Pluripotency is a unique biological state that allows cells to differentiate into any tissue type. Here we describe a candidate pluripotency factor, Ronin, that possesses a THAP domain, which is associated with sequence-specific DNA binding and epigenetic silencing of gene expression. Ronin is expressed primarily during the earliest stages of murine embryonic development, and its deficiency in mice produces periimplantational lethality and defects in the inner cell mass. Conditional knockout of Ronin prevents the growth of ES cells while forced expression of Ronin allows ES cells to proliferate without differentiation under conditions that normally do not promote self-renewal. Ectopic expression also partly compensates for the effects of Oct4 knockdown. We demonstrate that Ronin binds directly to HCF-1, a key transcriptional regulator. Our findings identify Ronin as an essential factor underlying embryogenesis and ES cell pluripotency. Its association with HCF-1 suggests an epigenetic mechanism of gene repression in pluripotent cells.
cardiomyogenesis ͉ cyclic GMP ͉ soluble guanylyl cyclase ͉ NO donors ͉ sGC activators E mbryonic stem (ES) cells are derived from the inner cell mass of the preimplantation embryo, and because of their selfrenewal and pluripotency, they are thought to revolutionize the field of regenerative medicine (1-3). Although transplantation of stem cells into animal models of cardiac injury and Parkinson's disease has revealed some beneficial effects, a better understanding of the role of specific signaling pathways involved in proliferation and differentiation of ES cells is necessary to improve their use in clinical medicine (4-6). Components of a number of signaling pathways such as Wnt/-catenin (7), phosphotidyle-inosital 3-kinase (8, 9), MAPK (10), and NO (11) have been shown to regulate proliferation and differentiation of stem cells.NO is a diffusible short-lived free radical and a signaling molecule with a number of important physiological functions such as smooth muscle relaxation, neurotransmission, and inhibition of platelet aggregation and host defense mechanisms (12). It also plays a role in the pathology of several inflammatory diseases and other pathological conditions such as cancer, diabetes, and neurodegenerative diseases (13,14). NO plays an important role in the control of heart rate, contractibility, coronary perfusion, and cardiac development (15, 16). It is synthesized by enzymes called nitric oxide synthases such as NOS-1 (neuronal NOS), NOS-2 (inducible NOS), and NOS-3 (endothelial NOS) that catalyze the oxidation of L-arginine into L-citruline with the release of NO. NO can also be measured in biological systems as metabolites of NO and as nitrites and nitrates (17). The NO receptor soluble guanylyl cyclase (sGC) is a heme-containing heterodimer with ␣ and  subunits (12). Binding of NO to the heme prosthetic group of sGC catalyzes the conversion of GTP into the second messenger cGMP that can exert many physiological effects, such as mediating vascular smooth muscle tone and motility, phototransduction, and maintenance of fluid and electrolyte homeostasis by interaction of cGMP with downstream effectors such as a family of cGMP-dependent protein kinases, cGMP-dependent phosphodiesterases, and cyclic nucleotide gated channels (11).Our previous studies with mouse and human ES cells demonstrated a time-dependent increase in mRNA and protein levels of different subunits of sGC (with the exception of 2 mRNA in H-9 cells) during both mouse and human ES cell differentiation into cells of cardiac lineage. Compared with NOS-1, NOS-2, and NOS-3 mRNA and protein levels were also induced during ES cell differentiation (18,19), thereby demonstrating the involvement of NO signaling components during differentiation of ES cells into cardiac cells. Previous studies by other investigators (20) have shown increased cardiomyogenesis with NO donors and by delivery of the NOS-2 gene in mouse ES cells.In this study, we demonstrate the role of NO and cGMP in differentiation of human and mouse ES cells by regulating t...
Lactogen-dependent Nb2 lymphoma cells, widely employed for studying prolactin (PRL) mitogenic mechanisms, are also useful for investigations of apoptosis in T-lineage lymphocytes. Utilizing PRL-dependent Nb2-11 cultures, apoptosis-regulatory genes were evaluated for participation in dexamethasone- (DEX) provoked cell death or its inhibition by PRL. Treatment of lactogen-starved, G1-arrested Nb2-11 cells with DEX (100 nM) activated apoptosis within 12 h evaluated by flow cytometric analysis of fragmented DNA. This effect was not associated with altered expression of bcl-2, bax, or pim-1. PRL (10 ng/mL), coincubated with DEX-treated cells, completely blocked DEX-induced apoptosis. This inhibition was associated with increased expression of bcl-2 and pim-1 mRNAs, genes reported to suppress apoptosis, within 2-6 h after addition of the hormone. Moreover, the increased transcription of bcl-2 and pim-1 was coupled to increases in their protein levels. The results suggest that bcl-2, bax, and pim-1 do not play a critical role in DEX-induced apoptosis in Nb2 cells. However, expression of bcl-2, together with pim-1, may have a role in mediating the antiapoptotic actions of PRL.
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