Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells

We have previously reported that deletion of the retinoblastoma gene Rb leads to rapid but transient p53 stabilisation. We investigated here the pathways involved. We show that upon Rb-deletion dysregulated E2F activates p19(ARF) expression that localises in the nucleoli. There it interacts with MDM2, leading to P53 stabilisation. At the same time, ATR is activated, activating CHK1 that may phosphorylate P53 but also contribute to inhibition of MnSOD expression leading to accumulation of ROS (reactive oxygen species) and subsequent DNA injury, which in turn maintains ATR/CHK1 activated. However, from 72 h after Rb deletion, NPM interacts with P19ARF and concomitantly the interaction between p19(ARF) and MDM2 decreases leading to a return to P53 degradation. This occurs despite the persistence of the DNA damage response pathways. We therefore observe in primary cells not subjected to exogenous gene expression or exogenous DNA damaging treatment, activation of 2 concomitant pathways of activation of P53 that are dealt with in independent manner: an oncogenic pathway with rapid activation of ARF which is 'switched off' downstream of p19(ARF) activation after 72 h of induction and a DNA damage response pathway keeping a low level of transcriptionally active P53 sufficient to deal with a physiological elevation of oxidative DNA injury. A possible connection between the two pathways is discussed.Publisher PDFPeer reviewe

Comparaison des pratiques bouchères et culinaires de différents groupes sibériens vivant de la renniculture

International audienceIn this paper, we present butchering and culinary practices of several different Siberian reindeer herding groups. The comparisons among these groups reveal similarities as well as few differences in the treatment of reindeer carcasses, the only subject presented in this study. The reference frame of cutmarks presented relative of Binford's one (1981) reveals the morphological variability of some cutmarks type, underlining the need for a survey of butchery patterns in other ethnic groups. Comparison with Paleolithic archaeological faunal assemblages show some dissimilarities that we try to explain.Les pratiques bouchères et culinaires de différents groupes sibériens vivant de la renniculture sont présentées. Les comparaisons réalisées mettent en évidence des similitudes mais également quelques différences dans la manière de traiter les carcasses de rennes qui sont notre seul sujet d'étude. Le référentiel de stries de boucherie présenté relativement à celui de L.R. Binford (1981) révèle la variabilité morphologique de certains types de traces, soulignant la nécessité de multiplier ce type d'approche. La comparaison avec les données issues du Paléolithique européen montre certaines différences que nous essayons d'interpréter

Efficient Generation of Stable Planar Cages for Chemistry

In this paper we describe an algorithm which generates all colored planar maps with a good minimum sparsity from simple motifs and rules to connect them. An implementation of this algorithm is available and is used by chemists who want to quickly generate all sound molecules they can obtain by mixing some basic components.Comment: 17 pages, 7 figures. Accepted at the 14th International Symposium on Experimental Algorithms (SEA 2015

Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFbeta cell cycle arrest

TGFbeta is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFbeta in disease. We asked how Rb-deficiency would affect responses to TGFbeta-induced cell cycle arrest.Publisher PDFPeer reviewe

Role of ATP hydrolysis in the DNA translocase activity of the bovine papillomavirus (BPV-1) E1 helicase

The E1 protein of bovine papillomavirus type-1 is the viral replication initiator protein and replicative helicase. Here we show that the C-terminal ∼300 amino acids of E1, that share homology with members of helicase superfamily 3 (SF3), can act as an autonomous helicase. E1 is monomeric in the absence of ATP but assembles into hexamers in the presence of ATP, single-stranded DNA (ssDNA) or both. A 16 base sequence is the minimum for efficient hexamerization, although the complex protects ∼30 bases from nuclease digestion, supporting the notion that the DNA is bound within the protein complex. In the absence of ATP, or in the presence of ADP or the non–hydrolysable ATP analogue AMP–PNP, the interaction with short ssDNA oligonucleotides is exceptionally tight (T(1/2) > 6 h). However, in the presence of ATP, the interaction with DNA is destabilized (T(1/2) ∼60 s). These results suggest that during the ATP hydrolysis cycle an internal DNA-binding site oscillates from a high to a low-affinity state, while protein–protein interactions switch from low to high affinity. This reciprocal change in protein–protein and protein–DNA affinities could be part of a mechanism for tethering the protein to its substrate while unidirectional movement along DNA proceeds

A General Framework for Statistical Performance Comparison of Evolutionary Computation Algorithms

This paper proposes a statistical methodology for comparing the performance of evolutionary computation algorithms. A two-fold sampling scheme for collecting performance data is introduced, and these data are analyzed using bootstrap-based multiple hypothesis testing procedures. The proposed method is sufficiently flexible to allow the researcher to choose how performance is measured, does not rely upon distributional assumptions, and can be extended to analyze many other randomized numeric optimization routines. As a result, this approach offers a convenient, flexible, and reliable technique for comparing algorithms in a wide variety of applications