The role of LYAR in normal development and oncogenesis

Guan Wang, Purdue University

Abstract

LYAR is a nucleolar protein that is highly expressed in some leukemic cells. LYAR is thought to have a role in cell growth, but its function is largely unknown. The purpose of this study is to determine LYAR's role in normal development and oncogenesis through the use of genetically engineered mice. Lyar knockout mice were developed using embryonic stem (ES) cells that contain a gene-trap insertion in the lyar gene locus, resulting in the disruption of lyar expression. Heterozygous founder mice were intercrossed, producing viable wild-type homozygotes (wt/wt), heterozygotes (wt/gt) and gene-trap homozygotes (gt/gt). Histological and growth rate analyses were performed to identify phenotypic changes in lyar-deficient mice and mouse embryos fibroblasts (MEFs). These studies revealed that LYAR is required for the proliferation of MEFs. The cell-cycle analysis revealed that the amount of cells in S phase was significantly lower in lyar-deficient MEFs. Despite this requirement for LYAR in cell growth, mice deficient in lyar are prone to tumor formation. Tumor development in lyar-deficient mice has a prolonged latency, which indicates that loss of LYAR may be insufficient to promote tumorigenesis and the acquisitions of additional genetic mutations are required for oncogenic transformation. Therefore, we analyzed progeny from lyarwt/gtp53wt/null× lyarwt/gtp53wt/null matings, which show clear deficiency of female lyarwt/gtp53 null/null and lyargt/gtp53 null/null mice. How the loss of a protein required for cell proliferation promotes tumorigenesis is an interesting conundrum and suggests that LYAR may be critical for maintaining cellular homeostasis.

Degree

M.S.

Advisors

Mendrysa, Purdue University.

Subject Area

Molecular biology|Genetics|Oncology

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