Differences in the ubiquitination of p53 by Mdm2 and the HPV protein E6

AbstractThe human papillomavirus (HPV) protein E6 can promote the ubiquitination of the p53 tumour suppressor in vitro, providing an explanation for the ability of E6 to induce p53 degradation in vivo and contribute to the potential tumorigenic effect of the virus. Instead, in non-infected cells, p53 levels are primarily destabilised by the ubiquitin E3 ligase activity of the Mdm2 protein. Here we have compared the effects of E6 and Mdm2 on p53 ubiquitination in vivo. We show that whereas in the presence of Mdm2 proteasome inhibitors induce the accumulation of ubiquitinated forms of p53, this does not occur in the presence of E6. Accordingly, we confirm that the effect of E6 and p53 is independent of the six C-terminal lysine residues in p53, which have previously been described to play an important role for effective ubiquitination and degradation of 53 mediated by Mdm2. We also show that other yet unidentified residues in p53 are also susceptible to ubiquitination. These results indicate that E6 does not induce ubiquitination of p53 in the same way as Mdm2 in order to promote its degradation, suggesting important differences between the Mdm2 and E6 effects on p53 degradation

Depression is associated with some patient-perceived cosmetic changes, but not with radiotherapy-induced late toxicity, in long-term breast cancer survivors.: Depression-associated factors in long-term breast cancer survivors

International audienceOBJECTIVE: Although depression is prevalent in long-term breast cancer survivors (LTBCS; ≥5 years since diagnosis), it is underdiagnosed and undertreated. A better understanding of factors associated with depression could improve depression screening, treatment, and prevention in this population. Our study aimed to assess the link between patient and doctor ratings of breast cosmetic outcomes, late radiotherapy toxicity, and depression in LTBCS. METHODS: In all, 214 patients recruited from the ARCOSEIN study were assessed for late radiotherapy toxicity (by using the LENT-SOMA scale) and patient and doctor ratings of breast cosmetic outcomes (mean = 6.7 years since the end of treatment). We reassessed 120 of these patients for depression (HAD) during a second wave of long-term assessment (mean = 8.1 years since the end of treatment). We used univariate analyses and polytomous logistic regression analyses to predict the HAD depression, which was defined as follows: normal, 0-7 points; and significant depression, ≥8 points (8-10 points, possible depression; ≥11 points, probable depression). RESULTS: The mean HAD depression score was 4.5 ± 3.6. 19. 2% of our population had significant depression, 6.7% with probable depression, and 12.5% with possible depression. Significant depression was not associated with late radiotherapy toxicity or initial cancer-related variables. Patients with probable depression reported worse cosmetic outcomes than nondepressed patients in terms of perceived breast largeness (p = 0.04), breast deformation (p = 0.02), and changes in skin pigmentation (p = 0.03). CONCLUSIONS: In LTBCS, depression seems to be more strongly associated with changes in some patients' perceived breast cosmetic outcome than late treatment toxicity or initial cancer-related variables. Copyright © 2012 John Wiley & Sons, Ltd

Increased dosage of tumor suppressors limits the tumorigenicity of iPS cells without affecting their pluripotency

Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent a promising therapeutic tool for many diseases, including aged tissues and organs at high risk of failure. However, the intrinsic self-renewal and pluripotency of ES and iPS cells make them tumorigenic, and hence, the risk of tumor development hinders their clinical application. Here, we present a novel approach to limit their tumorigenicity and increase their safety through increased copy number of tumor suppressors. iPS containing an extra copy of the p53 or Ink4a/ARF locus show normal pluripotency, as determined by in vitro and in vivo differentiation assays. Yet, while retaining full pluripotency, they also possess an improved engagement of the p53 pathway during teratocarcinoma formation, which leads to a reduced tumorigenic potential in various in vitro and in vivo assays. Furthermore, they show an improved response to anticancer drugs, which could aid in their elimination in case tumors arise with no adverse effects on cell function or aging. Our system provides a model for studying tumor suppressor pathways during reprogramming, differentiation, and cell therapy applications. This offers an improved understanding of the pathways involved in tumor growth from engrafted pluripotent stem cells, which could facilitate the use of ES and iPS cells in regenerative medicine

