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

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

Curved spacetimes with local κ -Poincaré dispersion relation

We use our previously developed identification of dispersion relations with Hamilton functions on phase space to locally implement the κ-Poincaré dispersion relation in the momentum spaces at each point of a generic curved spacetime. We use this general construction to build the most general Hamiltonian compatible with spherical symmetry and the Plank-scale-deformed one such that in the local frame it reproduces the κ-Poincaré dispersion relation. Specializing to Planck-scale-deformed Schwarzschild geometry, we find that the photon sphere around a black hole becomes a thick shell since photons of different energy will orbit the black hole on circular orbits at different altitudes. We also compute the redshift of a photon between different observers at rest, finding that there is a Planck-scale correction to the usual redshift only if the observers detecting the photon have different masses

Planck-scale-modified dispersion relations in homogeneous and isotropic spacetimes

The covariant understanding of dispersion relations as level sets of Hamilton functions on phase space enables us to derive the most general dispersion relation compatible with homogeneous and isotropic spacetimes. We use this concept to present a Planck-scale deformation of the Hamiltonian of a particle in Friedman-Lemaître-Robertson-Walker (FLRW) geometry that is locally identical to the κ-Poincaré dispersion relation, in the same way as the dispersion relation of point particles in general relativity is locally identical to the one valid in special relativity. Studying the motion of particles subject to such a Hamiltonian, we derive the redshift and lateshift as observable consequences of the Planck-scale deformed FLRW universe

Hamilton geometry: Phase space geometry from modified dispersion relations

Quantum gravity phenomenology suggests an effective modification of the general relativistic dispersion relation of freely falling point particles caused by an underlying theory of quantum gravity. Here we analyse the consequences of modifications of the general relativistic dispersion on the geometry of spacetime in the language of Hamilton geometry. The dispersion relation is interpreted as the Hamiltonian which determines the motion of point particles. It is a function on the cotangent bundle of spacetime, i.e. on phase space, and determines the geometry of phase space completely, in a similar way as the metric determines the geometry of spacetime in general relativity. After a review of the general Hamilton geometry of phase space we discuss two examples. The phase space geometry of the metric Hamiltonian Hg(x, p) = gab(x)papb and the phase space geometry of the first order q-de Sitter dispersion relation of the form HqDS(x, p) = gab(x)papb + Gabc(x)papbpc which is suggested from quantum gravity phenomenology. We will see that for the metric Hamiltonian Hg the geometry of phase space is equivalent to the standard metric spacetime geometry from general relativity. For the q-de Sitter Hamiltonian HqDS the Hamilton equations of motion for point particles do not become autoparallels but contain a force term, the momentum space part of phase space is curved and the curvature of spacetime becomes momentum dependent

Hamilton geometry: Phase space geometry from modified dispersion relations

We describe the Hamilton geometry of the phase space of particles whose motion is characterized by general dispersion relations. In this framework spacetime and momentum space are naturally curved and intertwined, allowing for a simultaneous description of both spacetime curvature and nontrivial momentum space geometry. We consider as explicit examples two models for Planck-scale modified dispersion relations, inspired from the q-de Sitter and κ-Poincaré quantum groups. In the first case we find the expressions for the momentum and position dependent curvature of spacetime and momentum space, while for the second case the manifold is flat and only the momentum space possesses a nonzero, momentum dependent curvature. In contrast, for a dispersion relation that is induced by a spacetime metric, as in general relativity, the Hamilton geometry yields a flat momentum space and the usual curved spacetime geometry with only position dependent geometric objects

FLASH degradation in response to UV-C results in histone locus bodies disruption and cell-cycle arrest

Eucaryotic cell nuclei contain a number of different organelles that are highly dynamic structures and respond to a variety of stimuli. Here we investigated the effect of UV irradiation on a recently identified group of organelles, Histone Locus Bodies. Histone Locus Bodies contain at least two main proteins, FLASH and NPAT, and have been shown to be involved in replication-dependent histone gene transcription. We show that these organelles are disrupted after sublethal irradiation and both FLASH and NPAT are degraded, which in turn results in cell-cycle arrest at the S/G2 transition. The effect on the cell cycle is due to reduced transcription of histone genes and restoring normal histone protein levels by stabilizing histone mRNA allows cells to progress through the cell cycle. This provides a novel mechanism of S-phase arrest in response to DNA damage that potentially allows DNA repair before cells continue into mitosis, and thus prevents transmission of genomic alterations