Wnt signalling and cancer stem cells

[Abstract] Intracellular signalling mediated by secreted Wnt proteins is essential for the establishment of cell fates and proper tissue patterning during embryo development and for the regulation of tissue homeostasis and stem cell function in adult tissues. Aberrant activation of Wnt signalling pathways has been directly linked to the genesis of different tumours. Here, the components and molecular mechanisms implicated in the transduction of Wnt signal, along with important results supporting a central role for this signalling pathway in stem cell function regulation and carcinogenesis will be briefly reviewed.Ministerio de Ciencia e Innovación; SAF2008-0060

The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression

Most preneoplastic lesions are quiescent and do not progress to form overt tumors. It has been proposed that oncogenic stress activates the DNA damage response and the key tumor suppressor p53, which prohibits tumor growth. However, the molecular pathways by which cells sense a premalignant state in vivo are largely unknown. Here we report that tissue-specific inactivation of the stress signaling kinase MKK7 in KRas G12D-driven lung carcinomas and NeuT-driven mammary tumors markedly accelerates tumor onset and reduces overall survival. Mechanistically, MKK7 acts through the kinases JNK1 and JNK2, and this signaling pathway directly couples oncogenic and genotoxic stress to the stability of p53, which is required for cell cycle arrest and suppression of epithelial cancers. These results show that MKK7 functions as a major tumor suppressor in lung and mammary cancer in mouse and identify MKK7 as a vital molecular sensor to set a cellular anti-cancer barrier. © 2011 Nature America, Inc. All rights reserved

Variants in STAT5B associate with serum TC and LDL-C levels.

Context: Known genetic variants influencing serum lipid levels do not adequately account for the observed population variability of these phenotypes. The GH/signal transducers and activators of transcription (STAT) signaling pathway is an evolutionary conserved system that exerts strong effects on metabolism, including that of lipids. Research Design and Methods: We analyzed the association of 11 single-nucleotide polymorphisms (SNP) spanning the STAT5B/STAT5A/STAT3 locus with serum lipid levels in six European populations (n = 5162 nondiabetic individuals). Results: After adjustment for age, sex, alcohol use, smoking, and body mass index, we identified STAT5B variants (rs8082391 and rs8064638) in novel association with total cholesterol (TC; P = 0.001 and P = 0.002) and low-density lipoprotein cholesterol (P = 0.002 and P = 0.004) levels. The minor alleles of these single-nucleotide polymorphisms were significantly enriched in hyperlipidemic individuals across the six discovery populations (P = 0.004 and P = 0.006). In transgenic mice deficient for hepatic STAT5A and STAT5B, reduced serum TC levels coincided with reduced hepatic cholesterol biosynthesis as demonstrated using gene expression profiling and pathway enrichment analysis. Conclusions: Genetic variants in STAT5B are associated with TC and low-density lipoprotein cholesterol levels among six populations. Mechanistically, STAT5B transcriptionally regulates hepatic cholesterol homeostasis

The repertoire of Adhesion G protein-coupled receptors in adipocytes and their functional relevance.

Background G protein-coupled receptors (GPCR) are well-characterized regulators of a plethora of physiological functions among them the modulation of adipogenesis and adipocyte function. The class of Adhesion GPCR (aGPCR) and their role in adipose tissue, however, is poorly studied. With respect to the demand for novel targets in obesity treatment, we present a comprehensive study on the expression and function of this enigmatic GPCR class during adipogenesis and in mature adipocytes. Methods The expression of all aGPCR representatives was determined by reanalyzing RNA-Seq data and by performing qPCR in different mouse and human adipose tissues under low- and high-fat conditions. The impact of aGPCR expression on adipocyte differentiation and lipid accumulation was studied by siRNA-mediated knockdown of all expressed members of this receptor class. The biological characteristics and function of mature adipocytes lacking selected aGPCR were analyzed by mass spectrometry and biochemical methods (lipolysis, glucose uptake, adiponectin secretion). Results More than ten aGPCR are significantly expressed in visceral and subcutaneous adipose tissues and several aGPCR are differentially regulated under high-caloric conditions in human and mouse. Receptor knockdown of six receptors resulted in an impaired adipogenesis indicating their expression is essential for proper adipogenesis. The altered lipid composition was studied in more detail for two representatives, ADGRG2/GPR64 and ADGRG6/GPR126. While GPR126 is mainly involved in adipocyte differentiation, GPR64 has an additional role in mature adipocytes by regulating metabolic processes. Conclusions Adhesion GPCR are significantly involved in qualitative and quantitative adipocyte lipid accumulation and can control lipolysis. Factors driving adipocyte formation and function are governed by signaling pathways induced by aGPCR yielding these receptors potential targets for treating obesity

Paternal diet defines offspring chromatin state and intergenerational obesity

The global rise in obesity has revitalized a search for genetic and epigenetic factors underlying the disease. We present a Drosophila model of paternal-diet-induced intergenerational metabolic reprogramming (IGMR) and identify genes required for its encoding in offspring. Intriguingly, we find that as little as 2 days of dietary intervention in fathers elicits obesity in offspring. Paternal sugar acts as a physiological suppressor of variegation, desilencing chromatin-state-defined domains in both mature sperm and in offspring embryos. We identify requirements for H3K9/K27me3-dependent reprogramming of metabolic genes in two distinct germline and zygotic windows. Critically, we find evidence that a similar system may regulate obesity susceptibility and phenotype variation in mice and humans. The findings provide insight into the mechanisms underlying intergenerational metabolic reprogramming and carry profound implications for our understanding of phenotypic variation and evolution

Mitochondrion and its related disorders: Making a comeback*

The great majority of genetic disorders are caused by defects in the nuclear genome. However, some significant diseases are the result of mitochondrial mutations. Because of the unique features of the mitochondria, these diseases display characteristic modes of inheritance and a large degree of phenotypic variability. Recent studies have suggested that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer