| 1. |
- Hartman, Johan, et al.
(författare)
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Tumor repressive functions of estrogen receptor beta in SW480 colon cancer cells
- 2009
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 69:15, s. 6100-6
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor beta (ERbeta) is the predominant ER in the colorectal epithelium. Compared with normal colon tissue, ERbeta expression is reduced in colorectal cancer. Our hypothesis is that ERbeta inhibits proliferation of colon cancer cells. Hence, the aim of this study has been to investigate the molecular function of ERbeta in colon cancer cells, focusing on cell cycle regulation. SW480 colon cancer cells have been lentivirus transduced with ERbeta expression construct with or without mutated DNA-binding domain or an empty control vector. Expression of ERbeta resulted in inhibition of proliferation and G(1) phase cell cycle arrest and this effect was dependent on a functional DNA-binding region. c-Myc is overexpressed in an overwhelming majority of colorectal tumors. By Western blot and real-time PCR, we found c-Myc to be down-regulated in the ERbeta-expressing cells. Furthermore, the c-Myc target gene p21((Waf1/Cip1)) was induced and Cdc25A was reduced by ERbeta at the transcriptional level. The second cdk2-inhibitor, p27(Kip1), was induced by ERbeta, but this regulation occurred at the posttranscriptional level, probably through ERbeta-mediated repression of the F-box protein p45(Skp2). Expression of the ERbeta-variant with mutated DNA binding domain resulted in completely different cell cycle gene regulation. We performed in vivo studies with SW480 cells +/- ERbeta transplanted into severe combined immunodeficient/beige mice; after three weeks of ERbeta-expression, a 70% reduction of tumor volume was seen. Our results show that ERbeta inhibits proliferation as well as colon cancer xenograft growth, probably as a consequence of ERbeta-mediated inhibition of cell-cycle pathways. Furthermore, this ERbeta-mediated cell cycle repression is dependent on functional ERE binding.
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| 2. |
- Lindhé, Cecilia, 1973-
(författare)
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Visuella vändningar : Bild och estetik i Kerstin Ekmans romankonst
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This is a dissertation on how an aesthetics of fiction is formulated at the intersection of, and oscillation between, image-construction and image-criticism in three novels by Kerstin Ekman: En stad av ljus (1983), Händelser vid vatten (1993), and Gör mig levande igen (1996). The purpose of the dissertation is to analyze the movement of this oscillation and demonstrate how it is intertwined, not only with the aesthetic practice characterizing these novels, but also with their interpretation of the past and the contemporary. Kerstin Ekman’s oeuvre formulates a criticism of images and their various representational forms (for example paintings, photographs, the images of virtual reality), while integrating different media’s aesthetic expressions by theme and narrative technique. Occasionally, images are represented as deserving credence, as possible to describe in words, but also with a faith in their power to animate or recreate the past, capture the moment and freeze time. But as often as being utilized as tools for creation, images are employed for careful aim of the critique of civilization that characterizes Ekman’s entire body of work. The tension between image-construction and image-criticism is intimately connected to the issues that at their core are bound up with the relation between verbal art and visual art which constitutes a fundamental trait of Ekman’s aesthetic practice. In addition to novels in various genres, Ekman has also worked with film, computer programming and hypertext. The interplay with other media is an important building block of Ekman’s fiction, and the classical opposition between verbal and visual arts is figured foremost through the camera, the film camera, and the computer. The dissertation also examines Ekman’s early fiction, from her debut novel, the detective story 30 meter mord (1959), to Mörker och blåbärsris (1972), and introduces the hypertext Hotagens minne (2006) and the computer game Rymdresa (1991).
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| 3. |
- Richter, Karin, et al.
