14-3-3ζ Interacts with Stat3 and Regulates Its Constitutive Activation in Multiple Myeloma Cells

The 14-3-3 proteins are a family of regulatory signaling molecules that interact with other proteins in a phosphorylation-dependent manner and function as adapter or scaffold proteins in signal transduction pathways. One family member, 14-3-3ζ, is believed to function in cell signaling, cycle control, and apoptotic death. A systematic proteomic analysis done in our laboratory has identified signal transducers and activators of transcription 3 (Stat3) as a novel 14-3-3ζ interacting protein. Following our initial finding, in this study, we provide evidence that 14-3-3ζ interacts physically with Stat3. We further demonstrate that phosphorylation of Stat3 at Ser727 is vital for 14-3-3ζ interaction and mutation of Ser727 to Alanine abolished 14-3-3ζ/Stat3 association. Inhibition of 14-3-3ζ protein expression in U266 cells inhibited Stat3 Ser727 phosphorylation and nuclear translocation, and decreased both Stat3 DNA binding and transcriptional activity. Moreover, 14-3-3ζ is involved in the regulation of protein kinase C (PKC) activity and 14-3-3ζ binding to Stat3 protects Ser727 dephosphorylation from protein phosphatase 2A (PP2A). Taken together, our findings support the model that multiple signaling events impinge on Stat3 and that 14-3-3ζ serves as an essential coordinator for different pathways to regulate Stat3 activation and function in MM cells

Cell Cycle Phase Regulates Glucocorticoid Receptor Function

The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1). Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G1. This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase

Prenatal exposures and exposomics of asthma

This review examines the causal investigation of preclinical development of childhood asthma using exposomic tools. We examine the current state of knowledge regarding early-life exposure to non-biogenic indoor air pollution and the developmental modulation of the immune system. We examine how metabolomics technologies could aid not only in the biomarker identification of a particular asthma phenotype, but also the mechanisms underlying the immunopathologic process. Within such a framework, we propose alternate components of exposomic investigation of asthma in which, the exposome represents a reiterative investigative process of targeted biomarker identification, validation through computational systems biology and physical sampling of environmental medi

Factors associated with suicide ideation among medically and surgically hospitalized patients

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Objective: To identify the factors associated with suicide ideation among medically and surgically hospitalized patients. Methods: A consecutive sample of 4328 individuals admitted to a general hospital completed a screening questionnaire comprised of demographic and clinical information, the Mini International Neuropsychiatric Interview item on current suicide ideation, the Hospital Anxiety and Depression Scale subscale for depression and the Alcohol use Disorder Identification Test. A multiple logistic regression produced a discriminate profile of individuals with suicide ideation. Results: The prevalence rate for current suicide ideation was 4.9% (95% Cl: 4.3-5.6). Patients admitted to the Infectious Disease, Oncology and Hematology units presented higher rates of suicide ideation (7.9%, 7.8% and 7.2%, respectively). Suicidal ideation was associated to depression [odds ratio (OR)=8.3], young age (18-35 years old: OR=2.5), alcohol use disorders (OR=2.3), and smoking (OR=1.8). Conclusion: Suicidal ideation was consistently associated with indicators of mental disorders. It is proxy, not for completed suicide, but for a variety of common psychiatric conditions that can and should be dealt with in the medical/surgical setting. (C) 2010 Published by Elsevier Inc.324396400Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [06/61885-6