Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1997-12-10
2001-08-14
Prouty, Rebecca E. (Department: 1652)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S023200, C536S023500, C435S069100, C435S252300, C435S325000, C435S320100
Reexamination Certificate
active
06274312
ABSTRACT:
FIELD OF THE INVENTION
The present invention pertains to compositions related to proteins which function, e.g., in controlling the cell cycle and transcription. In particular, it provides purified genes, proteins, antibodies, and related reagents useful, e.g., to regulate cell division and proliferation of various cell types, including tumor cells.
BACKGROUND OF THE INVENTION
Cancer can occur in any tissue of the body. It results from a change in certain cells that causes them to evade the normal growth limiting mechanisms, i.e., to no longer be under the feedback controls that normally stop cellular growth and reproduction after a given number of such cells have developed. Cell division and transcription are highly coordinated processes that play important roles in this feedback control. See, e.g., Beeson, et al. (eds.) (1979)
Textbook of Medicine
, 15th ed., W. B. Saunders Co., Philadelphia, Pa.; and DeVita, et al. (eds.) (1993) Cancer:
Principles and Practice of Oncology
, 4th ed., Lippincott, Philadelphia, Pa.
Molecules which function to regulate transcription and cell division play important roles in the controlled growth of various types of cells. Aberrations in these controls can lead to various disease states, e.g., oncogenesis, inappropriate immune responses to infections, improper wound healing, developmental abnormalities, and metabolic problems.
The cell cycle can be divided into four phases: the presynthetic phases (G
0
and G
1
); the phase of DNA synthesis (S); and the postsynthetic phase (G
2
). See, e.g., Guyton (ed.) (1976)
Textbook of Medical Physiology
, 5th ed., W.B. Saunders Co., Philadelphia, Pa.; Alberts, et al. (eds.) (1994)
Molecular Biology of the Cell
, 3rd ed., Garland Publishing, New York, N.Y.; and Darnell, et al. (eds.) (1990)
Molecular Cell Biology
, 2nd ed., W. H. Freeman, New York, N.Y. Effective chemot herapeutic agents are often those which target diseased cells in the S phase, e.g., choriocarcinoma, acute lymphocytic leukemia, lyphocytic lymphosarcoma, Burkitt's lymphoma, Hodgkin's disease, testicular neoplasms, Wilm's tumor, and Ewing's sarcoma. Unfortunately, oncogenic cells not actively dividing are less sensitive to these agents.
In the immune system, many of the effects of known cytokines on gene transcription are known to be mediated by cytokine inducible DNA binding proteins. See, e.g., Paul (ed.) (1994)
Fundamental Immunology
, 3rd ed., Raven Press, New York, N.Y. In particular, the family of Interferon Regulatory Factors (IFN), which are present in the promoters of interferon (IFN) genes, includes both activators and repressors of transcription. IFN mediated gene regulation is a complex cascade of events that leads, e.g., to acquisition of an antiviral state.
The lack of knowledge regarding the control of the cell cycle or transcriptional elements has hampered the ability of medical science to specifically regulate cell division or immune responses. The present invention provides compositions which will be important in the control of cell division and transcription.
SUMMARY OF THE INVENTION
The present invention is based in part upon the discovery of intracellular regulatory molecules which are hereby designated p150, p130, VCP, tsg101, and KWC02. p150, p130, and VCP are Cyclin E-Cdk associated proteins. Tsg101 and KWC02 are transcription factors.
