C Mejia-Pous1, F Damiola, O Gandrillon. 1. Bases Moléculaires de l'Autorenouvellement et de ses Altérations" Group, Université de Lyon, Université Lyon 1, Villeurbanne, Centre de Génétique Moléculaire et Cellulaire, Lyon, France.
Abstract
OBJECTIVES: Molecular mechanisms controlling cell fate decision making in self-renewing cells are poorly understood. A previous transcriptomic study, carried out in primary avian erythroid progenitor cells (T2ECs), revealed that the gene encoding oxidosqualene cyclase (OSC/LSS), an enzyme involved in cholesterol biosynthesis, is significantly up-regulated in self-renewing cells. The aim of the present work is to understand whether this up-regulation is required for self-renewal maintenance and what are the mechanisms involved. MATERIALS AND METHODS: To investigate OSC function, we studied effects of its enzymatic activity inhibition using Ro48-8071, a specific OSC inhibitor. In addition, we completed this pharmacological approach by RNAi-mediated OSC/LSS knockdown. The study of OSC inhibition was carried out on both self-renewing and differentiating cells to observe any state-dependent effect. RESULTS: Our data show that OSC acts both by protecting self-renewing T2EC cells from apoptosis and by blocking their differentiation program, as OSC inhibition is sufficient to trigger spontaneous commitment of self-renewing cells towards an early differentiation state. This is self-renewal specific, as OSC inhibition has no effect on erythroid progenitors that have already differentiated. CONCLUSIONS: Taken together, our results suggest that OSC/LSS expression and activity are required to maintain cell self-renewal and may be involved in the self-renewal versus differentiation/apoptosis decision making, by keeping cells in a self-renewal state.
OBJECTIVES: Molecular mechanisms controlling cell fate decision making in self-renewing cells are poorly understood. A previous transcriptomic study, carried out in primary avian erythroid progenitor cells (T2ECs), revealed that the gene encoding oxidosqualene cyclase (OSC/LSS), an enzyme involved in cholesterol biosynthesis, is significantly up-regulated in self-renewing cells. The aim of the present work is to understand whether this up-regulation is required for self-renewal maintenance and what are the mechanisms involved. MATERIALS AND METHODS: To investigate OSC function, we studied effects of its enzymatic activity inhibition using Ro48-8071, a specific OSC inhibitor. In addition, we completed this pharmacological approach by RNAi-mediated OSC/LSS knockdown. The study of OSC inhibition was carried out on both self-renewing and differentiating cells to observe any state-dependent effect. RESULTS: Our data show that OSC acts both by protecting self-renewing T2EC cells from apoptosis and by blocking their differentiation program, as OSC inhibition is sufficient to trigger spontaneous commitment of self-renewing cells towards an early differentiation state. This is self-renewal specific, as OSC inhibition has no effect on erythroid progenitors that have already differentiated. CONCLUSIONS: Taken together, our results suggest that OSC/LSS expression and activity are required to maintain cell self-renewal and may be involved in the self-renewal versus differentiation/apoptosis decision making, by keeping cells in a self-renewal state.
Authors: S Roy; R Luetterforst; A Harding; A Apolloni; M Etheridge; E Stang; B Rolls; J F Hancock; R G Parton Journal: Nat Cell Biol Date: 1999-06 Impact factor: 28.824
Authors: Xinghua Zhou; Thomas P Johnston; Daniel Johansson; Paolo Parini; Keiko Funa; Jan Svensson; Göran K Hansson Journal: Atherosclerosis Date: 2008-10-25 Impact factor: 5.162
Authors: Florian H Heidel; Lars Bullinger; Patricia Arreba-Tutusaus; Zhu Wang; Julia Gaebel; Carsten Hirt; Dietger Niederwieser; Steven W Lane; Konstanze Döhner; Valera Vasioukhin; Thomas Fischer; Scott A Armstrong Journal: J Exp Med Date: 2012-12-31 Impact factor: 14.307
Authors: Anita M Quintana; Fabrizio Picchione; Ramon I Klein Geltink; Michael R Taylor; Gerard C Grosveld Journal: Dis Model Mech Date: 2013-12-19 Impact factor: 5.758