Human kinase interacting protein 2 (KIP2)-related gene variant associated with lung cancers

#The invention relates to the nucleic acid of a novel human kinase interacting protein 2 (KIP2)-related gene variant (KIP2V), the polypeptide encoded thereby, the preparation process thereof, and the uses of the same in diagnosing diseases associated with the deficiency of human KIP2 gene, in particular, lung cancers.

#Lung cancer is one of the major causers of cancer-related deaths in the world. There are two primary types of lung cancers: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (Carney, (1992a) Curr. Opin. Oncol. 4:292-8). Small cell lung cancer accounts for approximately 25% of lung cancer and spreads aggressively (Smyth et al. (1986) Q J Med. 61: 969-76; Carney, (1992b) Lancet 339: 843-6). Non-small cell lung cancer represents the majority (about 75%) of lung cancer and is further divided into three main subtypes: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma (Ihde and Minna, (1991) Cancer 15: 105-54). In recent years, much progress has been made toward understanding the molecular and cellular biology of lung cancers. Many important contributions have been made by the identification of several key genetic factors associated with lung cancers. However, the treatments of lung cancers still mainly depend on surgery, chemotherapy and radiotherapy. This is because the molecular mechanisms underlying the pathogenesis of lung cancers remain largely unclear.

#A recent hypothesis suggests that lung cancer is caused by genetic mutations of at least 10 to 20 genes (Sethi, (1997) BMJ. 314: 652-655). Therefore, future strategies for the prevention and treatment of lung cancers will be focused on the elucidation of these genetic substrates, in particular, the genes localized on chromosome 11p15.5, a region shown to be associated with the development of lung cancer, in particular, the NSCLC (Bepler and Garcia-Blanco, (1994) Proc Natl Acad Sci USA 91:5513-7; Kondo et al. (1996) Oncogene 12:1365-8; Sanchez-Cespedes et al. (1997) Clin Cancer Res 3:1229-35; Pitterle et al. (1999) Mamm Genome 10:916-22). A human kinase interacting protein 2 (KIP2) gene, mapped on this region (Matsuoka et al. (1995) Genes Dev 9:650-62; Kondo et al. (1996) Oncogene 12:1365-8) is a member of Cip/Kip family involved in the negative regulation of the cell cycle at the G1 checkpoint (Lee et al. (1995) Genes Dev 9:639-49; Harper and Elledge, (1996) Curr Opin Genet Dev 6:56-64; Sherr, (1996) Science 274:1672-7; Lee and Yang, (2001) Cell Mol Life Sci 58:1907-22). The tumor suppressor activity of KIP2 was shown to be mediated via its interaction with cyclin A-CDK2 (Adkins and Lumb, (2002) Proteins 46:1-7) or proliferating cell nuclear antigen (PCNA; Watanabe et al. (1998) Proc Natl Acad Sci USA 95:1392-1397). Overexpression of KIP2 was reported to arrest cells in G1 (Lee et al. (1995) Genes Dev 9:639-49; Matsuoka et al. (1995) Genes Dev 9:650-62). Decreased expression of KIP2 has been observed in many cancers (Chung et al. (1996) Hum Mol Genet 5:1101-8; Oya and Schulz, (2000) Br J Cancer 83:626-31; Dauphinot et al. (2001) Oncogene 20:3258-65; Ito et al. (2001) Oncology 61:221-5). These findings strongly implicate that KIP2 may have a role in the tumorigenic process of NSCLC. Therefore, the discovery of gene variants of KIP2 from squamous cell lung cancer may be important targets for diagnostic markers of squamous cell lung cancer.

#FIGS. 1A and 1B show the nucleic acid sequence of KIP2V (SEQ ID NO:1) and the corresponding amino acid sequence thereof (SEQ ID NO:2).

#FIGS. 2A to 2F show the nucleotide sequence alignment between the human KIP2 gene and KIP2V.

#FIGS. 3A and 3B show the amino acid sequence alignment between the human KIP2 protein and the polypeptide encoded by KIP2V.

#According to the present invention, all technical and scientific terms used have the same meanings as commonly understood by persons skilled in the art.

#The term “antibody,” as used herein, denotes intact molecules (a polypeptide or group of polypeptides) as well as fragments thereof, such as Fab, R(ab′)2, and Fv fragments, which are capable of binding the epitopic determinutesant. Antibodies are produced by specialized B cells after stimulation by an antigen. Structurally, antibody consists of four subunits including two heavy chains and two light chains. The internal surface shape and charge distribution of the antibody binding domain are complementary to the features of an antigen. Thus, antibody can specifically act against the antigen in an immune response.

#The term “base pair (bp),” as used herein, denotes nucleotides composed of a purine on one strand of DNA which can be hydrogen bonded to a pyrimidine on the other strand. Thymine (or uracil) and adenine residues are linked by two hydrogen bonds. Cytosine and guanine residues are linked by three hydrogen bonds.