Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1999-11-24
2004-07-20
Harris, Alana M. (Department: 1642)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S320100, C435S325000, C530S300000, C530S350000, C536S001001, C536S001110, C536S018700, C536S022100, C536S023100, C536S023200, C536S023500
Reexamination Certificate
active
06764833
ABSTRACT:
1. FIELD OF THE INVENTION
This invention relates to a newly identified Src oncogene mutation, polypeptides containing such mutation, and polynucleotides encoding such mutation. This invention also relates to methods of identifying the Src mutation, to the use of such methods in therapy and diagnosis, and to methods of identifying agonist and antagonist compounds useful for treating and/or preventing clinical conditions associated with or caused by Src mutation. Methods and compositions are provided for identifying and treating malignant cells in a host such as human. Mutated DNA sequence probes and primers are made for determining the expression of mutated nucleic acid.
2. BACKGROUND OF THE INVENTION
The discovery of Rous sarcoma virus (RSV) led to the identification of a cellular oncogene Src (c-Src) (SEQ ID NO. 1), which encodes a non-receptor tyrosine kinase (phosphoprotein of molecular weight 60,000 Dalton or pp60c-Src) (SEQ ID NO. 2). The Src oncogene has been implicated in the development of numerous types of cancers via a yet to be elucidated mechanism (see for example Stehelin, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. Nature 260, 170-173 (1976); Brugge, J. S. & Erikson, R. L. Identification of a transformation-specific antigen induced by an avian sarcoma virus. Nature 269, 346-348 (1977); Jove, R. & Hanafusa, H. Cell transformation by the viral Src oncogene. Annu Rev Cell Biol 3, 31-56 (1987); Thomas, S. M. & Brugge, J. S. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13, 513-609 (1997)). The nucleic acid sequence of normal c-Src is as follows:
atgggtagca acaagagcaa gcccaaggat gccagccagc ggcgccgcag cctggagccc
60
(SEQ ID NO.1)
gccgagaacg tgcacggcgc tggcgggggc gctttccccg cctcgcagac ccccagcaag
120
ccagcctcgg ccgacggcca ccgcggcccc agcgcggcct tcgcccccgc ggccgccgag
180
cccaagctgt tcggaggctt caactcctcg gacaccgtca cctccccgca gagggcgggc
240
ccgctggccg gtggagtgac cacctttgtg gccctctatg actatgagtc taggacggag
300
acagacctgt ccttcaagaa aggcgagcgg ctccagattg tcaacaacac ggagggagac
360
tggtggctgg cccactcgct cagcacagga cagacaggct acatccccag caactacgtg
420
gcgccctccg actccatcca ggctgaggag tggtattttg gcaagatcac cagacgggag
480
tcagagcggt tactgctcaa tgcagagaac ccgagaggga ccttcctcgt gcgagaaagt
540
gagaccacga aaggtgccta ctgcctctca.gtgtctgact tcgacaacgc caagggcctc
600
aacgtgaagc actacaagat ccgcaagctg gacagcggcg gcttctacat cacctcccgc
660
acccagttca acagcctgca gcagctggtg gcctactact ccaaacacgc cgatggcctg
720
tgccaccgcc tcaccaccgt gtgccccacg tccaagccgc agactcaggg cctggccaag
780
gatgcctggg agatccctcg ggagtcgctg cggctggagg tcaagctggg ccagggctgc
840
tttggcgagg tgtggatggg gacctggaac ggtaccacca gggtggccat caaaaccctg
900
aagcctggca cgatgtctcc agaggccttc ctgcaggagg cccaggtcat gaagaagctg
960
aggcatgaga agctggtgca gttgtatgct gtggtttcag aggagcccat ttacatcgtc
1020
acggagtaca tgagcaaggg gagtttgctg gactttctca agggggagac aggcaagtac
1080
ctgcggctgc ctcagctggt ggacatggct gctcagatcg cctcaggcat ggcgtacgtg
1140
gagcggatga actacgtcca ccgggacctt cgtgcagcca acatcctggt gggagagaac
1200
ctggtgtgca aagtggccga ctttgggctg gctcggctca ttgaagacaa tgagtacacg
1260
gcgcggcaag gtgccaaatt ccccatcaag tggacggctc cagaagctgc cctctatggc
1320
cgcttcacca tcaagtcgga cgtgtggtcc ttcgggatcc tgctgactga gctcaccaca
1380
aagggacggg tgccctaccc tgggatggtg aaccgcgagg tgctggacca ggtggagcgg
1440
ggctaccgga tgccctgccc gccggagtgt cccgagtccc tgcacgacct catgtgccag
1500
tgctggcgga aggagcctga ggagcggccc accttcgagt acctgcaggc cttcctggag
1560
gactacttca cgtccaccga gccccagtac cagcccgggg agaacctcta g
1611
The c-Src nucleic acid sequence (SEQ ID NO. 1) encodes for a tyrosine kinase protein pp60, which has a following sequence:
1
MGSNKSKPKD ASQRRRSLEP AENVHGAGGC AFPASQTPSK PASADCHRGP SAAFAPAAAE
(SEQ ID NO.2)
61
PKLFGGFNSS DTVTSPQRAG PLAGGVTTTV ALYDYESRTE TDLSFKKGER LQIVNNTEGD
121
WWLAHSLSTG QTGYIPSNYV APSDSIQAEE WYFGKITRRE SERLLLNAEN PRGTFLVRES
181
ETTKGAYCLS VSDFDNAKGL NVKHYKIRKL DSGGFYITSR TQFNSLQQLV AYYSKHADGL
