20 research outputs found
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
The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with MHC-I mRNA degradation
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’expérience patient en chirurgie : du travail du patient à la sécurité des soins
International audienc
Strategies used by emergency care professionals to handle interpersonal difficulties with patients: a qualitative study
Objectives Identify the strategies implemented by emergency care professionals when facing tension and interpersonal violence from patients and their friends and family.Design Descriptive qualitative study based on 38 semidirective interviews.Participants Doctors, nurses, nursing assistants and administrative staff.Setting Four emergency departments (EDs) from three French university hospitals.Results According to the medical professionals interviewed, the difficulties that they encounter with patients or their accompanying family members can be explained by a lack of understanding of the functioning of EDs, by a general increase in individualistic behaviours leading to a lack of civility or by deviant behaviours (related to toxic substance abuse or mental illness). While managing deviant behaviours may sometimes require a collective intervention, ED staff also implement what are essentially individual communication strategies (with the use of rational explanation, seduction and empathy), confrontation or flight to deal with interpersonal difficulties.Conclusions Strategies used by staff members tend to be individualised for the most part, and some, such as confrontational or escape strategies, may not be adapted to all situations. In the face of difficulties between staff and patients, mediators, specialised in resolving conflict, could entrust some cases to professionals.Trial registration number ClinicalTrials.gov Registry (NCT03139110)
Interaction with 14-3-3 Adaptors Regulates the Sorting of hMex-3B RNA-binding Protein to Distinct Classes of RNA Granules
International audienc
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