LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes

Germline mutations of the LKB1 (STK11) tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS) and predisposition to cancer. LKB1 encodes a serine/threonine kinase generally inactivated in PJS patients. We identified the dual phosphatase and tumor suppressor protein PTEN as an LKB1-interacting protein. Several LKB1 point mutations associated with PJS disrupt the interaction with PTEN suggesting that the loss of this interaction might contribute to PJS. Although PTEN and LKB1 are predominantly cytoplasmic and nuclear, respectively, their interaction leads to a cytoplasmic relocalization of LKB1. In addition, we show that PTEN is a substrate of the kinase LKB1 in vitro. As PTEN is a dual phosphatase mutated in autosomal inherited disorders with phenotypes similar to those of PJS (Bannayan-Riley-Ruvalcaba syndrome and Cowden disease), our study suggests a functional link between the proteins involved in different hamartomatous polyposis syndromes and emphasizes the central role played by LKB1 as a tumor suppressor in the small intestin

Identification and characterization of human Mex-3 proteins, a novel family of evolutionarily conserved RNA-binding proteins differentially localized to processing bodies

In Caenorhabditis elegans, the Mex-3 protein is a translational regulator that specifies the posterior blastomere identity in the early embryo and contributes to the maintenance of the germline totipotency. We have now identified a family of four homologous human Mex-3 genes, called hMex-3A to -3D that encode proteins containing two heterogeneous nuclear ribonucleoprotein K homology (KH) domains and one carboxy-terminal RING finger module. The hMex-3 are phosphoproteins that bind RNA through their KH domains and shuttle between the nucleus and the cytoplasm via the CRM1-dependent export pathway. Our analysis further revealed that hMex-3A and hMex-3B, but not hMex-3C, colocalize with both the hDcp1a decapping factor and Argonaute (Ago) proteins in processing bodies (P bodies), recently characterized as centers of mRNA turnover. Taken together, these findings indicate that hMex-3 proteins constitute a novel family of evolutionarily conserved RNA-binding proteins, differentially recruited to P bodies and potentially involved in post-transcriptional regulatory mechanisms

Integrative analysis of RUNX1 downstream pathways and target genes

Background: The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. Results: Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBF[Beta], and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBF[Beta]. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. Conclusion: This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both familial and sporadic leukemia as well as therapeutic implications

L’émergence du patient-acteur dans la sécurité des soins en France : une revue narrative de la littérature entre sciences sociales et santé publique

International audienc

Evaluation of an interactive program for preventing adverse drug events in primary care: study protocol of the InPAct cluster randomised stepped wedge trial

BACKGROUND: Adverse drug events could often be prevented. One of their main causes is that patients rarely know how to detect them. Another cause is inadequate communication between patients and physicians. If patients were to be effectively trained in detecting and reporting adverse drug events, this should help to prevent their occurrence and subsequent complications. Our purpose is to present the protocol of the InPAct trial, which aims to evaluate an interactive program that encourages patients to report adverse drug events in primary care. METHODS/DESIGN: We will conduct a cluster randomised controlled stepped wedge trial, with eight clusters of 10 general practitioners each. The physicians will suggest to all of their antihypertensive-treated patients that they take part in this study. The InPAct program will be implemented in the clusters in random order along five successive three-month periods. Two new clusters will be trained in implementing the program at each step. The program features: an interactive patient booklet including informative paragraphs, several care plans and adverse drug event report forms; and standardised training of physicians in how to present the booklet to the patient. The primary outcome will be the reporting of adverse drug events by patients to their physician within three months. We assume that the number of patients reporting at least one adverse drug event will increase from 3% before program implementation to 7.5% afterward (coefficient of variation = 0.5, α = 0.05, β = 0.2), which means that 1,200 patients must be included. The effect of the intervention on the main outcome will be quantified and tested using a mixed logistic model to integrate cluster and time effects. DISCUSSION: Our choice of a stepped wedge design is particularly appropriate for evaluating the implementation of a patient safety program within the constraints of general practice. We describe the InPAct intervention, which is an original program that is intended to improve communication between patients and physicians. Indeed, none of the previously published intervention studies has combined a patient education program and a patient reporting system for adverse drug events with the aim of improving patient safety in primary care. TRIAL REGISTRATION: This study is registered in ClinicalTrials.gov NCT01610817