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United States Patent (19) 11 Patent Number: 6,146,876 Robision Et Al

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United States Patent (19) 11 Patent Number: 6,146,876 Robision Et Al USOO6146876A United States Patent (19) 11 Patent Number: 6,146,876 Robision et al. (45) Date of Patent: Nov. 14, 2000 54) 22025, A NOVEL HUMAN CYCLIC ID CN7A HUMAN, Jun. 1993. NUCLEOTDE PHOSPHODESTERASE ID CN7A MOUSE, Nov. 1996. 75 Inventors: Keith E. Robision, Wilmington; Houslay et al. (1997), “Tailoring cAMP-Signalling Rosana Kapeller-Libermann, Chestnut Responses Through Isoform Multiplicity', TiBS 22:217:224. Hill; David White, Holbrook, all of Mass. Bloom et al. (1996), “Identification and Tissue-Specific Expression of PDE7 Phosphodiesterase Splice Variants”, 73 Assignee: Millennium Pharmaceuticals, Inc., Proc. Natl. Acad. Sci. USA 93:14188-14192. Cambridge, Mass. Han et al. (1997), “Alternative Splicing of the High Affinity 21 Appl. No.: 09/330,970 cAMP-Specific Phosphodiesterase (PDE7A) mRNA in Human Skeletal Muscle and Heart”, The Journal of Bio 22 Filed: Jun. 11, 1999 logical Chemistry 272 (26):16152–16157. Related U.S. Application Data Beavo (1995), “Cyclic Nucleotide Phosphodiesterases: Functional Implications of Multiple Isoforms”, Physiologi 63 Continuation-in-part of application No. 09/277,423, Mar. cal Reviews 75(4):725–748. 26, 1999. DNA Blast Analysis Against NUC, PrevPatent Databases. 51 Int. Cl." ............................. C12N 1/20; C12N 15/00; CO7H 21/04 Protein Blast Analysis Against PNU, Patent Databases. 52 U.S. Cl. ................... 435/243; 435/252.3; 435/320.1; 536/23.2; 536/23.5; 536/24.31 Primary Examiner Bradley L. Sisson 58 Field of Search .................................. 536/23.2, 23.5, Attorney, Agent, or Firm-Alston & Bird LLP 536/24.31; 435/183, 243, 252.3, 320.1 57 ABSTRACT 56) References Cited The present invention relates to a newly identified human U.S. PATENT DOCUMENTS cyclic nucleotide phosphodiesterase belonging to the Super 5,527,896 6/1996 Wigler et al. .......................... 