The pituitary tumor-transforming gene (PTTG1) is a recently discovered oncogene implicated in the malignant progression of a number of neoplasms. It has been shown to drive both endocrine and non-endocrine malignancies, but has not yet been studied in the context of renal cell carcinoma (RCC). Clear cell RCC (ccRCC) is cytogenetically characterized by deletion of chromosome 3p, harboring the von-Hippel Lindau tumor suppressor gene, and amplification of chromosome 5q. The significance of copy number gain of chromosome 5 is not clear, but is presumed to be the location of oncogenes that influence ccRCC development or progression. The PTTG1 oncogene maps to chromosome 5q, and here we show that PTTG1 is amplified in clear cell RCC, is overexpressed in tumor tissue relative to adjacent normal kidney, and expression is associated with high grade, high stage, and poor prognosis. Furthermore, we establish a functional role for PTTG1 in ccRCC tumorigenesis and progression. PTTG1 ablation reduces both the tumorigenic ability of ccRCC cells in vitro and in vivo and the invasive ability of these cells in vitro. An analysis of genes whose transcription is regulated by PTTG1 was supportive of an association with invasive and metastatic disease. PTTG1-dependent expression of the Rho-GEF ECT2, another proto-oncogene, is observed in a number of ccRCC cell lines, and ECT2 expression correlates with PTTG1 expression, high stage, high grade, and poor prognosis ccRCC. As GEF's have been promoted as potential drug targets for targeted cancer therapeutics, the relationship between the PTTG1 and ECT2 oncogenes may be able to be exploited for the treatment of this disease.
Expression of the PTTG1 oncogene is associated with aggressive clear cell renal cell carcinoma.
Specimen part, Cell line
View SamplesTo select signatures of ccRCC, 265 ccRCC samples were obtained from the Van Andel Research Institute.
Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma.
Sex, Specimen part, Disease stage
View SamplesBACKGROUND: Despite the moderate incidence of papillary renal cell carcinoma
A molecular classification of papillary renal cell carcinoma.
No sample metadata fields
View SamplesPBRM1 was found to be mutated in a high percentage of clear cell RCCs. We performed knockdown of PBRM1 via siRNA and compared with scrambled control in three different RCC cell lines.
Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.
Specimen part, Cell line, Treatment
View SamplesThe receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (Raidd) functions as a dual adaptor protein due to its bipartite nature, and is therefore thought to be a constituent of different multiprotein complexes including the PIDDosome, where it connects the cell death-related protease, Caspase-2, with the p53-induced protein with a death domain 1 (Pidd1). As such, Raidd has been implicated in DNA-damage-induced apoptosis as well as in tumor suppression, the latter based on its role as a direct activator of Caspase-2, known to delay lymphomagenesis caused by overexpression of c-Myc or loss of ATM kinase. As loss of Caspase-2 leads to an acceleration of tumor onset in the E-Myc mouse model we set out to interrogate the role of Raidd in this process in more detail. Our data obtained analyzing E-Myc/Raidd-/- mice indicate that Raidd is unable to protect from c-MYC-driven lymphomagenesis. Similarly, we failed to observe an effect of Raidd-deficiency on thymic lymphomagenesis induced by y-irradiation or fibrosarcoma development driven by 3-methylcholanthrene. The role of Caspase-2 as a tumor suppressor can therefore be uncoupled from its ability to interact and auto-activate upon binding to Raidd. Further, we provide supportive evidence that the tumor suppressive role of Caspase-2 is related to maintaining genomic integrity and allowing efficient p53-mediated signaling. Overall, our findings suggest that Raidd, although described to be the key-adapter allowing activation of the tumor suppressor Caspase-2, fails to suppress tumorigenesis in vivo.
The tumor-modulatory effects of Caspase-2 and Pidd1 do not require the scaffold protein Raidd.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.
No sample metadata fields
View SamplesSystematic somatic mutation screening of 4000 genes in human clear cell renal cell carcinoma. Information on corresponding somatic mutations in each sample can be found at http://www.sanger.ac.uk/genetics/CGP/Studies/.
Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.
No sample metadata fields
View SamplesGlucocorticoids (GCs) are a central component in treating childhood acute lymphoblastic leukemia (chALL). They mainly act via regulating gene transcription. However, control of mRNA translation by GC has never been assessed systematically. In our research, T- and precursor B-ALL cells were cultured with and without GC for 6 hours and subjected to translational profiling, a technique combining sucrose gradient fractionation and microarray analysis of mRNA in different fractions. Analysis of GC regulation in different pools revealed no significant differences in regulation of mRNA translation by GC, suggesting no evidence for translational regulation by GC.
Translational profiling in childhood acute lymphoblastic leukemia: no evidence for glucocorticoid regulation of mRNA translation.
Cell line, Treatment
View SamplesTbx20 is a transcription factor important for heart development. To assess the role of Tbx20 in the adult heart, we generated a conditional knockout for this gene, specifically in cardiomyocytes. We profiled gene expression levels using RNA-seq in both normal and knockout adult mouse hearts to identify genes and pathways regulated by Tbx20. The article describing the Tbx20 knockout mouse is under review, a reference will be added when published. Overall design: Analysis of triplicate mRNA samples of adult mouse, comparing normal and knockout
Dual transcriptional activator and repressor roles of TBX20 regulate adult cardiac structure and function.
Age, Specimen part, Cell line, Subject
View SamplesWe generated mice with a transgenic BAC on a B6 background. The BAC contains Glo1, and the transgenic mice were found to overexpress Glo1.
Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal.
Sex, Specimen part
View Samples