Functional evolution of ADAMTS genes: Evidence from analyses of phylogeny and gene organization

BACKGROUND: The ADAMTS (A Disintegrin-like and Metalloprotease with Thrombospondin motifs) proteins are a family of metalloproteases with sequence similarity to the ADAM proteases, that contain the thrombospondin type 1 sequence repeat motifs (TSRs) common to extracellular matrix proteins. ADAMTS proteins have recently gained attention with the discovery of their role in a variety of diseases, including tissue and blood disorders, cancer, osteoarthritis, Alzheimer's and the genetic syndromes Weill-Marchesani syndrome (ADAMTS10), thrombotic thrombocytopenic purpura (ADAMTS13), and Ehlers-Danlos syndrome type VIIC (ADAMTS2) in humans and belted white-spotting mutation in mice (ADAMTS20). RESULTS: Phylogenetic analysis and comparison of the exon/intron organization of vertebrate (Homo, Mus, Fugu), chordate (Ciona) and invertebrate (Drosophila and Caenorhabditis) ADAMTS homologs has elucidated the evolutionary relationships of this important gene family, which comprises 19 members in humans. CONCLUSIONS: The evolutionary history of ADAMTS genes in vertebrate genomes has been marked by rampant gene duplication, including a retrotransposition that gave rise to a distinct ADAMTS subfamily (ADAMTS1, -4, -5, -8, -15) that may have distinct aggrecanase and angiogenesis functions

Divergent Genomic and Epigenomic Landscapes of Lung Cancer Subtypes Underscore the Selection of Different Oncogenic Pathways during Tumor Development

For therapeutic purposes, non-small cell lung cancer (NSCLC) has traditionally been regarded as a single disease. However, recent evidence suggest that the two major subtypes of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SqCC) respond differently to both molecular targeted and new generation chemotherapies. Therefore, identifying the molecular differences between these tumor types may impact novel treatment strategy. We performed the first large-scale analysis of 261 primary NSCLC tumors (169 AC and 92 SqCC), integrating genome-wide DNA copy number, methylation and gene expression profiles to identify subtype-specific molecular alterations relevant to new agent design and choice of therapy. Comparison of AC and SqCC genomic and epigenomic landscapes revealed 778 altered genes with corresponding expression changes that are selected during tumor development in a subtype-specific manner. Analysis of >200 additional NSCLCs confirmed that these genes are responsible for driving the differential development and resulting phenotypes of AC and SqCC. Importantly, we identified key oncogenic pathways disrupted in each subtype that likely serve as the basis for their differential tumor biology and clinical outcomes. Downregulation of HNF4α target genes was the most common pathway specific to AC, while SqCC demonstrated disruption of numerous histone modifying enzymes as well as the transcription factor E2F1. In silico screening of candidate therapeutic compounds using subtype-specific pathway components identified HDAC and PI3K inhibitors as potential treatments tailored to lung SqCC. Together, our findings suggest that AC and SqCC develop through distinct pathogenetic pathways that have significant implication in our approach to the clinical management of NSCLC

Testing cost-benefit models of parental care evolution using lizard populations differing in the expression of maternal care

Parents are expected to evolve tactics to care for eggs or offspring when providing such care increases fitness above the costs incurred by this behavior. Costs to the parent include the energetic demands of protecting offspring, delaying future fecundity, and increased risk of predation. We used cost-benefit models to test the ecological conditions favoring the evolution of parental care, using lizard populations that differ in whether or not they express maternal care. We found that predators play an important role in the evolution of maternal care because: (1) evolving maternal care is unlikely when care increases predation pressure on the parents; (2) maternal care cannot evolve under low levels of predation pressure on both parents and offspring; and (3) maternal care evolves only when parents are able to successfully defend offspring from predators without increasing predation risk to themselves. Our studies of one of the only known vertebrate species to exhibit interpopulation differences in the expression of maternal care provide clear support for some of the hypothesized circumstances under which maternal care should evolve (e.g., when nests are in exposed locations, parents are able to defend the eggs from predators, and egg incubation periods are brief), but do not support others (e.g., when nest-sites are scarce, life history strategies are "risky", reproductive frequency is low, and environmental conditions are harsh). We conclude that multiple pathways can lead to the evolution of parental care from a non-caring state, even in a single population of a widespread species

High anoxia tolerance in the subterranean salamander Proteus anguinus without oxidative stress nor activation of antioxidant defenses during reoxygenation

The present study describes a high anoxia tolerance in an amphibian at high temperature. Indeed, the subterranean salamander Proteus anguinus survived 12 h under anoxia at 12°C. Surprisingly, such experimental conditions did not affect P. anguinus oxidative status while muscles and liver antioxidant enzymes activities decreased under 8 h anoxia and only return to basal level during reoxygenation. To test if such adaptation is common in Urodels, equivalent experimentations have been conducted on another newt: the stream-dwelling Calotriton asper. This latter species exhibited only 1.5 h survival under anoxia in spite of higher antioxidant enzymes activities than P. anguinus. Furthermore, aerobic recovery after 1 h anoxia induced a 30% increase of oxidative damage partly explained by SOD and CAT activities that did not return to control values during reoxygenation, demonstrating a lower capacity to counteract ROS overproduction than P. anguinus. In addition, uncoupling protein (UCP) transcript was for the first time detected, partly sequenced and quantified in amphibian muscles and liver. UCP may be considered as a ROS production attenuator by mediating a discharge of the proton gradient generated by the respiratory chain. The putative role of UCP in post-anoxic oxidative status of both species is discussed