536/23.5 family of mammalian phosphodiesterases. The invention 5,702.936 12/1997 Beavo et al.. also relates to polynucleotides encoding the phosphodi 5,798.246 8/1998 Au-Young et al.. esterase. The invention further relates to methods using the 5,851,784 12/1998 Owens et al.. phosphodiesterase polypeptides and polynucleotides as a target for diagnosis and treatment in phosphodiesterase OTHER PUBLICATIONS mediated or -related disorders. The invention further relates Michaeli, Tamar, et al., “Isolation and Characterization of a to drug-Screening methods using the phosphodiesterase Previously Undetected Human cAMP Phosphodiesterase by polypeptides and polynucleotides to identify agonists and Complementation of cAMP Phosphodiesterase-deficient antagonists for diagnosis and treatment. The invention fur Saccharomyces cervisiae.” The Journal Of Biological ther encompasses agonists and antagonists based on the Chemistry, vol. 268, No. 17, pp. 12, Jun. 1993. phosphodiesterase polypeptides and polynucleotides. The Bloom, T, et al., “Identification and tissue-specific expres invention further relates to procedures for producing the sion of PDE7 phosphodiesterase splice variants.” Proceed phosphodiesterase polypeptides and polynucleotides. ings of the National Academy of Sciences, USA, Vol. 93, pp. 14188-14192, Nov. 1996. 8 Claims, 16 Drawing Sheets U.S. Patent Nov. 14, 2000 Sheet 4 of 16 6,146,876 U.S. Patent Nov. 14, 2000 Sheet S of 16 6,146,876 ? £8200-ld U.S. Patent Nov. 14, 2000 Sheet 7 of 16 6,146,876 )PSOOOO2/PDOCOOOO2/GLYCOSAMINDGLYCAN Glycosaminoglycan attachment site RU Acctional rules: RU There rust be at least two acidic amino acids (Glu or Asp) from -2 to RU -4 reotive to the Serine Query 479 SGSG 482 )PSOOOO4/PDDCOOOO4/CAMPPHDSPHD SITE CAMP- and cGMP-dependent protein kinase phosphorylation site, Query 15 SGSG 18 Query: 94 RRGS 97 )PSOOOOS/PDDCOOOO5/PKC PHOSPHOSITE Protein kinase C phosphorylation site, Query 117 TKK 119 Query: 390 SER 392 )PSOOOO6/PDOCOOO06/CK2. PHDSPHOSITE Casein kinase II phosphorylation site Query: 18 TGPE 21 Query: 56 SKSE 59 Query; 251 TPLD 254 Query; 292 SYLE 295 Query. 449 TLSE 452 Query: 481 SGPD 484 Query: 492 TESE 495 )PSOOOO!/PDDCOOOO7/TYRPHOSPHOSITE Tyrosine kinase phosphorylation site Query: 392 RVCEEFY 398 )PSOOOO8/PDOCOOO08/MYRISTYL N-myristoylation site, Query 22 GVLPSS 27 Query; 29 GSRPGC 34 Query: 67 GILDNE 7? Query 258 GLLAAA 263 Query; 477 GSSGSG 482 )PSOOOO9/PDDCOOOO9/AMIDATION Aridotion site Query 13 LGRR 16 FIG. 5B. U.S. Patent Nov. 14, 2000 Sheet 8 of 16 6,146,876 22O25C12, 3336 looses, 672 Check Strono) 1. GAGGGCCTGA AGACACAGGG AGGTTGTGCC AGGCTGGAGG 41 AGGCTTGTCT TTCCGAAGCT GGAGAGGATC TTACGGGGGT 81 TCGCTTTTCC CTGCCTGGGA AGAATTTCCC CTGTGGTAGC 121 AGCAGCAGCA GCAGCAGAAG CAGAAACAGC AGCAGCAGCA 1 6 1 ACAGCAGCAG CAGCAGCAGC ACCACCACCA CCACT ACCTC 2O1 