EDUCATION

Diploma in Chemical Engineering, Aristotle University of Thessaloniki, 2004

RESEARCH Project

Tumor suppressor p53 responds to cellular stress and elicits arrest of DNA synthesis and/or apoptosis. We have recently demonstrated that p53 is activated during Megakaryocytic (Mk) differentiation in both human primary cultured Mk cells and in the CHRF megakaryoblastic cell line. We also showed that miRNA-mediated down-regulation of p53 in CHRF cells results in higher Mk ploidy by means of enhancement of DNA synthesis and deferment of apoptosis. Hematopoietic progenitor cells from p53-/- mice induced with Thrombopoietin (Tpo) to undergo Mk differentiation, reached higher Mk ploidy classes than did wild-type cells. Because the stage of Mk polyploidy is known to correlate with the number of platelets released per Mk cell, we are currently looking into the kinetics of platelet production in p53-/- versus wild-type mice. Additionally, we have shown that down-regulation of p53 affects its transcriptional activity and modulates the level of expression of its canonical transcriptional targets. Using microarray analysis we are currently examining the p53 regulon in the context of megakaryopoiesis. We have hypothesized that p53 is activated during megakaryopoiesis in order to control polyploidization and the transition from endomitosis to apoptosis by impeding cell cycling and promoting apoptosis. An additional hypothesis is that Tpo-mediated stimulation of early hematopoietic progenitor and Mk cells also elicits p53 activation presumably through interplay of MAPK, PI3K and JAK-STAT signaling pathways in response to Tpo. Stabilization and activation of p53 involves a complex set of post-translational modifications such as phosphorylation, acetylation and ubiquitination. We propose that phosphorylation of distinct serine residues and acetylation of p53 are vital to its transcription factor role during megakaryopoiesis

ADVISOR

• Eleftherios Terry Papoutsakis, Professor, University of Delaware (and adjunct Professor at Northwestern University)
• William M. Miller, Professor, Northwestern University

SELECTED PUBLICATIONS

1. Chen C, Fuhrken PG, Huang LT, Apostolidis P, Wang M, Paredes CJ, Miller WM, Papoutsakis ET. A systems-biology analysis of isogenic megakaryocytic and granulocytic cultures identifies new molecular components of megakaryocytic apoptosis. BMC Genomics. 2007
2. Fuhrken PG, Chen C, Apostolidis PA, Wang M, Miller WM, Papoutsakis ET. Gene-Ontology driven transcriptional analysis of CD34+-cell initiated megakaryocytic cultures identifies new transcriptional regulators of megakaryopoiesis. Physiol Genomics. 2008
3. Giammona LM, Panuganti S, Kemper JM, Apostolidis PA, Lindsey S, Papoutsakis ET, Miller WM. Mechanistic studies on the effects of nicotinamide on megakaryocytic polyploidization and the roles of NAD(+) levels and SIRT inhibition. Exp Hematol. 2009 Aug 26. [Epub ahead of print]
4. Fuhrken PG, Apostolidis PA, Lindsey S, Miller WM, Papoutsakis ET. Tumor suppressor protein p53 regulates megakaryocytic polyploidization and apoptosis. J Biol Chem. 2008 Jun 6;283(23):15589-600. Epub 2008 Apr 8.

RESEARCH SUMMARY KEYWORDS

• Megakaryocytic differentiation
• p53
• Apoptosis
• Polyploidy
• CHRF