Déterminisme du recrutement de la sole. Phase pélagique - Résultats des campagnes 1985

In order to analyse the recruitment process of a commercial fish, the common sole has been selected for making researches into the mecanisms which have an effect upon the distribution of the young fish stages and upon the plenty of the recruitment. In 1985, during three surveys for eggs and larvae off the estuary of the river Loire in march and april, severa! points have been studied : - physical and chemical data of the sea - distribution of eggs and larvae - vertical distribution of larvae in a little scale - some results on nutrition of larvae.Afin d'analyser le processus du recrutement d'une espèce d'intérêt économique, la sole a été choisie pour rechercher les mécanismes déterminant la répartition des jeunes stades et influençant l'abondance de la phase recrutée.  En 1985, au cours de trois campagnes de récoltes d'oeufs et larves au large de l'estuaire de la Loire en mars et avril, plusieurs points ont été étudiés: - caractéristiques physiques et chimiques du milieu - distribution des oeufs et des larves - distribution verticale des larves à petite échelle - quelques résultats sur la nutrition des larves

Déterminisme du recrutement de la sole dans le golfe de Gascogne. Phase pélagique. Campagnes SOLDET IV. V. VI. 1986

The aim of these cruises following those initiated in 1985 is to identify the factors involved in the recruitment of the sole (Solea vulgaris) in the bay of Biscay. These cruises were carried out in an area between Belle-Ile and ile d' Yeu islands from the near shore to the 100 m bottom line. The main goals are the following: - Physics : evaluation of advection and diffusion parameters using remote sensing "drogues" (Argos) - Chemistry : identification of water masses (T, S , nutrients, chlorophyll, pheophytin) - Biology : distribution of sole eggs and larvae-and study of their variability (répliquates). Aging of larvae These goals will contribute to estimate the mortality of the different stages of the pelagic phases (eggs and larvae).Les trois campagnes font suite à celles entreprises en 1985 dans le golfe de Gascogne dans le but de connaître les facteurs qui déterminent le recrutement de la sole. Le secteur prospecté est compris entre Belle Ile et l'Ile d'Yeu de la côte jusqu' aux fonds de 100 m. Les objectifs retenus ont été les suivants : - En physique : estimation de l’advection et de la diffusion en utilisant des "drogues" équipées de balises "Argos" - En chimie : caractérisation des masses d'eau (T, S , sels nutritifs, chlorophylle, phéophytine) - En biologie : répartition des œufs et des larves et étude de la variabilité (reliquats) Ces objectifs permettront d'estimer la mortalité aux différentes phases de la vie pélagique de la sole (œufs et larves)

External quality assessment of BRAF molecular analysis in melanoma

The availability of BRAF inhibitors has given metastatic melanoma patients an effective new treatment choice and molecular testing to determine the presence or absence of a BRAF codon 600 mutation is pivotal in the clinical management of these patients. This molecular test must be performed accurately and appropriately to ensure that the patient receives the most suitable treatment in a timely manner. Laboratories have introduced such testing; however, some experience low sample throughput making it critical that an external quality assurance programme is available to help promote a high standard of testing, reporting and provide an educational aspect for BRAF molecular testing. Laboratories took part in three rounds of external quality assessment (EQA) during a 12-month period giving participants a measure of the accuracy of genotyping, clinical interpretation of the result and experience in testing a range of different samples. Formalin fixed paraffin embedded tissue sections from malignant melanoma patients were distributed to participants for BRAF molecular testing. The standard of testing was generally high but distribution of a mutation other than the most common, p.(Val600Glu), highlighted concerns with detection or reporting of the presence of rarer mutations. The main issues raised in the interpretation of the results were the importance of clear unambiguous interpretation of the result tailored to the patient and the understanding that the treatment is different from that given to other stratified medicine programmes. The variability in reporting and wide range of methodologies used indicate a continuing need for EQA in this field