CTCTTCTGGG, GCACAAGACA GAATGCCTGT GCT AGAGCGC METProVol LeuGlu Arg 241 TATTTCCACC CAGCAGAGCT AGGCAGGAGG, TGGACAGGCC ThyPheh is Pro A to Guleu GlyArgArg Try ThrglyP 281 CAGAAGGTGT GCTGCCCTCC TCCCCGGGAA GCCGGCCGGG roGluGlyVal LeuProSer SerProGlySer ArgFroGl 321 GTGCCAGCAG GGGCCGCTGC CCTGGGACTT GCCAGAGATG yCysG nGln GlyProLeuPro TrpAspLeu ProGluMET 361 ATCAGGATGG TAAAGCTGGT TTGGAAATCC AAAAGTGAGC I le ArgMETVo LysLeuVol TrpLysSer Lysser GluL 4O1 TGCAGGCGAC CAAACAGAGA GGCATTCTGG ACAATGAAGA euG nA loThr LysG nArg Gly I le LeuAsp AsnG uAs 441 TGCTCTCCGC AGCTTTCCAG GAGATATACG ACTAAGGGGT pA loLeu Arg SerPhe ProGly AspI le Arg LeuArgGly 481 CAGACGGGGG TTCGTGCTGA ACGCCGTGGC TCCTACCCAT GlnThrGlyVal ArgA to Glu Argarg(Gly SerTyrProP 521. TCATTGACTT CCGCCTACTT AACAGTACAA CATACT CAGG he I leAspPhe ArgleuLeu AsnSerThrThr Tyr SerGl 561 GGAGATTGGC ACCAAGAAAA AGGTGAAAAG ACTATTAAGC yGlute Gly ThrLysLysLys Wo Lys Arg LeuleuSer FIG. 6A. U.S. Patent Nov. 14, 2000 Sheet 9 of 16 6,146,876 22025C12, 3336 kooses, 672 Check Strono 6O1 TTTCAAAGAT ACTTCCATGC ATCAAGGCTG CTTCGTGGAA Phe GlnArgTyr Pheh is Alo Ser Argleu LeuArgG ty I 64 1 TTATACCACA AGCCCCTCTG CACCTGCTGG ATGAAG ACTA le I le ProGrn. A to ProLeu HisLeuLeuAsp GuAsply 681 CCTTGGACAA GCAAGGCATA TGCTCTCCAA AGTGGGAATG rLeuGlyGt rh Alo Argh is MET LeuSerLys Val GlyMET 721 TGGGATTTTG ACATTTTCTT GTTTGATCGC TTGACAAATG Trp-Asphe Asp I tePheLeu Phe AspArg Leu ThrasnG 761 GAAACAGCCT GGTAACACG TTGTGCCACC TCTTCAATAC ly AsnSerLeu Vol ThrLeu LeucysHisLeu Phe Asn Th 8O1 CCATGGACTC ATTCACCATT TCAAGTTAGA TATGGTGACC rHis GlyLeu I leHisHisPhe LysLeuAsp METVo. Thr 841 TTACACCGAT TTTTAGTCAT GGTTCAAGAA GATTACCACA LeuHis Arghe LeuVo MET Vol. GnGlu AspTyrHisS 881 GCCAAAACCC GTATCACAAT GCTGTTCACG CAGCCGACGT erG nAsnPro Tyrh is Asn Alo Vo His A to Ala AspVo 921 CACCCAGGCC AT GCACTGCT ACCTGAAAGA GCCAAAGCTT lThrGlnAto METHisCysTyr LeuLysGlu ProLysLeu 961 GCCAGCTTCC TCACGCCTCT GGACATCATG CTTGGACTGC A loSerPheleu ThrProLeu AspI leMET LeuGlyLeuL 1 OO1 TGGCTGCAGC AGCACACGAT GTGGACCACC CAGGGGTGAA eu.A lo Al QA to A to His Asp Wo Asphispro Gly Vol. As 1 O41 CCAGCCATTT TTGATAAAAA CTAACCACCA TCTTGCAAAC nGLnProPhe LeuI leLys Thr AsnHisHis LeuA to Asn 1 O81 CTATATCAGA ATATGTCTGT GCTGGAGAAT CATCACTGGC LeuTyrG nAsn METSerVa LeuguAsn Hish is Trpa 1121 GATCTACAAT TGGCATGCTT CGAGAATCAA GGCTTCTTGC rgSerThr I le GlyMETLeu ArgGuSer Arg LeuLeuAl 1161 TCATTTGCCA AAGGAAATGA CGTAAGTGCT GCCGAGATGA OH isLeuPro LysGuMETThr STP F.G. 6B. U.S. Patent Nov. 14, 