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The p53 transcription factor is involved in cell cycle, apoptosis and differentiation. However, the mechanism of p53 mediated differentiation is not fully understood. Here, we show that recently discovered dual oxidase maturation factor 1 (DUOXA1), which was implicated in neuronal differentiation, is regulated by p53 and may be an important factor in neuronal differentiation. We show that DUOXA1 is highly expressed in mouse neuronal stem cells with intensive nuclear localization. A strong interaction between DUOXA1 and p53 is observed in undifferentiated cells and declines in terminally differentiated neurons. Overexpressed p53 induces marked DUOXA1 expression in P19 cells and intensifies neuronal differentiation in the presence of retinoic acid, which suggests that p53 and DUOXA1 possess a neural differentiation potential. At day 3 of retinoic acid induced differentiation when cells showed a typical morphology of neuronal progenies, CD133 expression was down-regulated. The expression level of CD133 was significantly decreased in p53 over-expressing cells and was accompanied by a substantial increase in the expression level of neurofilament. In conclusion, DUOXA1 is a novel p53-regulated neurogenic factor involved in p53 dependent neuronal differentiation., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Recently, we reported that cancer cells that recover from a potentially lethal damage gain new phenotypic features comprised of mitochondrial structural remodeling associated with increased glycolytic dependency and drug resistance. Here, we demonstrate that a subset of cancer cells, upon recovery from a potentially lethal damage, undergo dedifferentiation and express genes, which are characteristic of undifferentiated stem cells. While these cells are competent in maintaining differentiated progeny of tumor, they also exhibit transdifferentiation potential. Dedifferentiation is characterized by accumulation of hydrogen sulfide (H 2 S), which triggers up-regulation of nicotinamide phosphoribosyltransferase (Nampt) accompanied by changes in the redox state. The molecular events triggered by Nampt include elevated production of NAD + and up-regulation of H 2 S producing enzymes, cystathionine beta synthase (CBS) and cystathionase (CTH) with 3-mercaptopyruvate sulfurtransferase (MST) being detectable only in 3D spheroids. Suppression of Nampt, or inactivation of H 2 S producing enzymes, all reduce H 2 S production and reverse the ability of cells to dedifferentiate. Moreover, H 2 S induced stem cell markers in parental cancer cells in a manner similar to that observed in damage recovered cells. These data suggest of existence of a positive feedback loop between H 2 S and Nampt that controls dedifferentiation in cancer cells that recover from a potentially lethal damage. [ABSTRACT FROM AUTHOR]

In this study, we describe a role for the mammalian Numb-interacting protein 1 (Nip1) in regulation of neuronal differentiation in stem cells. The expression of Nip1 was detected in the developing mouse brain, embryonic stem cells, primary neuronal stem cells, and retinoic acid-treated P19 embryonal carcinoma cells. The highest expression of Nip1 was observed in undifferentiated neuronal stem cells and was associated with Duox1-mediated reactive oxygen species ROS production. Ectopic nip1 expression in P19 embryonal carcinoma cells induced neuronal differentiation, and this phenotype was also linked to elevated ROS production. The neuronal differentiation in nip1-overexpressing P19 cells was achieved in a retinoic acid-independent manner and was corroborated by an increase in the expression of the neuronal basic helix-loop-helix transcription factors and neural-lineage cell markers. Furthermore, depletion of nip1 by short hairpin RNA led to a decrease in the expression of neuronal basic helix-loop-helix transcription factors and ROS. However, inhibition of ROS production in nip1-overexpressing P19 cells restricted but did not extinguish neuronal differentiation. Microarray and mass spectrometry analysis identified intermediate filaments as the principal cytoskeletal elements affected by up-regulation of nip1. We show here the first evidence for a functional interaction between Nip1 and a component of the nuclear lamina, lamin A/C. associated with a neuronal-specific phenotype. Taken together, our data reveal an important role for Nip1 in the guidance of neuronal differentiation through ROS generation and modulation of intermediate filaments and implicate Nip1 as a novel intrinsic regulator of neuronal cell fate. [ABSTRACT FROM AUTHOR]