TP53 is mutated in 50% of all cancers, and is often functionally compromised in cancers where it is not mutated. We demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of the ribosomal protein L26 (RPL26), a positive regulator of p53 translation. Mutation analysis confirms that RPL26, whose expression inversely correlates with Six1 expression in numerous tumor types, inhibits miR-27a binding to the p53 3UTR and prevents microRNA-mediated translational inhibition of p53. Thus, through simultaneous downregulation of RPL26 and upregulation of miR-27a, Six1 efficiently lowers p53 levels despite regulation of p53 at the level of the proteasome. Consequently, Six1 overexpression, which is observed in numerous tumor types, leads to dramatic resistance to nutlins, as well as other therapies targeting the p53-MDM2 interaction.
The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p.
Specimen part, Treatment
View SamplesGenome-wide association studies (GWAS) have been pivotal to increasing our understanding of intestinal disease. However, the mode by which genetic variation results in phenotypic change remains largely unknown, with many associated polymorphisms likely to modulate gene expression. Analyses of expression quantitative trait loci (eQTL) to date indicate that as many as 50% of these are tissue specific. Here we report a comprehensive eQTL scan of intestinal tissue.
Expression quantitative trait loci analysis identifies associations between genotype and gene expression in human intestine.
Sex, Disease
View SamplesThe involvement of skeletal muscle in the process of palatal development in mammals is an example of Waddingtonian epigenetics. Our earlier study showed that the cleft palate develops in the complete absence of skeletal musculature during embryonic development in mice. This contrasts with previous beliefs that tongue obstruction prevents the elevation and fusion of the palatal shelves. We argue that the complete absence of mechanical stimuli from the adjacent muscle, i.e., the lack of both static and dynamic loading, results in disordered palatogenesis. We further suggest that proper fusion of the palatal shelves depends not only on mechanical but also on paracrine contributions from the muscle. The muscle's paracrine role in the process of palatal fusion is achieved through its being a source of certain secreted and/or circulatory proteins.
Role of skeletal muscle in palate development.
Specimen part
View SamplesThe experiment aims to identify mRNAs illustrating the unique nature of the gd T-cell subtype
Human Vδ2 T cells are a major source of interleukin-9.
Specimen part
View SamplesSkeletal (striated) muscle is one of the four basic tissue types, together with the epithelium, connective and nervous tissues. Lungs, on the other hand, develop from the foregut and among various cell types contain smooth, but not skeletal muscle. Therefore, during earlier stages of development, it is unlikely that skeletal muscle and lung depend on each other. However, during the later stages of development, respiratory muscle, primarily the diaphragm and the intercostal muscles, execute so called fetal breathing-like movements (FBMs), that are essential for lung growth and cell differentiation. In fact, the absence of FBMs results in pulmonary hypoplasia, the most common cause of death in the first week of human neonatal life. Most knowledge on this topic arises from in vivo experiments on larger animals and from various in vitro experiments. In the current era of mouse mutagenesis and functional genomics, it was our goal to develop a mouse model for pulmonary hypoplasia.
Role of skeletal muscle in lung development.
Specimen part
View SamplesThis study describes a cDNA microarray analysis that compared developing mouse MyoD-/- limb musculature (MyoD-dependent, innervated by Lateral Motor Column motor neurons) and Myf5-/- back (epaxial) musculature (Myf5-dependent, innervated by Medial Motor Column motor neurons) to the control and to each other, at embryonic day 13.5 which coincides with the robust programmed cell death of motor neurons and the inability of myogenesis to undergo its normal progression in the absence of Myf5 and MyoD that at this embryonic day cannot substitute for each other.
Role of skeletal muscle in motor neuron development.
Specimen part
View SamplesMicroarray whole-transcriptome profiling in HCT116 and HepG2 cells treated with Melicope ptelefolia leaf extract reveals transcriptome profles exhibiting anticancer activity
Microarray gene expression profiling in colorectal (HCT116) and hepatocellular (HepG2) carcinoma cell lines treated with <i>Melicope ptelefolia</i> leaf extract reveals transcriptome profiles exhibiting anticancer activity.
Specimen part, Cell line, Treatment
View SamplesPrevious analysis of Myf5-/-:MyoD-/- mouse fetuses lacking skeletal muscle demonstrated the importance of muscle contraction and static loading in mouse skeletogenesis. Previous analysis of Myf5-/-:MyoD-/- mouse fetuses lacking skeletal muscle demonstrated the importance of muscle contraction and static loading in mouse skeletogenesis. Among abnormal skeletal features, micrognathia (mandibular hypoplasia) was detected: small, bent and posteriorly displaced mandible. As an example of Waddingtonian epigenetics, we suggest that muscle, in addition to acting via mechanochemical signal transduction pathways, networks and promoters, also exerts secretory stimuli on skeleton. Our goal is to identify candidate molecules at that muscle-mandible interface. By employing Systematic Subtractive Microarray Analysis approach, we compared gene expression between mandibles of amyogenic and wild type mouse fetuses.
Role of skeletal muscle in mandible development.
Specimen part
View SamplesThe esophagus is a muscular tube which transports swallowed content from the oral cavity and the pharynx to the stomach. Early in mouse development, an entire layer of the esophagus, the muscularis externa, consists of differentiated smooth muscle cells. Starting shortly after mid-gestation till about two weeks after birth, the muscularis externa almost entirely consists of striated muscle. This proximal-to-distal replacement of smooth muscle by the striated muscle depends on a number of factors. To identify the nature of the hypothetical “proximal” (mainly striated muscle originating) and “distal” (mainly smooth muscle originating) signals that govern the striated-for-smooth muscle replacement, we compared the esophagus of Myf5:MyoD null fetuses completely lacking striated muscle to the normal control using cDNA microarray analysis, followed by a comprehensive databases search. Here we provide an insight into the nature of “proximal” and “distal” signals that govern the striated-for-smooth muscle replacement in the esophagus.
Striated-for-smooth muscle replacement in the developing mouse esophagus.
Specimen part
View SamplesWe performed a transcriptome-wide study to compare gene expression profiles of ECFC, human coronary artery endothelial cells (HCAEC) and human umbilical vein endothelial cells (HUVEC) utilising subcutaneous adipose tissue-derived stromal vascular fraction (SAT-SVF) as a negative control population. Baseline gene expression in ECFC fully corresponds to their endothelial specification and may contribute to the basement membrane organisation, fulfilling the requirements for the suitable cell population for in vitro pre-endothelialisation of tubular scaffolds. Overall design: Comparison of gene expression in 4 cell types by Hiseq sequencing.
Human Peripheral Blood-Derived Endothelial Colony-Forming Cells Are Highly Similar to Mature Vascular Endothelial Cells yet Demonstrate a Transitional Transcriptomic Signature.
Specimen part, Cell line, Subject
View Samples