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Stem Cell Gene Expression Changes Induced Specifically by Mutated K-ras

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K-Ras proteins transduce signals from membrane-bound receptors via multiple downstream effector pathways and thereby regulate fundamental stem cell processes that affect neoplasia, including proliferation, apoptosis, and differentiation, but their contribution to tumourigenesis is unclear. Because cancers develop from stem cells, we set out to determine the characteristic changes in gene expression brought about by mutated K-ras (without interference from normal K-ras) in otherwise normal stem cells. cDNA microarrays were used to analyze gene expression profiles comparing wild-type murine embryonic stem (ES) cells with K-rasVal12 expressing ES cells (previously made null for both endogenous K-ras alleles and transfected with K-rasVal12 , with valine for glycine at codon 12). K-rasVal12 was expressed at 1.2-fold normal K-ras levels and produced transcripts for both activated K-Ras4A and 4B isoforms. The array expression data were confirmed by real-time quantitative PCR analysis of selected genes expressed both in the K-rasVal12 expressing ES cells (R = 0.91 with array data) and in the normal intestinal tissues of K-rasVal12 transgenic mice (R = 0.91 with array data). Changes in gene expression were correlated with the effects of K-rasVal12 expression on ES cells of enhancing self-renewal in an undifferentiated state, increasing susceptibility to DNA damage-induced apoptosis, and increased proliferation. These expression data may explain, at least in part, some neoplasia-related aspects of the phenotypic changes brought about in this ES cell line by mutated K-ras, in that upregulation of cell growth-related proteins and DNA-associated proteins is consistent with increased proliferation; upregulation of certain apoptosis-related proteins is consistent with a greater susceptibility to DNA damage-induced apoptosis; and downregulation of structural proteins, extracellular matrix components, secretory proteins and receptors is consistent with a less differentiated phenotype.
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Keywords: Apoptosis; Differentiation; Gene expression; K-ras; Stem cell

Document Type: Research Article

Affiliations: 1: Department of Pathology, Addenbrooke's Hospital, Hills Road, University of Cambridge, Cambridge, CB2 2QQ, UK 2: Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK

Publication date: February 1, 2007

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  • Gene Expression, The Journal of Liver Research will publish articles in all aspects of hepatology. Hepatology, as a research discipline, has seen unprecedented growth especially in the cellular and molecular mechanisms of hepatic health and disease, which continues to have a major impact on understanding liver development, stem cells, carcinogenesis, tissue engineering, injury, repair, regeneration, immunology, metabolism, fibrosis, and transplantation. Continued research and improved understanding in these areas will have a meaningful impact on liver disease prevention, diagnosis, and treatment. The existing journal Gene Expression has expanded its focus to become Gene Expression, The Journal of Liver Research to meet this growing demand. In its revised and expanded scope, the journal will publish high-impact original articles, reviews, short but complete articles, and special articles (editorials, commentaries, opinions) on all aspects of hepatology, making it a unique and invaluable resource for readers interested in this field. The expanded team, led by an Editor-in-Chief who is uniquely qualified and a renowned expert, along with a dynamic and functional editorial board, is determined to make this a premier journal in the field of hepatology.
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