 -/- and
wildtype mice. Cultured Cox2 -/- bone marrow stromal cells showed a
defect in osteogenesis that could be completely rescued by addition of
prostaglandin E2. Addition of Bmp2 (112261) enhanced bone formation to a
level above that observed with prostaglandin E2 alone in both wildtype
and Cox2 -/- cells, indicating the BMP2 is downstream of prostaglandin
production. Expression of Cbfa1 (RUNX2; 600211) and osterix (SP7;
606633) was downregulated in Cox2 -/- cells. Addition of prostaglandin
E2 rescued this defect, and Bmp2 enhanced Cbfa1 and osterix in Cox2 -/-
and wildtype cells. Zhang et al. (2002) concluded that COX2 regulates
induction of CBFA1 and osterix to mediate normal skeletal repair.

Zhang et al. (2003) generated a transgenic mouse model overexpressing
TGM2 (190196) in cardiomyocytes and found that the mice had an
age-dependent left ventricular hypertrophy and cardiac decompensation,
characterized by cardiomyocyte apoptosis and fibrosis and a delayed
impact on survival. Expression of COX2, thromboxane synthase (274180),
and the thromboxane receptor (188070) were increased coincident with the
emergence of the cardiac phenotype. The COX2-dependent increase in
thromboxane A2 augmented cardiac hypertrophy, whereas formation of PGI2
by the same isozyme, as well as administration of COX2 inhibitors,
rescued the cardiac phenotype. Zhang et al. (2003) concluded that TGM2
activation regulates expression of COX2, and that its products may
differentially modulate cell death or survival of cardiomyocytes.

Boccaccio et al. (2005) developed a mouse model of sporadic
tumorigenesis in which they targeted the activated human MET oncogene
(164860) to adult liver. They observed slowly progressive
hepatocarcinogenesis, which was preceded and accompanied by a
disseminated intravascular coagulation (DIC)-like thrombohemorrhagic
syndrome. Genomewide expression profiling of MLP29 cells transduced with
the activated MET oncogene revealed prominent upregulation of
plasminogen activator inhibitor-1 (PAI1; 173360) and COX2, and in vivo
administration of a PAI1 or COX2 inhibitor slowed the evolution towards
full-blown DIC. Boccaccio et al. (2005) concluded that this study
provided the first direct genetic evidence for the link between oncogene
activation and hemostasis.

Brown et al. (2007) found that Myd88 (602170) -/- mice and Ptgs2 -/-
mice exhibited a profound inhibition of endothelial proliferation and
cellular organization within rectal crypts after injury. The effects of
injury in both mutant mouse strains could be rescued by exogenous PGE2,
suggesting that Myd88 signaling is upstream of Ptgs2 and PGE2. In
wildtype mice, the combination of injury and Myd88 signaling led to
repositioning of a subset of Ptgs2-expressing stromal cells from the
mesenchyme surrounding the middle and upper crypts to an area
surrounding the crypt base adjacent to colonic epithelial progenitor
cells. Brown et al. (2007) concluded that the MYD88 and prostaglandin
signaling pathways interact to preserve epithelial proliferation during
injury, and that proper cellular mobilization within the crypt niche is
critical to repair after injury.

Vardeh et al. (2009) observed that mice with conditional deletion of
Cox2 in neurons and glial cells, but not in peripheral immune cells,
showed no difference in basal nociception to mechanical or thermal pain
sensitivity from wildtype mice. There was also no difference in fever
induction. However, after induction of peripheral inflammation, mutant
mice had loss of Cox2 expression in the spinal cord and showed loss of
mechanical hypersensivity. The findings suggested that induction of Cox2
in neural cells in the central nervous system contributes to mechanical
pain hypersensitivity after peripheral inflammation, as is seen in
postoperative pain and arthritis. Peripheral Cox2 induction appears to
regulate thermal hypersensitivity, such as seen in sunburn or other
dermatologic conditions.

Shim et al. (2010) found that transgenic mice overexpressing human COX2
died shortly after birth, likely due to inability to inflate lungs.
Transgenic embryos exhibited severe skeletal malformations, generalized
edema, midfacial hypoplasia, and occasional umbilical hernia. The
skeletal defects were due to abnormal apoptosis of sclerotomal cells in
early embryonic development, which resulted in impaired precartilaginous
sclerotomal condensation.