(författare)
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Global gene expression analyses of hematopoietic stem cell-like cell lines with inducible Lhx2 expression
- 2006
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 7, s. 75-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Expression of the LIM-homeobox gene Lhx2 in murine hematopoietic cells allows for the generation of hematopoietic stem cell (HSC)-like cell lines. To address the molecular basis of Lhx2 function, we generated HSC-like cell lines where Lhx2 expression is regulated by a tet-on system and hence dependent on the presence of doxycyclin (dox). These cell lines efficiently down-regulate Lhx2 expression upon dox withdrawal leading to a rapid differentiation into various myeloid cell types.Results: Global gene expression of these cell lines cultured in dox was compared to different time points after dox withdrawal using microarray technology. We identified 267 differentially expressed genes. The majority of the genes overlapping with HSC-specific databases were those down-regulated after turning off Lhx2 expression and a majority of the genes overlapping with those defined as late progenitor-specific genes were the up-regulated genes, suggesting that these cell lines represent a relevant model system for normal HSCs also at the level of global gene expression. Moreover, in situ hybridisations of several genes down-regulated after dox withdrawal showed overlapping expression patterns with Lhx2 in various tissues during embryonic development.Conclusion: Global gene expression analysis of HSC-like cell lines with inducible Lhx2 expression has identified genes putatively linked to self-renewal / differentiation of HSCs, and function of Lhx2 in organ development and stem / progenitor cells of non-hematopoietic origin.
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| 4. |
- Richter, Karin, et al.
(författare)
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Global gene expression analyses of hematopoietic stem cell-like cell lines with inducible Lhx2 expression
- 2006
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 7, s. 75-
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Tidskriftsartikel (refereegranskat)abstract
- Background Expression of the LIM-homeobox gene Lhx2 in murine hematopoietic cells allows for the generation of hematopoietic stem cell (HSC)-like cell lines. To address the molecular basis of Lhx2 function, we generated HSC-like cell lines where Lhx2 expression is regulated by a tet-on system and hence dependent on the presence of doxycyclin (dox). These cell lines efficiently down-regulate Lhx2 expression upon dox withdrawal leading to a rapid differentiation into various myeloid cell types. Results Global gene expression of these cell lines cultured in dox was compared to different time points after dox withdrawal using microarray technology. We identified 267 differentially expressed genes. The majority of the genes overlapping with HSC-specific databases were those down-regulated after turning off Lhx2 expression and a majority of the genes overlapping with those defined as late progenitor-specific genes were the up-regulated genes, suggesting that these cell lines represent a relevant model system for normal HSCs also at the level of global gene expression. Moreover, in situ hybridisations of several genes down-regulated after dox withdrawal showed overlapping expression patterns with Lhx2 in various tissues during embryonic development. Conclusion Global gene expression analysis of HSC-like cell lines with inducible Lhx2 expression has identified genes putatively linked to self-renewal / differentiation of HSCs, and function of Lhx2 in organ development and stem / progenitor cells of non-hematopoietic origin.
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| 5. |
- Svensson, Per, et al.
(författare)
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Gene array identification of Ipf1/Pdx1(-/-) regulated genes in pancreatic progenitor cells
- 2007
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Ingår i: BMC Developmental Biology. - : Springer Science and Business Media LLC. - 1471-213X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Background: The homeodomain transcription factor IPF1/PDX1 exerts a dual role in the pancreas; Ipf1/Pdx1 global null mutants fail to develop a pancreas whereas conditional inactivation of Ipf1/Pdx1 in beta-cells leads to impaired beta-cell function and diabetes. Although several putative target genes have been linked to the beta-cell function of Ipf1/Pdx1, relatively little is known with respect to genes regulated by IPF1/PDX1 in early pancreatic progenitor cells. Results: Microarray analyses identified a total of III genes that were differentially expressed in e10.5 pancreatic buds of Ipf1/Pdx1(-/-) embryos. The expression of one of these, Spondin 1, which encodes an extracellular matrix protein, has not previously been described in the pancreas. Quantitative real-time RT-PCR analyses and immunohistochemical analyses also revealed that the expression of FgfR2IIIb, that encodes the receptor for FGF10, was down-regulated in Ipf1/Pdx1(-/-) pancreatic progenitor cells. Conclusion: This microarray analysis has identified a number of candidate genes that are differentially expressed in Ipf1/Pdx1(-/-) pancreatic buds. Several of the differentially expressed genes were known to be important for pancreatic progenitor cell proliferation and differentiation whereas others have not previously been associated with pancreatic development.
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| 6. |
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| 7. |
- Williams, Cecilia, 1969-, et al.
(författare)
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A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells.
