Alterations in hepatic gene expression induced by chromic exposure to high levels of the SV40 LT/st oncoproteins (4P)
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Nikolaus Schultz
PROVIDER: E-GEOD-5958 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Hepatic gene expression induced by chromic exposure to low levels of the SV40 LT/st oncoproteins (4P) Affymetrix mouse genome U74Av2 platform was used, duplicate measurements for wild-type and transgenic animals
2014-12-22 | E-GEOD-6232 | biostudies-arrayexpress
Project description:Hepatic gene expression induced by chromic exposure to low levels of the SV40 LT/st oncoproteins (4P)
2014-12-22 | GSE6232 | GEO
Project description:Hepatic gene expression induced by chromic exposure to high levels of the SV40 LT/st oncoproteins (4P)
2014-12-22 | GSE5958 | GEO
Project description:The SV40 large (LT) and small (st) antigens are produced from a single alternatively spliced pre-mRNA, that when co-expressed, transform a variety of cells in vitro and in vivo. However, 17kT, a relatively uncharacterized third protein that is co-linear with LT for the first 131 amino acids, is also produced from the early viral pre-mRNA by removal of an additional intron from the LT transcript. Here we report a line of transgenic mice expressing a liver-specific dox-inducible viral transcript that fails to yield any detectable LT protein, yet produces abundant 17kT. Comparative analysis of livers of transgenic mice expressing either 17kT or LT demonstrates that while 17kT is a potent stimulator of cell proliferation, it is ineffective at inducing liver tumor development, due in part, to the failure of 17kT to effectively induce the expression of growth regulators and reactivate expression of imprinted and developmentally regulated hepatic genes. These studies highlight key functional differences between LT and 17kT in their ability to transform quiescent primary epithelial cells in vivo, and demonstrate how specific functional domains within LT impact cell-specific gene expression to promote oncogenesis. Keywords: genetic modification, SV40, 17kT, LT, Rb, p53, hepatocellular carcinoma, hepatic hyperplasia, differentiation. Affymetrix mouse genome 430 A and B platform was used, single measurements for wild-type and transgenic animals.
2010-03-31 | E-GEOD-5242 | biostudies-arrayexpress
Project description:MED1 (Mediator complex subunit 1) is expressed by human epidermal keratinocytes and functions as a coactivator of several transcription factors. To elucidate the role of MED1 in keratinocytes, we established keratinocyte-specific MED1-null (MED1epi-/-) mice using the K5Cre-LoxP system. To elucidate the mechanism(s) underlying abnormalities of keratinocytes derived from MED1epi-/- mice, we compared the gene expression patterns of MED1epi-/--derived keratinocytes with their wild type counterparts by microarray analysis. Generation of the MED1 conditional null mutation in epidermal keratinocytes and cell culture: MED1flox/flox mice (Jia et al, J Biol Chem 279:24427. 2004) were mated with K5Cre mice (Tarutani et al, Proc Natl Acad Sci U S A 94:7400. 1997) to generate F1 K5Cre+;MED1flox/+ mice. The K5Cre+;MED1flox/+ mice were then mated with MED1flox/flox mice to generate K5Cre+;MED1flox/flox mice (MED1epi-/-). Mice were screened for presence of the transgene by PCR using specific primers for the floxed MED1 gene and the human K5 gene according to the previous reports. Skin of newborn mice was excised after the mice were sacrificed with excessive anesthetic and were treated with dispase followed by trypsin to separate the epidermis from the dermis. Keratinocytes were seeded on type I collagen coated dishes, and were cultured in CnT07 conditioned culture medium (CELLnTEC, Bern, Switzerland). Keratinocytes were used for the experiment as a primary culture. All animal studies were conducted according to protocols approved by the Institutional Animal Care and Use Committee at Osaka University. Microarray analysis: For comprehensive comparison of gene expression patterns between keratinocytes derived from MED1epi-/- and from WT mice, microarray analysis was used. Total RNAs were extracted using an RNeasy kit (Qiagen, San Diego, CA). Then, 2μg total RNA was reverse transcribed to cDNA with T7 oligo d(T) primer (Affymetrix, Santa Clara, CA). The cDNA synthesis products were used for in vitro transcription reactions containing T7 RNA polymerase and biotinylated nucleotide analogue (pheudouridine base) cRNAs. The labeled cRNA products were then fragmented and loaded onto GeneChip(R) Mouse Genome 430 2.0 arrays (Affymetrix), and were hybridized according to the manufacturer’s protocol. Streptavidin-Phycoerythrin (Molecular Probes) was used as the fluorescent conjugate to detect hybridized target sequences. Raw intensity data from the GeneChip array were analyzed by GeneChip Operating Software (Affymetrix).
