p63 isoforms regulate metabolism of cancer stem cells

p63 is an important regulator of epithelial development expressed in different variants containing (TA) or lacking (\u394N) the N-terminal transactivation domain. The different isoforms regulate stem-cell renewal and differentiation as well as cell senescence. Several studies indicate that p63 isoforms also play a role in cancer development; however, very little is known about the role played by p63 in regulating the cancer stem phenotype. Here we investigate the cellular signals regulated by TAp63 and \u394Np63 in a model of epithelial cancer stem cells. To this end, we used colon cancer stem cells, overexpressing either TAp63 or \u394Np63 isoforms, to carry out a proteomic study by chemical-labeling approach coupled to network analysis. Our results indicate that p63 is implicated in a wide range of biological processes, including metabolism. This was further investigated by a targeted strategy at both protein and metabolite levels. The overall data show that TAp63 overexpressing cells are more glycolytic-active than \u394Np63 cells, indicating that the two isoforms may regulate the key steps of glycolysis in an opposite manner. The mass-spectrometry proteomics data of the study have been deposited to the ProteomeXchange Consortium (http://proteomecentral. proteomexchange.org) via the PRIDE partner repository with data set identifiers PXD000769 and PXD000768

FLASH Knockdown Sensitizes Cells To Fas-Mediated Apoptosis via Down-Regulation of the Anti-Apoptotic Proteins, MCL-1 and Cflip Short

FLASH (FLICE-associated huge protein or CASP8AP2) is a large multifunctional protein that is involved in many cellular processes associated with cell death and survival. It has been reported to promote apoptosis, but we show here that depletion of FLASH in HT1080 cells by siRNA interference can also accelerate the process. As shown previously, depletion of FLASH halts growth by down-regulating histone biosynthesis and arrests the cell cycle in S-phase. FLASH knockdown followed by stimulating the cells with Fas ligand or anti-Fas antibodies was found to be associated with a more rapid cleavage of PARP, accelerated activation of caspase-8 and the executioner caspase-3 and rapid progression to cellular disintegration. As is the case for most anti-apoptotic proteins, FLASH was degraded soon after the onset of apoptosis. Depletion of FLASH also resulted in the reduced intracellular levels of the anti-apoptotic proteins, MCL-1 and the short isoform of cFLIP. FLASH knockdown in HT1080 mutant cells defective in p53 did not significantly accelerate Fas mediated apoptosis indicating that the effect was dependent on functional p53. Collectively, these results suggest that under some circumstances, FLASH suppresses apoptosis

Drosophila histone locus bodies form by hierarchical recruitment of components

An assembly process involving sequential recruitment of components and hierarchical dependency drives formation of the nuclear structures known as histone locus bodies

BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages

The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential

First proposal of a Business Architecture to refine the model elaborated by the Sponsorship on Standardisation

This deliverable aims at illustrating a proposal of a Business Architecture (BA) model that can be considered as a starting point to refine the approach produced by the Sponsorship on Standardisation. This renewed model should be shared between the ESSnet on standardisation project members and can represent a first step towards the development of a BA characterised by common frameworks and principles within each Institute/Organisation, so as to work in a more efficient and optimised way

A Business Architecture Model to foster standardisation in official statistics

Business Architecture (BA) is called to play a central role in a programme as complex as that of modernisation and standardisation of the official statistical information production. This study aims at illustrating a BA model for achieving a unity of views, so as to ensure the strategic alignment in each part of an Organisation and to carry out an innovation consistent with the standardisation objective that should be reached. This BAmodel individuates four different business lines (Strategy; Corporate support; Production; Capability) and is led by common infrastructures and principles that become instruments and guidelines for the implementation of each business line group of actions. Both principles and infrastructures facilitate and enhance the standardisation process

Business Architecture Principles to Foster Industrialisation and Standardisation at the Italian National Institute of Statistics

The Italian National Institute of Statistics has recently adopted the common vision proposed for the European Statistic al System, envisaging a different production process of the statistical information, based on its standardisation and industrialisation, thus achieving higher efficiency and quality levels together with lower respondent burden. In order to ensure a proper governance of the transition process, a rigorous definition of the “to be” model is needed: for this purpose, Istat has defined a Business Architecture model, clearly stating the characteristics of the statistical value chain, the way the activities in the different domains interact, the general principles informing the whole process, and the infrastructures required so as to ensure its optimality

Business Architecture model within an official statistical context

Several Official Statistical Institutions/Organisations are currently facing commitments towards modernisation and standardisation of their work processes, both from an organisational and a production-related point of view. In this context, this paper aims at illustrating a reference Business Architecture (BA) model that can be used to enhance this relevant evolution phase and represents a first step towards the development of a sharable common framework, so as to work in a more efficient and optimised way