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*FIELD* CN
Ada Hamosh - updated: 3/15/2012
Patricia A. Hartz - updated: 8/12/2010
Ada Hamosh - updated: 6/14/2010
Ada Hamosh - updated: 11/10/2009
Cassandra L. Kniffin - updated: 9/16/2009
Ada Hamosh - updated: 8/14/2009
Ada Hamosh - updated: 7/19/2007
Ada Hamosh - updated: 6/4/2007
Paul J. Converse - updated: 4/12/2007
Ada Hamosh - updated: 1/11/2006
Patricia A. Hartz - updated: 10/14/2005
Matthew B. Gross - updated: 10/14/2005
Ada Hamosh - updated: 8/15/2005
Marla J. F. O'Neill - updated: 3/23/2005
Ada Hamosh - updated: 12/28/2004
Cassandra L. Kniffin - updated: 7/26/2004
Marla J. F. O'Neill - updated: 3/15/2004
Marla J. F. O'Neill - updated: 3/4/2004
Marla J. F. O'Neill - updated: 2/18/2004
Patricia A. Hartz - updated: 2/9/2004
Paul J. Converse - updated: 9/5/2003
Jane Kelly - updated: 5/9/2003
Stylianos E. Antonarakis - updated: 4/22/2003
John A. Phillips, III - updated: 1/8/2003
Ada Hamosh - updated: 11/15/2002
John A. Phillips, III - updated: 7/1/2002
Deborah L. Stone - updated: 3/22/2002
John A. Phillips, III - updated: 9/25/2001
Victor A. McKusick - updated: 7/3/2001
Ada Hamosh - updated: 3/27/2001
John A. Phillips, III - updated: 3/26/2001
John A. Phillips, III - updated: 3/15/2001
Victor A. McKusick - updated: 3/5/2001
Ada Hamosh - updated: 10/31/2000
Ada Hamosh - updated: 5/29/2000
John A. Phillips, III - updated: 3/20/2000
Wilson H. Y. Lo - updated: 11/22/1999
Stylianos E. Antonarakis - updated: 6/24/1998
Stylianos E. Antonarakis - updated: 11/19/1997

*FIELD* CD
Victor A. McKusick: 12/21/1994

*FIELD* ED
terry: 03/15/2013
terry: 8/22/2012
alopez: 3/15/2012
mgross: 12/16/2011
wwang: 5/5/2011
mgross: 8/19/2010
terry: 8/12/2010
alopez: 6/18/2010
terry: 6/14/2010
terry: 5/20/2010
alopez: 11/11/2009
terry: 11/10/2009
wwang: 9/23/2009
ckniffin: 9/16/2009
alopez: 8/20/2009
terry: 8/14/2009
ckniffin: 2/5/2008
alopez: 7/24/2007
terry: 7/19/2007
alopez: 6/19/2007
terry: 6/4/2007
mgross: 4/12/2007
alopez: 1/13/2006
terry: 1/11/2006
mgross: 10/14/2005
alopez: 8/18/2005
terry: 8/15/2005
alopez: 3/23/2005
tkritzer: 1/3/2005
terry: 12/28/2004
ckniffin: 7/26/2004
alopez: 4/2/2004
carol: 3/31/2004
tkritzer: 3/8/2004
terry: 3/4/2004
carol: 2/18/2004
mgross: 2/9/2004
alopez: 10/16/2003
mgross: 9/5/2003
cwells: 5/9/2003
mgross: 4/22/2003
alopez: 1/8/2003
mgross: 12/10/2002
alopez: 11/19/2002
terry: 11/15/2002
alopez: 7/1/2002
carol: 4/8/2002
terry: 3/22/2002
cwells: 9/26/2001
cwells: 9/25/2001
alopez: 7/16/2001
mcapotos: 7/3/2001
alopez: 3/28/2001
terry: 3/27/2001
alopez: 3/26/2001
alopez: 3/15/2001
mcapotos: 3/12/2001
mcapotos: 3/7/2001
terry: 3/5/2001
mgross: 11/2/2000
terry: 10/31/2000
alopez: 6/1/2000
terry: 5/29/2000
mgross: 3/31/2000
terry: 3/20/2000
carol: 11/22/1999
terry: 8/10/1999
terry: 8/20/1998
carol: 6/24/1998
carol: 11/19/1997
alopez: 7/8/1997
mark: 1/11/1997
terry: 1/9/1997
mark: 9/11/1996
mark: 1/11/1996
mark: 12/4/1995
terry: 12/30/1994
carol: 12/21/1994