- 2008
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 27:7, s. 1019-1032
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptional effects of estrogen result from its activation of two estrogen receptor (ER) isoforms; ERalpha that drives proliferation and ERbeta that is antiproliferative. Expression of ERbeta in xenograft tumors from the T47D breast cancer cell line reduces tumor growth and angiogenesis. If ERbeta can halt tumor growth, its introduction into cancers may be a novel therapeutic approach to the treatment of estrogen-responsive cancers. To assess the complete impact of ERbeta on transcription, we have made a full transcriptome analysis of ERalpha- and ERbeta-mediated gene regulation in T47D cell line with Tet-Off regulated ERbeta expression. Of the 35 000 genes and transcripts analysed, 4.1% (1434) were altered by ERalpha activation. Tet withdrawal and subsequent ERbeta expression inhibited the ERalpha regulation of 998 genes and, in addition, altered expression of 152 non-ERalpha-regulated genes. ERalpha-induced and ERbeta-repressed genes were involved in proliferation, steroid/xenobiotic metabolism and ion transport. The ERbeta repressive effect was further confirmed by proliferation assays, where ERbeta was shown to completely oppose the ERalpha-E2 induced proliferation. Additional analysis of ERbeta with a mutated DNA-binding domain revealed that this mutant, at least for a quantity of genes, antagonizes ERalpha even more strongly than ERbeta wt. From an examination of the genes regulated by ERalpha and ERbeta, we suggest that introduction of ERbeta may be an alternative therapeutic approach to the treatment of certain cancers.
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| 8. |
- Williams, Cecilia, et al.
(författare)
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Catalog of gene expression in adult neural stem cells and their in vivo microenvironment
- 2006
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Ingår i: Experimental Cell Research. - San Diego : Elsevier BV. - 0014-4827 .- 1090-2422. ; 312:10, s. 1798-1812
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Tidskriftsartikel (refereegranskat)abstract
- Stem cells generally reside in a stem cell micro environment, where cues for self-renewal and differentiation are present. However, the genetic program underlying stem cell proliferation and multipotency is poorly understood. Transcriptome analysis of stem cells and their in vivo microenvironment is one way of uncovering the unique sternness properties and provides a framework for the elucidation of stem cell function. Here, we characterize the gene expression profile of the in vivo neural stem cell microenvironment in the lateral ventricle wall of adult mouse brain and of in vitro proliferating neural stem cells. We have also analyzed an Lhx2-expressing hematopoietic-stem-cell-like cell line in order to define the transcriptome of a well-characterized and pure cell population with stem cell characteristics. We report the generation, assembly and annotation of 50,792 high-quality 5'-end expressed sequence tag sequences. We further describe a shared expression of 1065 transcripts by all three stem cell libraries and a large overlap with previously published gene expression signatures for neural stem/progenitor cells and other multipotent stem cells. The sequences and cDNA clones obtained within this framework provide a comprehensive resource for the analysis of genes in adult stem cells that can accelerate future stem cell research.
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| 9. |
- Williams, Cecilia, 1969-, et al.
(författare)
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Gene expression in murine mammary epithelial stem cell-like cells shows similarities to human breast cancer gene expression.
- 2009
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Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-542X. ; 11:3, s. R26-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Mammary stem cells are bipotential and suggested to be the origin of breast cancer development, but are elusive and vaguely characterized. Breast tumors can be divided into subgroups, each one requiring specific treatment. To determine a possible association between mammary stem cells and breast cancer, a detailed characterization of the transcriptome in mammary stem cells is essential.METHODS: We have used a murine mammary epithelial stem-like cell line (HC11) and made a thorough investigation of global gene-expression changes during stepwise differentiation using dual-color comparative microarray technique. Subsequently, we have performed a cross-species comparison to reveal conserved gene expression between stem cells and subtype-specific and prognosis gene signatures, and correlated gene expression to in vivo mammary gland development.RESULTS: Our analysis of mammary stem-like and stepwise cell differentiation, and an in-depth description of our findings in a breast cancer perspective provide a unique map of the transcriptomic changes and a number of novel mammary stem cell markers. We correlate the alterations to in vivo mammary gland differentiation, and describe novel changes in nuclear receptor gene expression. Interestingly, our comparisons show that specific subtypes of breast cancers with poor prognosis and metastasizing capabilities show resemblance to stem-like gene expression.CONCLUSIONS: The transcriptional characterization of these mammary stem-like cells and their differentiation-induced gene expression patterns is here made widely accessible and provides a basis for research on mammary stem-like cells. Our comparisons suggest that some tumors are more stem-like than others, with a corresponding worse prognosis. This information would, if established, be important for treatment decisions. We also suggest several marker candidates valuable to investigate further.
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