2000 Sheet 10 of 16 6,146,876 22025C12, 3336 looses, 672 Check Strono 12O1 AACATACTGA TGTGCATGCA GTAAAGATAA GCCACTTTCT 1241 CTAGGGCAGG, CTTGGGACCT TTTGCGTGAA TGGCAGAGAG 1 281 CCCCCCGCT GTACTTCCTG CCTGCACTGA GCTGTCTATC 1321 AGAGGAGATT TGGTGTCAGT TACAGCAACC CAGAAACCAA 1.361 AATCTCTCTG TGTGCTTTGA AAGGGCCTTG CAGAGTCAAT 14O1 GACCTACAGT CAGGAAAAGG GATAATAAAC AGCTCTCAGT 1441 TTTCACACGC TTCAGTATCA GTGCTCGACT TTGCCAAATT 1481 CCCGACCTTT AGTTTAGCAA AATTGTCCTT CCATGTAGCT 1521 CCAAATAGTA AATATTTATC AAGAAGGAAC CCAGGCATTC 1561 TAAAGCTAGA GTTCAAAAAA GTATATTTTG TAATTGCTAG 16O1 TCTCAGCAAA AAT AGAAGTC AGAAATTCTT TTCTAAAATG 1641 TCTTTTGCTA AGTAATTGAA ATGGCCCTAG CATTTTTTTC 1681 ACCAATTAAT TTACCTTACG TCTCTTGCAC TTTAAACAGA 1721 AGGGGAGACA CTCATTTTCT GGTTCACTAT TTGATAGCCA 1761 TGGTATGTAG GCTGAGTCCC ACTAAATCTG AGGCCATTGT FIG. 6C. U.S. Patent Nov. 14, 2000 Sheet 11 of 16 6,146,876 22O25C12, 3336 looses, 672 Check Strono 18O1 TTCATTTTCC TGGTGGCCCC AAGTTAGCTG CTAATACTGT 1841 CTTCCAAGGC CACCATTAAT TCTGATCTGT TTAATGAACA 1881 CGTGCAGAAC CCAAGAAACC TAGGTGAAAA GAGTACATAG 1921 ATTGCTGTAC CCTTCTTCAA GACAAGCACA TAACTTGAGG 1961 TCAAGGACCA AGTGCTGTCT CCCAACTGAA CAAGCAGTAT 2OO1 ACTCTGGGTT GTGGATTGAT TCCTGGCCCT CTGATTTGAT 2O41 CTCATGCTGT TTCCTAGCAC CCAGAGGAAT GTGAAATTTG 2O81 CAGGAGGAAT TTCAGTTCTG ATAAATTTTT A CTCCCTGGA 21 21 ACTAAATAAA ACCAGTTCTC GTGCATGGAA TAAAAACTTA 21 61 TGCCTCTTAC TAGAATAATA AATTGCAAAG ATTGAAAGAA 22O1 TTAAATGCAA AAAGAACTAA AAACTAGAGC AAAAGATCAA 2241 GTGAGAAGAA GAAAAGAGGA GGTAAGGAGA GAGACAAGGA 2281 AGAAAGAAGG AGAAGGAAAG GAAGAAT AGT GAGGACAGGA 2321 AAGAAGAAAA TGCAAGGGAA ATGGGAAAGG ACTCTGGGGT 2361 GACCAGACTT CTCCTGGTCA GTACCGCAT TCATCCTGTT FIG. 6D. U.S. Patent Nov. 14, 2000 Sheet 12 of 16 6,146,876 22025C12, 3336 looses, 672 Check Stronc 24O1 TGTTACT CAA TATTTCTTTC CTAAAATATT CATTTCACAT 2441 CTATGGATTC CAATGAAAAA TATATTTTTA TGTGTCTTTG 2481 TGGAACACAG TGTTATAAAT TGTTTTTGCC AGAAGAATAA 2521 TTGTTATACA ATAATATATG TGAAAACTTT ATTACAAAAG 2561 CCATTATCAT AATCATTATT ATTCCTTCTA TCACAGGTAA 26O1 ATGCTTTAAT GTCATTTTTC TGATTTTAAA AGTAGGGCAG 2641 GTTAATTGTA GAAAGTAAGG AAAATTCAGG AAAGTGTTAG 2681 TTTGAACTAT GTGAAGTTGC TCTTTTTAAG GGCCAAAAAC 2721 AGGAGACTTT TAGCACTTTC ATATGTTTCA GCTTGATATG 2761 AAAGAGAAAA CTGAAACTGC TAGTAATCCT GCCATCCAGG 28O1 TATAGTTCAT GTTAACCTGG CTAGTTTATT TTCTTTTAGT 2841 CTTTTTTCAA TACAAACTTA TTTTAACAAA ATATGATTAN 2881 ATTTGGGGAA CTTATTTTAC AGTTTACGTC CTGAAATTTT 2921 TTATTTACAA TAAAGACTTT TTTCCAAATC
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