The present invention provides substantially pure or recombinant p150, p130, VCP, tsg101, or KWC02 antigenic or peptide fragments. The peptide may be a full length natural protein or peptide from a human; comprise at least one polypeptide segment of SEQ ID NO: 2, 4, 6, 8, or 10; or exhibit a post-translational modification pattern distinct from a natural p150, p130, VCP, tsg101, or KWC02 protein. Also encompassed is a fusion protein and peptidomimetic. Various compositions of matter are further provided, e.g., selected from: a substantially pure or recombinant p150 protein or peptide exhibiting at least about 85% sequence identity over a length of at least about 12 amino acids to SEQ ID NO: 2; a natural sequence p150 of SEQ ID NO: 2; a fusion protein comprising p150 sequence; a substantially pure or recombinant p130 protein or peptide exhibiting at least about 85% sequence identity over a length of at least about 12 amino acids to SEQ ID NO: 4; a natural sequence p130 of SEQ ID NO: 4; a fusion protein comprising p130 sequence; a substantially pure or recombinant VCP protein or peptide exhibiting at least about 85% sequence identity over a length of at least about 12 amino acids to SEQ ID NO: 6; a natural sequence VCP of SEQ ID NO: 6; a fusion protein comprising VCP sequence; a substantially pure or recombinant tsg101 protein or peptide exhibiting at least about 85% sequence identity over a length of at least about 12 amino acids to SEQ ID NO: 8; a natural sequence tsg101 of SEQ ID NO: 8; a fusion protein comprising tsg101 sequence; a substantially pure or recombinant KWC02 protein or peptide exhibiting at least about 85% sequence identity over a length of at least about 12 amino acids to SEQ ID NO: 10; a natural sequence KWC02 of SEQ ID NO: 10; or a fusion protein comprising KWC02 sequence. In other preferred embodiments, the substantially pure or isolated protein comprises a segment exhibiting sequence identity to a corresponding portion of: a p150, wherein: said homology is at least about 90% identity and said portion is at least about 9 amino acids; said homology is at least about 80% identity and said portion is at least about 17 amino acids; or said homology is at least about 70% identity and said portion is at least about 25 amino acids; a p130, wherein: said homology is at least about 90% identity and said portion is at least about 9 amino acids; said homology is at least about 80% identity and said portion is at least about 17 amino acids; or said homology is at least about 70% identity and said portion is at least about 25 amino acids; a VCP, wherein: said homology is at least about 90% identity and said portion is at least about 9 amino acids; said homology is at least about 80% identity and said portion is at least about 17 amino acids; or said homology is at least about 70% identity and said portion is at least about 25 amino acids; a tsg101, wherein: said homology is at least about 90% identity and said portion is at least about 9 amino acids; said homology is at least about 80% identity and said portion is at least about 17 amino acids; or said homology is at least about 70% identity and said portion is at least about 25 amino acids; or a KWC02, wherein: said homology is at least about 90% identity and said portion is at least about 9 amino acids; said homology is at least about 80% identity and said portion is at least about 17 amino acids; or said homology is at least about 70% identity and said portion is at least about 25 amino acids. In other embodiments, the: p150: comprises a mature sequence of Table 1; or protein or peptide: is from a warm blooded animal selected from a mammal, including a primate; comprises at least one polypeptide segment of SEQ ID NO: 2; exhibits a plurality of portions exhibiting said identity; is a natural allelic variant of p150; has a length at least about 30 amino acids; exhibits at least two non-overlapping epitopes which are specific for a mammalian p150; exhibits a sequence identity at least about 90% over a length of at least about 20 amino acids to a primate p150; exhibits at least two non-overlapping epitopes which are specific for a primate p150; exhibits a sequence identity at least about 90% over a length of at least about 20 amino acids to a primate p150; is glycosylated; is a synthetic polypeptide; is attached to a solid substrate; is conjugated to another chemical moiety; is a 5-fold or less substitution from natural sequence; or is a deletion or insertion variant from a natural sequence; p130: comprises a mature sequence of Table 2; or protein or peptide: is from a warm blooded animal selected from a mammal
1
, including a primate; ii) comprises at least one polypeptide segment of SEQ ID NO: 4; exhibit
Gish Kurt C.
Lees Emma M.
McClanahan Terrill K.
Seghezzi Wolfgang
Shanahan Frances
Ching Edwin P.
Keleher Gerald P.
Mohan-Peterson Sheela
Monshipouri M.
Prouty Rebecca E.
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