Transcription profiling by array of mouse wild type or srx knockouts after lipopolysaccharide-induced endotoxic shock
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Linhda COUVELARD
PROVIDER: E-MEXP-2856 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Background: Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and elucidating the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Method: Expression studies of RING ligase praja2 and tyrosine kinase receptors (RTKs) in renal cell carcinoma was evaluated by immunoblot and immunohistochemistry. Gene transcription profiling in RCC cells was evaluated by RNA sequencing and Ingenuity Pathway Analysis. Imunofluorescence assays were used to evaluate the intracellular distribution and clearance of membrane receptors in cells devoid of praja2. Ubiquitin modifications and protein-protein interaction networks were monitored by IP, western blot, mass spectrometry and proteomic analysis. Experiments in vitro and in vivo were performed to define the role of praja2 in RTKs turnover, metabolism, renal cell carcinoma growth and metastatic diffusion. Results: We report here that the ubiquitin ligase praja2 controls endocytosis and the signal strength of different types of receptors (EGFR, VEGFR, TfR). Praja2 forms a complex with- and ubiquitinates the adaptor protein AP2m required for the activity of ATPase and acidification of endosomes and lysosomes necessary for receptor endocytosis and clearance. Downregulation of praja2 blocks the endocytosis of several membrane receptors, including EGFR, VEGFR and TfR and amplifies mitogenic and proliferative signaling as shown in the clear cell renal cell carcinoma (ccRCC). Restoring praja2 expression in RCC cells reduces EGFR levels, rewires cancer cell metabolism and inhibits growth and metastatic diffusion. In vivo, praja2 knockout mice show upregulation of tyrosine kinase receptors (RTKs) and pronounced histopathological renal alterations. Conclusion: Our findings identify praja2 as an important regulator of tyrosine kinase receptor(s) turnover and can be considered a bona fide oncosuppressor because it finely regulates signaling of several types of receptors and its loss supports kidney cancer growth and diffusion.
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Project description:Gene-expression profiles of liver and hepatocellular carcinoma induced by diethylnitrosamine (DEN) in KLF6 +/- and wild type KLF6 mice. Inactivation of the KLF6 tumor suppressor is common in HCC due to hepatitis C virus (HCV), consistent with its anti-proliferative activity in HCC-derived cell lines and in hepatocytes of transgenic mice. We have evaluated the impact of KLF6 depletion on human HCC and experimental hepatocarcinogenesis. In patients with surgically resected HCC, those with significantly reduced tumor expression of KLF6 had a significantly decreased survival. We modeled this event in KLF6 +/- mice, which displayed significantly more tumorigenicity than KLF6 +/+ animals in response to the hepatic carcinogen DEN, associated with recapitulation of gene signatures in both surrounding tissue and tumors that are associated with aggressive human HCCs. In DNA microarrays, mdm2 mRNA expression was increased in tumors from KLF6 +/- compared to KLF6 +/+ mice, which was validated by realtime qPCR and Western blot in both human HCC and DEN-induced murine tumors. Moreover, chromosomal immunoprecipitation and co-transfection assays established the P2 intronic promoter of mdm2 as a bona fide transcriptional target repressed by KLF6. Whereas KLF6 over-expression in HCC cell lines led to reduced MDM2 levels and increased p53 protein and transcriptional activity, reduction in KLF6 by siRNA led to increased MDM2 and reduced p53. Our findings indicate that KLF6 deficiency contributes significantly to the carcinogenic milieu in human and murine HCC, and uncover a novel tumor suppressor activity of KLF6 in HCC, by linking its transcriptional repression of MDM2 to stabilization of p53. Keywords: Liver, Hepatocellular carcinoma, Expression array, Exon array, Affymetrix KLF6 +/- mice were previously generated by homologous recombination in which exon 2 was targeted using an 11-kb targeting construct, and replaced with neomycin/lacZ cassette. After selection with neomycin, the ES clones were injected into C57BL/6 mouse blastocysts and implanted into pseudo pregnant females; two lines of KLF6 +/- mice were generated from the resulting chimeric animals (Blood 107;1357, Oncogene 26;4428). Whereas KLF6 -/- mice are embryonic lethal, KLF6 +/- animals had no demonstrable abnormalities in the absence of any stressor. Male KLF6 +/- mice were bred with wild type C57BL/6 to generate mixed litters of KLF6 +/- and KLF6 +/+ animals. Progeny were genotyped using PCR-amplified tail DNA, using primers as previously described (Oncogene 26;4428). Amplified fragments were separated on a 2.5% agarose gel, revealing bands of ~200 bp (wild type KLF6) and ~100 bp (Neo), as expected. At 2 weeks of age, KLF6 +/+ and KLF6 +/- mice were injected intraperitoneally with either a single dose of diethyl nitrosamine (DEN), 5 µg/g body weight in 100 µl of saline, or vehicle alone. Vehicle and DEN-treated mice were maintained on standard chow, and then sacrificed 3, 6 or 9 months later. At the time of sacrifice the animals were weighed, and blood and liver samples were harvested for analysis and tumor quantification.
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Project description:We previously identified a novel SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for Hunk in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer. Together, these findings establish a role for Hunk in metastasis and an in vivo function for this kinase. Hunk-deficient animals were crossed to mice harboring an MMTV-c-myc transgene (Leder et al., 1986). Hunk heterozygous, MMTV-c-myc mice were backcrossed to Hunk heterozygous animals. MMTV-c-myc female animals of each Hunk genotype were mated twice, then monitored twice weekly for mammary tumors. Mice possessing tumors with a maximum diameter of 20 mm were sacrificed and organs were examined at necropsy. Tumor nodules were identified by examination of organs through a Leica Wild MZ8 dissection microscope.
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Project description:Transcription factor pancreatic and duodenal homeobox 1 (Pdx1) plays an essential role in the pancreas to regulate its development and maintain proper islet function. However, less is known about the function of Pdx1 in the small intestine. We aim to investigate the role of Pdx1 in mature proximal small intestine by profiling the expression of genes differentially regulated in response to Pdx1 inactivation restricted to the intestinal epithelium in mice. Pdx1 was conditionally inactivated in the intestinal epithelium of Pdx1flox/flox;VilCre mice, by crossing mutant mice homozygous for loxP site-flanked Pdx1 alleles with transgenic mice expressing Cre recombinase under the control of the mouse villin 1 gene promoter. Total RNA was isolated from the first five centimeters of the small intestine from adult Pdx1flox/flox;VilCre and littermate control mice. Microarray analysis was performed to investigate genome-wide transcriptional profiles in the proximal small intestine.
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