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Flores I.,Stem Cell Group | Blasco M.A.,Telomeres and Telomerase Group
FEBS Letters | Year: 2010

Stem cells regenerate our bodies. In a similar manner to match ignition, stem cell " ignition" has to be precisely tuned to avoid uncontrolled proliferation as may occur in tumors or, inversely, the lack of proliferation as happens in degenerative disorders. During the last years it has become evident that telomeres and telomerase are main components of the stem cell " ignition" mechanism, providing a way to restrain cancer and delay aging. © 2010 Federation of European Biochemical Societies. Source


Leroy E.,Ludwig Institute for Cancer Research | Leroy E.,Catholic University of Louvain | Defour J.P.,Ludwig Institute for Cancer Research | Defour J.P.,Catholic University of Louvain | And 10 more authors.
Journal of Biological Chemistry | Year: 2016

Ligand binding to the extracellular domain of the thrombo-poietin receptor (TpoR) imparts a specific orientation on the transmembrane (TM) and intracellular domains of the receptors that is required for physiologic activation via receptor dimerization. To map the inactive and active dimeric orientations of the TM helices, we performed asparagine (Asn)-scanning mutagenesis of the TM domains of the murine and human TpoR. Substitution of Asn at only one position (S505N) activated the human receptor, whereas Asn substitutions at several positions activated the murine receptor. Second site mutational studies indicate that His499 near the N terminus of the TM domain is responsible for protecting the human receptor from activation by Asn mutations. Structural studies reveal that the sequence preceding His499 is helical in the murine receptor but non-helical in peptides corresponding to the TM domain of the inactive human receptor. The activating S505N mutation and the small molecule agonist eltrombopag both induce helix in this region of the TM domain and are associated with dimerization and activation of the human receptor. Thus, His499 regulates the activation of human TpoR and provides additional protection against activating mutations, such as oncogenic Asn mutations in the TM domain. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Source


Tekpli X.,National Institute of Occupational Health | Tekpli X.,Stem Cell Group | Landvik N.E.,National Institute of Occupational Health | Anmarkud K.H.,National Institute of Occupational Health | And 3 more authors.
Cancer Immunology, Immunotherapy | Year: 2013

Epidemiologic and experimental evidences support the concept that inflammation promotes the development and progression of cancers. Interleukins (ILs) regulate the expression of several molecules and signaling pathways involved in inflammation. High expression of some ILs in the tumor microenvironment has been associated with a more virulent tumor phenotype. To examine the role of IL-1β, IL-6, and IL-8 in non-small cell lung cancer, we measured mRNA levels and promoter DNA methylation in a panel of cultured human lung cells (n = 23) and in matched pair lung tumor versus adjacent non-tumorous tissues (n = 24). We found that lung cancer cells or tissues had significantly different DNA methylation and mRNA levels than normal human bronchial epithelial cells or adjacent non-tumorous tissues, respectively. High DNA methylation of ILs promoters in lung cancer cells or tissues was associated with low mRNA levels. We found an inverse correlation between DNA methylation of IL1B, IL6, and IL8 gene promoters and their corresponding mRNA levels, such inverse correlation was more significant for IL1B (i.e., all cancer cell lines used in this study had a hypermethylated IL1B promoter which was associated with silencing of the gene). Our results underline for the first time the role of epigenetic modifications in the regulation of the expression of key cytokines involved in the inflammatory response during lung cancer development. © 2012 Springer-Verlag. Source


Hua J.,Northwest University, China | Hua J.,Stem Cell Group | Sidhu K.S.,Stem Cell Group | Sidhu K.S.,University of New South Wales
Open Stem Cell Journal | Year: 2011

Reports have shown that murine embryonic stem cells (mESC) can differentiate into primordial germ cells (PGC) and then to early gametes (oocytes and sperm) that after fertilization form blastocysts. Preliminary studies indicated that hESC also have the potential to differentiate into germ cells. Currently, there are no reports on directed differentiation of hESCs into oocytes. Here, we investigated the effects of human fetal testicular extracts (HFTE) and hormones i.e. follicle-stimulating hormone (FSH), human chorionic gonadotropin (hCG) to coax hESC to differentiate into oocytes. The embryoid bodies (EBs) derived from hESC formed ovarian-like structures (OLS) after treatment with HFTE for 7 days and with hormones (FSH + hCG) for 20-30 days. OLS exhibited typical oocyte-like spherical shape of variable sizes and some with zona pellucida-like covering RT-PCR, immunological fluorescence staining and flow cytometry analyses showed that these structures are positive for specific germ cell and oocyte markers such as OCT4, SCP3, C-KIT and DDX4, STELLA, FIGLA, GDF9, NANOG FSHR, ZP1, ZP2 and ZP3. Quantitative RT-PCR analysis showed that FSHR, GDF9 and FIGLA were up-regulated during OLS differentiation from EB in a time-dependent manner. These results demonstrated that hESC have the ability to differentiate into ovarian structures. This study thus provides an in vitro model to study germ-cell formation from hESC and these germ cells may generate a potential source of oocytes for therapeutic cloning. © Hua and Sidhu. Source


Dontu G.,Stem Cell Group | Ince T.A.,University of Miami
Journal of Mammary Gland Biology and Neoplasia | Year: 2015

Tissue based research requires a background in human and veterinary pathology, developmental biology, anatomy, as well as molecular and cellular biology. This type of comparative tissue biology (CTB) expertise is necessary to tackle some of the conceptual challenges in human breast stem cell research. It is our opinion that the scarcity of CTB expertise contributed to some erroneous interpretations in tissue based research, some of which are reviewed here in the context of breast stem cells. In this article we examine the dissimilarities between mouse and human mammary tissue and suggest how these may impact stem cell studies. In addition, we consider the differences between breast ducts vs. lobules and clarify how these affect the interpretation of results in stem cell research. Lastly, we introduce a new elaboration of normal epithelial cell types in human breast and discuss how this provides a clinically useful basis for breast cancer classification. © 2015, The Author(s). Source

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