UNIVERSITY OF MALTA
LIFE SCIENCE RESEARCH SEMINARS
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Cell proliferation signals in an erythroid cell line model
Dr Godfrey Grech
Department of Pathology, Medical School, Mater Dei Hospital
2340 1868
godfrey.grech@um.edu.mt
22nd November 2010
Approximately 200-250 words. Please email to scisem@um.edu.mt.
Abstract
Haematopoiesis is the life-long process of blood cell formation derived from haematopoietic
stem cells (HSC). In haematopoietic precursor cells, the PI3K/mTOR pathway plays an
important role in controlling the balance between proliferation and differentiation.
Previously we described that constitutive expression of alpha4, a regulatory subunit of the
phosphatase pp2a, inhibits the negative feedback of the phosphatase on mTOR downstream
effectors.
This resulted in a potent arrest of erythroblast differentiation to mature
erythrocytes. Progenitor cells constitutively expressing alpha4 in fact proliferate
exponentially for at least 72 hours without evidence of differentiation.
Current studies are focusing on the signalling pathway, PI3K/mTOR and the negative
feedback by the pp2a. Activation of mTOR downstream effectors, 4EBP and S6K are
investigated to elucidate the effect of the PI3K pathway and its negative feedback, both in
proliferative conditions by adding Erythropoeitin and Stem Cell Factor (SCF) and in
conditions that induce differentiation.
This study shows that S6K phosphorylation, in
erythroid progenitors, depends on erythropoietin signal and requires stem cell factor
signalling to maintain the phosphorylated state.
Interestingly, activation of pp2a by
FTY720 in our erythroid progenitor model, resulted in induced differentiation also in the
presence of SCF. This supports the key role of the phosphatase, pp2a, in the control of
proliferation and differentiation of erythroid progenitors.