Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-07-23
2001-04-24
Prouty, Rebecca E. (Department: 1652)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C436S086000, C530S350000
Reexamination Certificate
active
06221843
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of human keratins and to the use of these sequences in the diagnosis, treatment, and prevention of epithelial, cell proliferative, developmental, and reproductive disorders.
BACKGROUND OF THE INVENTION
Keratins, members of the intermediate filament superfamily, are cytoskeletal proteins that assemble into approximately 10 nm diameter filaments that give structural support to epithelial cells. Intermediate filaments are so-named because their diameter is intermediate between those of microtubules and microfilaments. Keratins are abundant in soft epithelia such as skin and cornea, hard epithelia such as nails and hair, and in epithelia that line internal body cavities.
Keratins have a central &agr;-helical rod region interrupted by short nonhelical linker segments. The rod region is bracketed, in most cases, by non-helical head and tail domains. The rod regions of two different keratin monomers associate to form a parallel coiled-coil heterodimer. A highly ordered assembly process leads from the heterodimers to the approximately 10 nm diameter intermediate filaments. (Lodish, H. et al. (1995)
Molecular Cell Biology,
Scientific American Books, New York, N.Y., pp. 1106-1116; and Fuchs, E. and Cleveland, D. W. (1998) Science 279:514-519.)
About thirty keratin genes have been identified, and these genes are differentially expressed in epithelial tissues at various stages of differentiation and development. (Fuchs, E. (1997) Mol. Biol. Cell 8:189-203.) Keratins are divided into Type I (acidic) and Type II (basic) families. In general keratins are expressed in pairs as the heterodimers form from one Type I keratin and one Type II keratin. Type II keratin 6 (K6) is a basic keratin which is coexpressed with Type I keratin 16 or Type I keratin 17. K6 is expressed in various normal tissues including filiform papillae of tongue, stratified epithelia lining the oral mucosa and esophagus, outer root sheath of hair follicles, and glandular epithelia. K6 expression, which appears to be associated with fast cell turnover rate, is induced in epidermis and other stratified epithelia that are undergoing hyperproliferation, for example wound healing, psoriasis, actinic keratosis, viral infections, and cancer. Multiple human isoforms of K6 have been identified. (Takahashi, K. et al. (1995) J. Biol. Chem. 270:18581-18592.)
Type II keratin 5 (K5) is coexpressed in stratified squamous epithelia with its assembly partner Type I keratin 14. (Eckert, R. L. and Rorke, E. A. (1988) DNA 7:337-345; and Lersch, R. et al. (1989) Mol. Cell Biol. 9:3685-3697.) Mutations in K5 cause the severe autosomal dominant skin blistering disorder epidermolysis bullosa simplex. (Uttam, J. et al. (1996) Proc. Natl. Acad. Sci. USA 93:9079-9084.)
Cytokeratin 19 (K19), the smallest known keratin, is a Type I keratin that differs from other keratins in that it lacks a carboxy-terminal nonhelical tail domain and does not have a designated partner keratin for filament formation. K19 is expressed in embryonic and adult simple epithelia and in stratified epithelia. (Bader, B. L. et al. (1986) EMBO J. 5:1865-1875; and Lussier, M. et al. (1990) Gene 95:203-213.) K19 may be expressed in the early human embryo. (Savtchenko, E. S. et al. (1988) Am. J. Hum. Genet. 43:630-637.)
Keratins are associated with many disease states. Mutations in keratin genes are responsible for skin diseases such as epidermolysis bullosa simplex, epidernolytic hyperkeratosis, ichthyosis bullosa of Siemens, epidermal nevi/epidermolytic hyperkeratosis type, and epidermolytic and nonepidermolytic palmoplantar keratoderma, some of which cause severe skin blistering. Keratin mutations are also responsible for pachyonychia congenita, a disease of the nails and hair, and for the hair disease monilethrix. Other disorders caused by keratin mutations include white sponge nevus, Meesmann's corneal dystrophy, chronic hepatitis/cryptogenic cirrhosis, and colorectal hyperplasia. (Fuchs and Cleveland, supra; Fuchs, supra; and Corden, L. E. and McLean, W. H. (1996) Exp. Dermatol. 5:297-307.)
Keratins are associated with cell proliferative disorders. As described above, K6 expression is induced in epidermis and other stratified epithelia that are undergoing hyperproliferation. Keratins may have roles in development and embryogenesis. K19, as well as keratins 8 and 18, may be expressed in the early human embryo. (Savtchenko, supra.) The expression of many keratin genes is controlled by retinoic acid, an important regulator of development and differentiation. (Tomic-Canic, M. et al. (1996) J. Biol. Chem. 271:1416-1423.)
The discovery of new human keratins and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of epithelial, cell proliferative, developmental, and reproductive disorders.
SUMMARY OF THE INVENTION
The invention features substantially purified polypeptides, human keratins, referred to collectively as “KERT” and individually as “KERT-1”, “KERT-2”, and “KERT-3”. In one aspect, the invention provides a substantially purified polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, a fragment of SEQ ID NO:1, a fragment of SEQ ID NO:2, and a fragment of SEQ ID NO:3.
The invention further provides a substantially purified variant having at least 90% amino acid identity to the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3, or to a fragment of any of these sequences. The invention also provides an isolated and purified polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, a fragment of SEQ ID NO:1, a fragment of SEQ ID NO:2, and a fragment of SEQ ID NO:3. The invention also includes an isolated and purified polynucleotide variant having at least 90% polynucleotide sequence identity to the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, a fragment of SEQ ID NO:1, a fragment of SEQ ID NO:2, and a fragment of SEQ ID NO:3.
Additionally, the invention provides an isolated and purified polynucleotide which hybridizes under stringent conditions to the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, a fragment of SEQ ID NO:1, a fragment of SEQ ID NO:2, and a fragment of SEQ ID NO:3, as well as an isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide encoding the polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, a fragment of SEQ ID NO:1, a fragment of SEQ ID NO:2, and a fragment of SEQ ID NO:3.
The invention also provides an isolated and purified polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, a fragment of SEQ ID NO:4, a fragment of SEQ ID NO:5, and a fragment of SEQ ID NO:6. The invention further provides an isolated and purified polynucleotide variant having at least 90% polynucleotide sequence identity to the polynucleotide sequence comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, a fragment of SEQ ID NO:4, a fragment of SEQ ID NO:5, and a fragment of SEQ ID NO:6, as well as an isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, a fragment of SEQ ID NO:4, a fragment of SEQ ID NO:5, and a fragment of SEQ ID NO:6.
The invention further provides an expression vector containing at least a fragment of the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from
Baughn Mariah
Corley Neil C.
Hillman Jennifer L.
Tang Y. Tom
Incyte Genomics Inc.
Incyte Genomics, Inc.
Monshipouri M.
Muenzen Colette
Murry Lynn E.
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