Oncogenic roles of GOLPH3 in the physiopathology of cancer

Golgi phosphoprotein 3 (GOLPH3), un effettore del fosfatidilinositolo 4-fosfato [PI (4) P] al Golgi, è necessaria per il mantenimento della struttura del nastro del Golgi, il traffico di vescicole e la glicosilazione del Golgi. GOLPH3 è stato convalidato come oncoproteina combinando la genomica integrativa con l'analisi clinopatologiche e funzionali. È spesso amplificato in diversi tipi di tumori solidi tra cui melanoma, cancro ai polmoni, cancro al seno, glioma e cancro del colon-retto. La sovraespressione di GOLPH3 è correlata a una prognosi infausta in più tipi di tumore, compreso il 52% dei tumori al seno e dal 41% al 53% del glioblastoma. I ruoli di GOLPH3 nella tumorigenesi possono essere correlati a diverse attività cellulari, tra cui: (i) regolazione del traffico dal Golgi alla membrana plasmatica e contributo a fenotipi secretori maligni; (ii) controllare l'internalizzazione e il riciclaggio di molecole di segnalazione chiave o aumentare la glicosilazione delle glicoproteine ​​rilevanti per il cancro; e (iii) influenzare la risposta al danno al DNA e il mantenimento della stabilità genomica. Qui riassumiamo le attuali conoscenze sui percorsi oncogeni che coinvolgono GOLPH3 nel cancro umano, l'influenza di GOLPH3 sul metabolismo del tumore e sullo stroma circostante e il suo possibile ruolo nella formazione di metastasi tumorali.Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for Golgi ribbon structure maintenance, vesicle trafficking and Golgi glycosylation. GOLPH3 has been validated as an oncoprotein through combining integrative genomics with clinopathological and functional analyses. It is frequently amplified in several solid tumor types including melanoma, lung cancer, breast cancer, glioma, and colorectal cancer. Overexpression of GOLPH3 correlates with poor prognosis in multiple tumor types including 52% of breast cancers and 41% to 53% of glioblastoma. Roles of GOLPH3 in tumorigenesis may correlate with several cellular activities including: (i) regulating Golgi-to-plasma membrane trafficking and contributing to malignant secretory phenotypes; (ii) controlling the internalization and recycling of key signaling molecules or increasing the glycosylation of cancer relevant glycoproteins; and (iii) influencing the DNA damage response and maintenance of genomic stability. Here we summarize current knowledge on the oncogenic pathways involving GOLPH3 in human cancer, GOLPH3 influence on tumor metabolism and surrounding stroma, and its possible role in tumor metastasis formation

Invariant measures of the 2D Euler and Vlasov equations

We discuss invariant measures of partial differential equations such as the 2D Euler or Vlasov equations. For the 2D Euler equations, starting from the Liouville theorem, valid for N-dimensional approximations of the dynamics, we define the microcanonical measure as a limit measure where N goes to infinity. When only the energy and enstrophy invariants are taken into account, we give an explicit computation to prove the following result: the microcanonical measure is actually a Young measure corresponding to the maximization of a mean-field entropy. We explain why this result remains true for more general microcanonical measures, when all the dynamical invariants are taken into account. We give an explicit proof that these microcanonical measures are invariant measures for the dynamics of the 2D Euler equations. We describe a more general set of invariant measures, and discuss briefly their stability and their consequence for the ergodicity of the 2D Euler equations. The extension of these results to the Vlasov equations is also discussed, together with a proof of the uniqueness of statistical equilibria, for Vlasov equations with repulsive convex potentials. Even if we consider, in this paper, invariant measures only for Hamiltonian equations, with no fluxes of conserved quantities, we think this work is an important step towards the description of non-equilibrium invariant measures with fluxes.Comment: 40 page

The interplay between shell effects and electron correlations in quantum dots

We use the Path Integral Monte Carlo method to investigate the interplay between shell effects and electron correlations in single quantum dots with up to 12 electrons. By use of an energy estimator based on the hypervirial theorem of Hirschfelder we study the energy contributions of different interaction terms in detail. We discuss under which conditions the total spin of the electrons is given by Hund's rule, and the temperature dependence of the crystallization effects.Comment: 6 pages, 4 figure

COG7 deficiency in Drosophila generates multifaceted developmental, behavioral and protein glycosylation phenotypes

Congenital disorders of glycosylation (CDG) comprise a family of human multisystemic diseases caused by recessive mutations in genes required for protein N-glycosylation. More than 100 distinct forms of CDGs have been identified and most of them cause severe neurological impairment. The Conserved Oligomeric Golgi (COG) complexmediates tethering of vesicles carrying glycosylation enzymes across the Golgi cisternae. Mutations affecting human COG1, COG2 and COG4-COG8 cause monogenic forms of inherited, autosomal recessive CDGs.We have generated a Drosophila COG7-CDG model that closely parallels the pathological characteristics of COG7-CDG patients, including pronounced neuromotor defects associated with altered N-glycome profiles. Consistent with these alterations, larval neuromuscular junctions of Cog7 mutants exhibit a significant reduction in bouton numbers. We demonstrate that the COG complex cooperates with Rab1 and Golgi phosphoprotein 3 to regulate Golgi trafficking and that overexpression of Rab1 can rescue the cytokinesis and locomotor defects associated with loss of Cog7. Our results suggest that the Drosophila COG7-CDG model can be used to test novel potential therapeutic strategies by modulating trafficking pathways

Lyapunov exponent of many-particle systems: testing the stochastic approach

The stochastic approach to the determination of the largest Lyapunov exponent of a many-particle system is tested in the so-called mean-field XY-Hamiltonians. In weakly chaotic regimes, the stochastic approach relates the Lyapunov exponent to a few statistical properties of the Hessian matrix of the interaction, which can be calculated as suitable thermal averages. We have verified that there is a satisfactory quantitative agreement between theory and simulations in the disordered phases of the XY models, either with attractive or repulsive interactions. Part of the success of the theory is due to the possibility of predicting the shape of the required correlation functions, because this permits the calculation of correlation times as thermal averages.Comment: 11 pages including 6 figure

Nessun Dorma, a novel centralspindlin partner, is required for cytokinesis in Drosophila spermatocytes

Nessun Dorma is a component of the ring canal with a polysaccharide-binding domain, which is important for cytokinesis during male meiosis

Combined inhibition of Aurora-A and ATR kinase results in regression of MYCN-amplified neuroblastoma

Amplification of MYCN is the driving oncogene in a subset of high-risk neuroblastoma. The MYCN protein and the Aurora-A kinase form a complex during S phase that stabilizes MYCN. Here we show that MYCN activates Aurora-A on chromatin, which phosphorylates histone H3 at serine 10 in S phase, promotes the deposition of histone H3.3 and suppresses R-loop formation. Inhibition of Aurora-A induces transcription-replication conflicts and activates the Ataxia telangiectasia and Rad3 related (ATR) kinase, which limits double-strand break accumulation upon Aurora-A inhibition. Combined inhibition of Aurora-A and ATR induces rampant tumor-specific apoptosis and tumor regression in mouse models of neuroblastoma, leading to permanent eradication in a subset of mice. The therapeutic efficacy is due to both tumor cell-intrinsic and immune cell-mediated mechanisms. We propose that targeting the ability of Aurora-A to resolve transcription-replication conflicts is an effective therapy for MYCN-driven neuroblastoma (141 words)