214
CHRLTTVCPT SKPQTQGLAK DAWEIPRESL RLEVKLGQGC FGEVWMGTWN GTTRVAIKTL
301
KPGTMSPEAF LQEAQVMKKL RHEKLVQLYA VVSEEPIYIV TEYMSKGSLL DFLKGETGKY
361
LRLPQLVDMA AQIASGMAYV ERMNYVHRDL RAANILVGEN LVCKVADFGL ARLIEDNEYT
421
ARQCAKFPIK WTAPEAALYG RFTIKSDVWS FGILLTELTT KGRVPYPGMV NREVLDQVER
481
GYRMPCPPEC PESLHDLMCQ CWRKEPEERP TFEYLQAFLE DYFTSTEPQY
531
QPGENL
Amino acids are abbreviated as 1-letter codes and corresponding 3-letter codes as follows: Alanine is A or Ala; Arginine R or Arg, Asparagine N or Asn; Aspartic acid D or Asp; Cysteine C or Cys; Glutamine Q or Gln; Glutamic acid E or Glu; Glycine G or Gly; Histidine H or His; Isoleucine I or Ile; Leucine L or Leu; Lysine K or Lys; Methionine M or Met; Phenylalanine F or Phe; Proline P or Pro; Serine S or Ser; Threonine T or Thr; Tryptophan W or Trp; Tyrosine Y or Tyr; and Valine V or Val.
The cellular Src oncogene (c-Src) (SEQ ID NO. 1) is the normal counterpart of the transforming viral Rous sarcoma oncogene (v-Src). v-Src has been shown to induce the production of specific metalloproteinases (Hamaguchi, M. et al. Augmentation of metalloproteinase (gelatinase) activity secreted from Rous sarcoma virus-infected cells correlates with transforming activity of Src. Oncogene 10, 1037-1043 (1995)) and to foster the metastatic phenotype (Egan, S. et al. Transformation by oncogenes encoding protein kinases induces the metastatic phenotype. Science 238 202-205 (1987); Tatsuka, M. et al. Different metastatic potentials of ras- and Src-transformed BALB/c 3T3 A31 variant cells. Mol. Carcinog. 15, 300-308 (1996)). However, as opposed to cellular c-Src (SEQ ID NO. 1) the retroviral v-Src has 19 C-terminal residues replaced by a sequence of 12 amino acids, lacking the regulatory tyrosine.
The non receptor tyrosine kinase c-Src consists of an SH3, SH2 and tyrosine kinase domain. c-Src appears to be the most important to the normal function of osteoclasts, as determined from studies of Src-knock-out mice (see for example U.S. Pat. No. 5,541,109). The catalytic activity of c-Src and other nonreceptor tyrosine kinases is inhibited by the intramolecular association of their intrinsic SH2 domain to the carboxy-terminal tail upon phosphorylation of Tyr (position 530, avian position 527). Protein tyrosine phosphorylation is believed to be an important regulatory event in cell growth and differentiation. Phosphorylation on tyrosine can either decrease or increase the enzymatic activity of substrate proteins. Tyrosine phosphorylated sequences associate with Src homology 2 (SH2) domains, and thus tyrosine phosphorylation also serves to regulate protein/protein interactions. Many protein tyrosine kinases have been described to date: several are the receptors for peptide growth factors; others are expressed in the cytoplasm and nucleus. Tyrosine kinases can be of the receptor type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular). There are 19 known families of receptor tyrosine kinases including the Her family (EGFR, Her 2, Her 3, Her 4), the insulin receptor family (insulin receptor, IGF-1R, insulin-related receptor), the PDGF receptor family (PDGF-R alpha and beta, CSF-1R, Kit, Flk2), the Flk family (Flk-1, Flt-1, Flk-4), the FGF-receptor family (FGF-Rs 1 through 4), the Met family (Met, Ron), etc. There are 11 known families of non-receptor type tyrosine kinases including the Src family (Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, Yrk), Abl family (Abl, Arg), Zap 70 family (Zap 70, Syk) and Jak family (Jak 1, Jak 2, Tyk 2, Jak 3). Many of these tyrosine kinases have been found to be involved in cellular signaling pathways leading to pathogenic conditions such as cancer, psoriasis, hyperimmune response, etc. Other roles for tyrosine kinases include cellular responses to a variety of extracellular signals, such as those arising from growth factors and cell-cell interactions, as well as in differentiating developmental processes in both vertebrates and invertebrates.
Among various types of tumors, e.g., sarcoma, neuroblastoma, breast carcinoma among many others, c-Src ha
Irby Rosalyn B.
Yeatman Timothy J.
Harris Alana M.
Saliwanchik Lloyd & Saliwanchik
University of South Florida
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