Novel Functions of LAMMER-related Kinases in Gene Expression

Claremont Mc Kenna College, Claremont CA

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Abstract

LAMMER-related kinases play major roles in cell growth, differentiation, hepatitis B virus infection, cancer development and sensitivity to anti-cancer drugs, insulin-regulated glucose metabolism and nutrient homeostasis. Members of the kinase family are subjects of extensive interest because of their potential to serve as therapeutic targets for various human diseases. Despite their importance and disease relevance, considerable gaps of knowledge exist regarding the mechanisms by which the LAMMER-related kinases carry out their functions. Building upon previous work on their functions in cell cycle control and pre-mRNA splicing, the PI's laboratory obtained preliminary data that implicate the fission yeast members of the LAMMER-related kinases, Dsk1 and Kic1/Lkh1, in nuclear export of mRNA and centromeric gene silencing. The primary goal of the proposed research is to decipher the molecular basis underlying the novel roles of Dsk1 and Kic1 kinases in mRNA export and centromeric gene silencing. The experiments are designed to test the hypothesis that Dsk1 and Kic1 may execute their novel roles in gene expression by modulating the activity of poly(A)-binding protein Pabp in mRNA export and participating in Swi6/HP1 phosphorylation cascade for centromeric gene silencing. Molecular genetics, biochemical and fluorescence microscopy will be employed to assess in vivo phosphorylation and cellular localization of Pabp and Swi6 proteins affected by the kinases, as well as to determine the possible kinase-substrate relationship of Dsk1/Kic1 with Pabp or Swi6. The fission yeast Schizosaccharomyces pombe, as a genetically and a cell biologically tractable system with small genome size of less redundancy, offers a valuable model organism to dissect the multifaceted kinase functions. Achieving the goal of the research will not only provide insights into the molecular mechanisms of LAMMER kinase function in all eukaryotes but also contribute to elucidation of molecular pathology of the diseases involved and unraveling more targets for developing therapeutics. The proposed project will lay the foundation for the long- term investigation to ultimately address the interplay between the kinase functions in multiple steps of eukaryotic gene expression and cell-division cycle, the fidelity of which is the central issue of cancer prevention and treatment. Furthermore, the educational objectives of the proposal are intertwined with the specific research aims to integrate the project into course-based investigation, to enhance students' understanding of the project themes, and to encourage women and underrepresented groups in science to participate in research. This project aims to provide crucial opportunities for student research experience in the areas relevant to public health, stimulate their interest in sciences, and diversify the next-generation of professionals working in health-related fields. Both the significance of the proposed research and the enhancement in investigative components of science education strengthen the research environment of the Keck Science Department and the Claremont Colleges.