Role of Fas in Hematopoietic Defects in Mice Open Access

Lim, Jaims (2014)

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Hematopoiesis is the proliferation and differentiation of hematopoietic stem cells into different blood cells such as erythrocytes and leukocytes. When there are complications in hematopoiesis, various blood disorders such as leukemia and anemia may occur. PP2A is a serine/threonine protein phosphatase that regulates cellular pathways involved in cell development, growth, and differentiation. PP2A is post-translationally regulated by a methyltransferase and a methylesterase. LCMT-1 (leucine carboymethyltransferase-1) is one of the main regulators of PP2A, and it activates PP2A by methylating the PP2A C-subunit carboxy-terminal leucine. Other functions of LCMT-1 include being a positive regulator for the Raf-1 protein, a cellular kinase and proto-oncogene. Previous research shows that Raf-1 down-regulates Fas, a death receptor located on cell membranes that activates caspase pathways and triggers cell death. Keeping this in mind, when LCMT-1, a core regulator of PP2A, is knocked out, various hematopoietic defects result. We hypothesized that the knockout of LCMT-1 causes a down regulation of Raf-1 and in effect causes an up-regulation of the Fas (death receptor) leading to a high amount of cell death and consequental liver and blood defects. In this study, a Fas mutant allele (Lpr) was introduced in order to see if it relieved any of the hematopoietic defects caused by LCMT knockout. LCMT-1 +/- Fas Lpr/Lpr mice were intercrossed with each other to see if LMCT-1 knockout embryos carrying the Fas Lpr allele showed any sign of phenotypic rescue from embryonic lethality, reduced liver size, and increased liver cell death. Two strains of mice, 129S2/SvHsd and C57BL/6J, were used in this study. Results showed that the Fas Lpr allele did not reverse the embryonic lethality, increased cellular death, and reduced liver sizes seen in LCMT-1 knockout mice. Although reduction of Fas by the Fas Lpr allele did not reverse the phenotypic defects caused by the knockout of LCMT-1, other pathways and proteins should be investigated to see if the LMCT-1 knockout mice can be rescued.

Table of Contents

Table of Contents

List of Abbreviations 1

Introduction 2

Methods 8

Results 16

Discussion 21

Figures 24

Literature Cited 35

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