The role of putative oncogene LYAR in cell growth regulation

Li Chen, Purdue University

Abstract

LYAR (Ly-1 antibody reactive clone) is a putative oncogene overexpressed in many types of human cancer including B cell lymphoma and breast cancer. High levels of LYAR are also expressed in many leukemic T-, leukemic B- lineage cell lines and at early stages in radiation-induced T-cell leukemia cells in mice model. Together, these observations suggest that LYAR is an oncogene that is involved in the development of the immune system. However, the function of LYAR is largely unknown. The goal of my research is to investigate the role of LYAR in biological processes, particularly in cell growth regulation. My results demonstrate that LYAR is distributed throughout the three subcomponents of the nucleolus and that nucleolar localization of LYAR is dependent upon amino acid residues 170-241. Further experiments have revealed that upon Actinomycin D-induced cellular stress LYAR translocates out of the nucleolus into the nucleoplasm. In stressed cells, a subset of LYAR gathers at the edges of the nucleoli, while another subset either diffuses in the nucleoplasm or translocates into nucleoplasm to form small foci. The identity of these LYAR-associated foci is not known. However, results from this study confirm that these foci are not nuclear speckles or PML bodies. To shed light on LYAR function and discover genetic interactions and pathways in which LYAR is involved, I have performed a synthetic dosage lethality screening using yeast as a model system. In this screening, I identified a total of 163 genes involved in a diverse range of biological processes. The genes identified in this screening were enriched for genes that encoded proteins involved in chromatin remodeling complexes that function in the repression of gene transcription, sporulation, and telomere silencing. These results raise the possibility that LYAR may function in transcriptional repression, particularly in silencing. I have confirmed that in yeast lacking lug1 (the orthologue of mammalian LYAR), transcriptional silencing at the telomere locus is modestly impaired. This phenotype was augmented when lug1 was deleted in a set1 mutant background. In addition, yeast with set1 and lug1 double deletion showed an obvious cell growth defect. The synthetic sickness phenotype caused by set1 and lug1 double deletion suggest that these two genes encode proteins that operate in functionally related pathways. Taken together, this study has provided important insights into the biological function of the putative oncoprotein LYAR.

Degree

M.S.

Advisors

Mendrysa, Purdue University.

Subject Area

Molecular biology|Genetics|Cellular biology|Oncology

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