: Prédicteurs de qualité de vie à long terme dans le cancer du sein

International audienceINTRODUCTION: This study aimed to assess the impact of late treatment toxicity (especially radiotherapy toxicity), chemoradiotherapy treatment type (concurrent or sequential), depression and anxiety on overall, physical and emotional quality of life (QoL) in long-term breast cancer survivors. Method. We assessed 117 patients (mean follow-up since the end of treatment = 8.1 years) for late radiotherapy toxicity (LENT-SOMA scale), patient and doctor ratings of breast cosmetic outcomes, QoL (EORTC QLQ-C30), depression and anxiety (Hospital and Anxiety Depression scale). RESULTS: In univariate analyses, factors associated with significantly decreased QoL were: use of sequential treatment and decreased overall QoL (P = 0.002) and emotional QoL (P = 0.02) ; few radiotherapy late toxicity symptoms (pain and decreased physical QoL, P = 0.01 ; fibrosis and decreased emotional QoL, P = 0.04) ; probable depression or probable anxiety and decreased overall, physical and emotional QoL (P ≤ 0.005). In multivariate analyses, probable depression and probable anxiety were the most stronger predictors for decreased QoL in the overall, physical and emotional domains (P ≤ 0.02). CONCLUSION: Improving screening for and treatment of depression and anxiety might improve QoL in long-term breast cancer survivors

Personality disorders, but not cancer severity or treatment type, are risk factors for later generalised anxiety disorder and major depressive disorder in non metastatic breast cancer patients

International audienceThis study aimed to determine whether personality disorders were associated with later Major Depressive Disorder (MDD) or Generalised Anxiety Disorder (GAD) in breast cancer patients. This longitudinal and multicentric study included 120 French non-metastatic breast cancer patients. After cancer diagnosis (T1) and 7 months after diagnosis (T3), we assessed MDD and GAD (Mini International Neuropsychiatric Interview 5.0). We assessed personality disorders 3 months after diagnosis (VKP). We used multiple logistic regression analysis to determine what were the factors associated with GAD and MDD at T3. At T3, prevalence rate was 10.8% for MDD and 19.2% for GAD. GAD at T3 was significantly and independently associated with GAD at T1 and with existence of a personality disorder, no matter the cluster type. MDD at T3 was significantly and independently associated with MDD at T1 and with the existence of a cluster C personality disorder. Initial cancer severity and the type of treatment used were not associated with GAD or MDD at T3. Breast cancer patients with personality disorders are at higher risk for GAD and MDD at the end of treatment. Patients with GAD should be screened for personality disorders. Specific interventions for patients with personality disorders could prevent psychiatric disorders

Lung cancer risk in nonsmokers and GSTM1 and GSTT1 genetic polymorphism

Glutathione S-transferase (GST) polymorphism may contribute to the individual variability in detoxifying lung carcinogens. This effect might be particularly relevant at low-level exposure to environmental carcinogens, such as in nonsmokers exposed to environmental tobacco smoke (ETS). We conducted a case-control study among 122 nonsmoking lung cancer cases and 121 nonsmoking controls from eight countries. Information on environmental exposures was obtained through a personal interview. The presence of GSTM1 and GSTT1 genes was determined using multiplex PCR. GSTM1-positive samples were then analyzed for *1A and *1B polymorphism using an allele-specific amplification-PCR method. GSTM1*2 (null) individuals had an odds rati

The p53 isoforms are differentially modified by Mdm2

The discovery that the single p53 gene encodes several different p53 protein isoforms has initiated a flurry of research into the function and regulation of these novel p53 proteins. Full-length p53 protein level is primarily regulated by the E3-ligase Mdm2, which promotes p53 ubiquitination and degradation. Here, we report that all of the novel p53 isoforms are ubiquitinated and degraded to varying degrees in an Mdm2-dependent and -independent manner, and that high-risk human papillomavirus can degrade some but not all of the novel isoforms, demonstrating that full-length p53 and the p53 isoforms are differentially regulated. In addition, we provide the first evidence that Mdm2 promotes the NEDDylation of p53β. Altogether, our data indicates that Mdm2 can distinguish between the p53 isoforms and modify them differently