Tissue-Specific Target Analysis of Disease-Associated MicroRNAs in Human Signaling Pathways

MicroRNAs are a large class of post-transcriptional regulators that bind to the 3′ untranslated region of messenger RNAs. They play a critical role in many cellular processes and have been linked to the control of signal transduction pathways. Recent studies indicate that microRNAs can function as tumor suppressors or even as oncogenes when aberrantly expressed. For more general insights of disease-associated microRNAs, we analyzed their impact on human signaling pathways from two perspectives. On a global scale, we found a core set of signaling pathways with enriched tissue-specific microRNA targets across diseases. The function of these pathways reflects the affinity of microRNAs to regulate cellular processes associated with apoptosis, proliferation or development. Comparing cancer and non-cancer related microRNAs, we found no significant differences between both groups. To unveil the interaction and regulation of microRNAs on signaling pathways locally, we analyzed the cellular location and process type of disease-associated microRNA targets and proteins. While disease-associated proteins are highly enriched in extracellular components of the pathway, microRNA targets are preferentially located in the nucleus. Moreover, targets of disease-associated microRNAs preferentially exhibit an inhibitory effect within the pathways in contrast to disease proteins. Our analysis provides systematic insights into the interaction of disease-associated microRNAs and signaling pathways and uncovers differences in cellular locations and process types of microRNA targets and disease-associated proteins

Islet Endothelial Activation and Oxidative Stress Gene Expression Is Reduced by IL-1Ra Treatment in the Type 2 Diabetic GK Rat

Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra)

Truncated isoforms of BRCA1-associated protein BARD1 are expressed in NSCLC and are potential targets for treatment

Mutations in the BRCA1 gene predispose carriers to breast and ovarian cancer, but are also associated with sporadic cancers of other organs. BRCA1, as heterodimer with its protein binding partner BARD1, has tumor suppressor functions in DNA repair and cell cycle control, due to the ubiquitin ligase activity of the BRCA1-BARD1 complex. While formation of the BRCA1-BARD1 heterodimer depends on the N-terminal RING fingers of both proteins, the C-terminus of the BARD1 has also a function in mitosis. Interestingly, cancer cells express BARD1 isoforms that lack the RING finger and repress full length (FL) BARD1. SiRNA depletion of isoforms in cancer cells deficient of FL BARD1 leads to growth arrest in vitro. Furthermore, an N-terminally truncated isoform, but not FL BARD1, can bind to the mitotic kinase Aurora B, which is often upregulated in cancer. We investigated the role of BARD1 isoforms in NSCLC. Immunohistochemistry and RT-PCR, performed on biopsies, showed loss of BARD1 N-terminal epitopes and exons, respectively. Since the C-terminus of BARD1 is involved in pro-proliferative functions through binding to Aurora B, we investigated whether expression of BARD1 isoforms was correlated with Aurora B expression in NSCLC. Co-expression of Aurora B and BARD1 isoforms was found in bronchoalveolar carcinoma. Our data demonstrate that truncated BARD1 isoforms that are deficient of BRCA1-linked tumor suppressor functions are expressed in NSCLC. Since BARD1 isoforms can interact with Aurora B in vitro, the co-expression of truncated BARD1 and Aurora B in NSCLC suggests that they act in a common oncogenic pathway