MCV Truncated Large T antigen interacts with BRD4 in tumors.

Among Polyomaviridae family of viruses, Merkel Cell Polyomavirus (MCV) is the only human polyomavirus with convincing data supporting its classification as a direct causative agent of a human skin malignancy, Merkel Cell Carcinoma. Oncogenic transformation by MCV requires the integration of the viral genome into the human genome, truncation of the large T antigen (LT) to render the viral genome replication deficient and expression of small T antigen oncoprotein. The chromatin binding protein BRD4, was recently shown to transcriptionally regulate the expression of virus oncoproteins, thereby enhancing the tumorigenesis of virus-associated cancers, such as HPV associated cervical cancer. Previous work by Wang et al. revealed that BRD4 interacts with MCV full length LT during viral replication. In this study, we demonstrated that MCV truncated tumor LT antigen also interacts with BRD4 protein. We showed that the MCV tumor LT antigen and BRD4 protein complex co-localizes within the nucleus. Furthermore, we tested whether BRD4 protein transcriptionally regulates MCV Non Coding Control Region (NCCR), where we found that though full length LT and sT together, along with the BRD4 protein showed enhanced transcriptional activity whereas tumor truncated LT did not. These findings on the interactions of the MCV tumor truncated LT antigen with the BRD4 protein add to existing knowledge about interactions with LT and its role in tumorigenesis, and assist in efforts to more precisely define new therapy targets for this disease

Impact of Deleterious Mutations on Structure, Function and Stability of Serum/Glucocorticoid Regulated Kinase 1: A Gene to Diseases Correlation.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a Ser/Thr protein kinase involved in regulating cell survival, growth, proliferation, and migration. Its elevated expression and dysfunction are reported in breast, prostate, hepatocellular, lung adenoma, and renal carcinomas. We have analyzed the SGK1 mutations to explore their impact at the sequence and structure level by utilizing state-of-the-art computational approaches. Several pathogenic and destabilizing mutations were identified based on their impact on SGK1 and analyzed in detail. Three amino acid substitutions, K127M, T256A, and Y298A, in the kinase domain of SGK1 were identified and incorporated structurally into original coordinates of SGK1 to explore their time evolution impact using all-atom molecular dynamic (MD) simulations for 200 ns. MD results indicate substantial conformational alterations in SGK1, thus its functional loss, particularly upon T256A mutation. This study provides meaningful insights into SGK1 dysfunction upon mutation, leading to disease progression, including cancer, and neurodegeneration

Animal models of COPD: What do they tell us?

© 2016 Asian Pacific Society of Respirology COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progression of COPD are incompletely understood. Animal models of disease provide a valuable, ethically and economically viable experimental platform to examine these mechanisms and identify biomarkers that may be therapeutic targets that would facilitate the development of improved standard of care. Here, we review the different established animal models of COPD and the various aspects of disease pathophysiology that have been successfully recapitulated in these models including chronic lung inflammation, airway remodelling, emphysema and impaired lung function. Furthermore, some of the mechanistic features, and thus biomarkers and therapeutic targets of COPD identified in animal models are outlined. Some of the existing therapies that suppress some disease symptoms that were identified in animal models and are progressing towards therapeutic development have been outlined. Further studies of representative animal models of human COPD have the strong potential to identify new and effective therapeutic approaches for COPD

Aim2 suppresses cigarette smoke-induced neutrophil recruitment, neutrophil caspase-1 activation and anti-Ly6G-mediated neutrophil depletion.

The accepted version of the above article was posted prematurely on 17 February 2022, owing to a technical error. The corrected version will be made fully available at a later date