We have cloned a novel human kinase encoding gene (STKI5/BTAKaurora2), harbored on chromosome 20q13 that is amplified/overexpressed in many different human tumor cell types (Sen et al, Oncogene 14:2195-2200; Zhoui Kuang, Zhong, Kuo, Gray, Brinkley and Sen. Nature Genetics 20:189-193, 1998). Over-expression of this gene induces abnormal centrosome duplication/distribution, aneuploidy and tumorigenic transformation in mammalian cells. Over expression of STK1 5 has been detected in about 50 percent of unselected primary colon tumors and gene amplification detected in about 12 percent of unselected primary breast tumors. Over all goals of this project include elucidating the STK1 5 pathway that is involved in maintaining genomic stability and induction of aneuploidy in normal and cancer cells respectively. We also propose to evaluate the patho-genetic significance of STK1 5 protein and STK1 5 interacting proteins in human colon cancer cells.
The specific aims of this project are to: 1. Identify the interactions of STK1 5 kinase with its potential regulator and effector proteins through the G2-M phase of the cell division cycle. The results would help understand the role of these interactions in G2-M-Anaphase progression of cells. 2. Investigate amino acid structural requirements and post-translational modifications required for a) STK1 5 sub-cellular localization including targeting to centrosomes, and b) binding to interacting proteins. Results would help elucidate the biochemical mechanisms regulating STK1 5 localization and their functional relevance. 3. Investigate the role of STK1 5 and its interacting proteins in the regulation of centrosome function and chromosomal stability in proliferating cells in vivo through co-transfection experiments with appropriate wild type and mutant expression constructs. The findings of these studies are expected to elucidate the pathway that involves STK1 5 in maintaining genomic stability as well as in activating changes leading to transformation of cells due to abnormally elevated expression of the gene. 4. Determine the expression profiles of STK15 kinase and its interacting proteins in colon cancer specimens of different histological grades and stages with or without chromosomal instability phenotypes. Results would help assess the diagnostic and prognostic significance of STK1 5 pathway in this cancer.
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