2012-09-02 | E-GEOD-35406 | biostudies-arrayexpress
Project description:The SV40 large (LT) and small (st) antigens are produced from a single alternatively spliced pre-mRNA, that when co-expressed, transform a variety of cells in vitro and in vivo. However, 17kT, a relatively uncharacterized third protein that is co-linear with LT for the first 131 amino acids, is also produced from the early viral pre-mRNA by removal of an additional intron from the LT transcript. Here we report a line of transgenic mice expressing a liver-specific dox-inducible viral transcript that fails to yield any detectable LT protein, yet produces abundant 17kT. Comparative analysis of livers of transgenic mice expressing either 17kT or LT demonstrates that while 17kT is a potent stimulator of cell proliferation, it is ineffective at inducing liver tumor development, due in part, to the failure of 17kT to effectively induce the expression of growth regulators and reactivate expression of imprinted and developmentally regulated hepatic genes. These studies highlight key functional differences between LT and 17kT in their ability to transform quiescent primary epithelial cells in vivo, and demonstrate how specific functional domains within LT impact cell-specific gene expression to promote oncogenesis. Keywords: genetic modification, SV40, 17kT, LT, Rb, p53, hepatocellular carcinoma, hepatic hyperplasia, differentiation.
2010-04-01 | GSE5242 | GEO
Project description:The generation of induced pluripotent stem cells (iPSCs) often results in aberrant silencing of the imprinted Dlk1-Dio3 gene cluster, which compromises their ability to generate entirely iPSC-derived mice (âall-iPSC miceâ). Here, we show that reprogramming in the presence of ascorbic acid attenuates hypermethylation of Dlk1-Dio3 by enabling a chromatin configuration at its imprint control region that interferes with abnormal binding of the DNA methyltransferase Dnmt3a. This approach allowed us to generate adult all-iPSC mice from mature B cells, which have thus far failed to support the development of exclusively iPSC-derived postnatal mice. Our data demonstrate that factor-mediated reprogramming can endow a defined, terminally differentiated cell type with a developmental potential equivalent to that of embryonic stem cells. More generally, these findings indicate that the choice of culture conditions used for transcription factor-mediated reprogramming can strongly influence the epigenetic and biological properties of resultant iPSCs. This series consists of quadruplicated mRNA expression microarray data (Affymetrix mouse 430_2 3'-IVT array) for iPS cells derived from MEF cells under cell culture conditions with or without ascorbic acid supplementation. iPS cells were generated from MEFs of the Col-OKSM reprogrammable mice. In the presence of doxycycline, the reprogramming transcription factors Oct4, Sox2, Klf4, and cMyc were induced in MEFs to derivate iPS cells. Total RNA was isolated from iPS cells derivated in the presence or absence of ascorbic acid in culture medium.
2012-02-01 | E-GEOD-34761 | biostudies-arrayexpress
Project description:Linker-free PROTACs efficiently induce the degradation of oncoproteins
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Project description:Chromosomal translocations involving the Lysine-Methyl-Tansferase-2A (KMT2A) locus generate potent oncogenes that cause highly aggressive acute leukemias KMT2A and the most frequent translocation partners encode proteins that interact with DNA to regulate developmental gene expression. KMT2A-oncogenic fusion proteins (oncoproteins) contribute to the epigenetic mechanisms that allow KMT2A-rearranged leukemias to evade targeted therapies. By profiling the oncoprotein-target sites of 34 KMT2A-rearranged leukemia samples, we find that the genomic enrichment of oncoprotein binding is highly variable between samples. At high levels of expression, the oncoproteins preferentially activate either the lymphoid or myeloid lineage program depending on the fusion partner. These fusion-partner-dependent binding sites correspond to the frequencies of each mutation in acute lymphoid leukemia versus acute myeloid leukemia. By profiling a sample that underwent a lymphoid-to-myeloid lineage switching event in response to lymphoid-directed treatment, we find the global oncoprotein levels are reduced and the oncoprotein-target gene network changes. At lower levels of expression, the oncoprotein shifts to a non-canonical regulatory program that favors the myeloid lineage, and in a subset of resistant patients, the Menin inhibitor Revumenib induces a similar response. The dynamic shifts in KMT2A oncoproteins we describe likely contribute to epigenetic resistance of KMT2A-rearranged leukemias to targeted therapies.
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Project description:The life cycle of human papillomaviruses (HPV) is strictly linked to the differentiation of their natural host cells. The HPV E6 and E7 oncoproteins can delay the normal differentiation program of keratinocytes, however, the exact mechanisms responsible for this have not yet been identified. The goal of this study was to investigate the effects of HPV16 oncoproteins on the expression of genes involved in keratinocyte differentiation. Primary human keratinocytes transduced by LXSN (control) retroviruses or virus vectors expressing HPV16 E6, E7 or E6/E7 genes were subjected to gene expression profiling. The results of microarray analysis showed that HPV 16 E6 and E7 have the capacity to down-regulate the expression of several genes involved in keratinocyte differentiation. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to confirm microarray data. To investigate the effects of the HPV oncoproteins on the promoters of selected keratinocyte differentiation genes, luciferase reporter assays were performed. Our results suggest that the HPV 16 E6 and/or E7 oncogenes are able to down-regulate the expression of several genes involved in keratinocyte differentiation, at least partially by down-regulating their promoter activity. This activity of the HPV oncoproteins may have a role in the productive virus life cycle, and also in virus induced carcinogenesis. Primary human foreskin keratinocytes were transduced by retrovirus vectors containing HPV 16 E6, E7, E6/E7 or the control vector LXSN. The global gene expression patterns of transduced keratinocytes were analyzed on Affymetrix microarrays
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