02599nas a2200229   4500008004100000245010300041210006900144260001500213300001200228490000800240520175600248100002902004700003802033700002802071700002902099700001802128700002002146700002002166700002302186700003002209856013002239       2010                        eng d00aFM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status.0 aFM19G11 a new hypoxiainducible factor HIF modulator affects stem  c2010 Jan 8  a1333-420 v2853 a<p>The biology of the alpha subunits of hypoxia-inducible factors (HIFalpha) has expanded from their role in angiogenesis to their current position in the self-renewal and differentiation of stem cells. The results reported in this article show the discovery of FM19G11, a novel chemical entity that inhibits HIFalpha proteins that repress target genes of the two alpha subunits, in various tumor cell lines as well as in adult and embryonic stem cell models from rodents and humans, respectively. FM19G11 inhibits at nanomolar range the transcriptional and protein expression of Oct4, Sox2, Nanog, and Tgf-alpha undifferentiating factors, in adult rat and human embryonic stem cells, FM19G11 activity occurs in ependymal progenitor stem cells from rats (epSPC), a cell model reported for spinal cord regeneration, which allows the progression of oligodendrocyte cell differentiation in a hypoxic environment, has created interest in its characterization for pharmacological research. Experiments using small interfering RNA showed a significant depletion in Sox2 protein only in the case of HIF2alpha silencing, but not in HIF1alpha-mediated ablation. Moreover, chromatin immunoprecipitation data, together with the significant presence of functional hypoxia response element consensus sequences in the promoter region of Sox2, strongly validated that this factor behaves as a target gene of HIF2alpha in epSPCs. FM19G11 causes a reduction of overall histone acetylation with significant repression of p300, a histone acetyltransferase required as a co-factor for HIF-transcription activation. Arrays carried out in the presence and absence of the inhibitor showed the predominant involvement of epigenetic-associated events mediated by the drug.</p>1 aMoreno-Manzano, Victoria1 aRodríguez-Jiménez, Francisco, J1 aAceña-Bonilla, Jose, L1 aFustero-Lardíes, Santos1 aErceg, Slaven1 aDopazo, Joaquin1 aMontaner, David1 aStojkovic, Miodrag1 aSánchez-Puelles, Jose, M  uhttp://clinbioinfosspa.es/content/fm19g11-new-hypoxia-inducible-factor-hif-modulator-affects-stem-cell-differentiation-status