Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-09-09
2001-07-10
Burke, Julie (Department: 1642)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023500, C435S091100
Reexamination Certificate
active
06258942
ABSTRACT:
TECHNICAL FIELD
The present invention encompasses a novel protein designated tumor associated diagnostic gene 7 (TADG7), a novel TADG7 cDNA and mRNA segments coding for the TADG7 protein, chimeric cells comprising the TADG7 DNA segment, vectors and plasmids comprising the TADG7 DNA segment and methods for producing the TADG7 protein as well as methods for detection and use of measurement of the expression of the gene coding for the TADG7 protein as a diagnostic tool in early detection of ovarian cancer. Measurement methods may detect either the TADG7 mRNA, or the TADG7 protein. Novel antibodies useful in detection and purification of the TADG7 protein are also provided.
BACKGROUND OF THE INVENTION
Proteins involved in cell cycle regulation containing various characteristic regions have been previously identified. For example, protein tyrosine kinases comprising SH3 and SH2 domains are disclosed in U.S. Pat. No. 5, 439,819. Proteins including SH2 and SH3 domains have been found to be important in cell cycle processes, especially in signal transduction pathways. Receptor tyrosine kinases are known participants in signal transduction processes. Numerous proteins involved in signal transduction are discussed by Fantl et al.,Ann. Rev. Biochem. (1993), 62:453, Dohlwan, et al., Ann. Rev. Biochem. (1991), 60:653; and Simon et al., Cell (1993), 73:169. Over expression of cell cycle proteins has been observed in numerous tumors, and often serves as a diagnostic tool.
Interfering in the intracellular signal transduction pathways may provide a mechanism for numerous therapeutic applications. While several proteins have been identified that interfere with various signal transduction mechanisms, new active proteins are important in providing alternatives for therapy and drug development. The novel protein of the invention provides a heretofore unknown molecule that is useful as a diagnostic marker in ovarian tumors. The gene is also expressed in brain tissue and may play a role in signal processing in the brain.
Two partial DNA sequences entered into a database of so-called expressed sequence tags (EST) have 97% and 96% homology over approximately 405 and 374 nucleotides to the 3′ end of the TADG7 gene. These fragmentary sequences do not in themselves provide any clues as to either the nature or use of the TADG7 protein, or its sequence, or the DNA sequence of the complete gene.
SUMMARY OF THE INVENTION
The invention is a novel TADG7 protein having the amino acid sequence set out in Seq. I.D. No. 1, novel TADG7 cDNA and mRNA segments coding for the TADG7 protein, isolated from human genetic material. The cDNA sequence is set out in Seq. I.D. No. 2, the mRNA is set out in Seq. I.D. No. 3. The invention in another embodiment includes a construct comprising the open reading frame found at base 151 (beginning the initial methionine codon) to base 1548 or optionally through base 1553 (end of the polyadenylation sequence downstream of the open reading frame), or a sequence analog there of. Preferably the open reading frame segment 151 to 1548 or 1553 is coupled with a promoter segment and optionally coupled with additional DNA coding for a fusion protein segment useful in purification such as a poly histidine tail or an enzyme such as GST. Such an embodiment of the subject invention may comprise one or more of the following components operably linked from 5′ to 3′ to form an expression plasmid vector: (a) a promoter; (b) a signal sequence, (c) 5′ portion of a highly expressed endogenous gene preferably one whose product is secreted from the host cells (i.e. glucoamylase gene in Aspergillis); (d) a linker sequence; and (e) a nucleotide sequence corresponding to the desired TADG7 protein or a TADG7 polypeptide fragment. Alternatively a resistance selectable marker gene may also be inserted after the TADG7 nucleotide sequence, following a transcription termination sequence, and having the appropriate components to function as a means for selecting clones containing the vector. In an alternative embodiment expression level of the cDNA, measured either by quanitation of TADG7 mRNA or detection of the TADG7 protein in a tumor specimen to be characterized provide a diagnostic method for detection of ovarian carcinomas.
In additional embodiments the invention also provides chimeric cells adapted to express the TADG7 protein, which preferably comprise vectors constructed as described above. The vectors may also include DNA coding for TADG7 fusion proteins. The invention further provides methods for production of the TADG7 protein including expression of the TADG7 DNA or substitution analogs thereof in chimeric cells.
The TADG7 protein comprises regions with overall homology with members of the receptor tyrosine kinase (RTK) subfamily, particularly RTK Class III of the protein kinase family. These regions augment the utility of the protein, DNA and mRNA as diagnostic tools. Of course the protein is useful as a source of amino acids, as a nutrition supplement, and as a marker for human tissue, as well as having potential therapeutic uses due to its primary role in cell cycle control. In addition, the protein itself or specific peptides generated from the protein sequence could be used as antigens for the production of polyclonal and monoclonal antibodies useful in tissue typing and tumor diagnostics. Further, the gene itself can be used as an antisense vehicle for cell cycle control by shutting down signaling or cell division.
REFERENCES:
Hillier et al Genome Research vol. 6 807-828, 1996.*
Ausubel et al Current Protocols in Molecular Biology Chapter 16 pp. 16.0.1 through 16.2.1, 1990.
Moon Sung
O'Brien Timothy J.
Adler Benjamin Aaron
Burke Julie
The Board of Trustees of the University of Arkansas
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