An orchestrated interplay of adaptor and signaling proteins at mechano-sensitive sites is essential to maintain cardiac contractility and when defective leads to heart failure. We recently showed that Integrin-linked Kinase (ILK), ß-Parvin and PINCH form the IPP-complex to grant tuned Protein Kinase B (PKB) signaling in the heart. Loss of one of the IPP-complex components results in destabilization of the whole complex, defective PKB signaling and finally heart failure. Two components of IPP, ILK and ß-Parvin directly bind to Paxillin; however, the impact of this direct interaction on the maintenance of heart function is not known yet. Here, we show that targeted gene inactivation of Paxillin results in progressive decrease of cardiac contractility and heart failure in zebrafish without affecting IPP-complex stability and PKB phosphorylation. However, we found that Paxillin deficiency leads to the destabilization of its known binding partner Focal Adhesion Kinase (FAK) and vice versa resulting in degradation of Vinculin and thereby heart failure. Our findings highlight an essential role of Paxillin and FAK in controlling cardiac contractility via the recruitment of Vinculin to mechano-sensitive sites in cardiomyocytes.

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Summary: Gene therapeutic approaches to cure genetic diseases require tools to express the rescuing gene exclusively within the affected tissues. Viruses are often chosen as gene transfer vehicles but they have limited capacity for genetic information to be carried and transduced. In addition, to avoid off‐target effects the therapeutic gene should be driven by a tissue‐specific promoter in order to ensure expression in the target organs, tissues, or cell populations. The larger the promoter, the less space will be left for the respective gene. Thus, there is a need for small but tissue‐specific promoters. Here, we describe a compact unc45b promoter fragment of 195 bp that retains the ability to drive gene expression exclusively in skeletal and cardiac muscle in zebrafish and mouse. Remarkably, the described unc45b promoter fragment not only drives muscle‐specific expression but presents heat‐shock inducibility, allowing a temporal and spatial quantity control of (trans)gene expression. Here, we demonstrate that the transgenic expression of the smyd1b gene driven by the unc45b promoter fragment is able to rescue the embryonically lethal heart and skeletal muscle defects in smyd1b‐deficient flatline mutant zebrafish. Our findings demonstrate that the described muscle‐specific unc45b promoter fragment might be a valuable tool for the development of genetic therapies in patients suffering from myopathies. genesis 54:431–438, 2016. © 2016 The Authors. Genesis Published by Wiley Periodicals, Inc.

Cancers arising from the large intestine or rectum are called colorectal cancer (CRC) and represent the fourth leading cause of cancer-related death worldwide. Since casein kinase 1 (CK1) isoforms are involved in many cellular processes and have been reported to be deregulated in various tumor entities, CK1 has become an interesting drug target. In this study, we examined the potential of CK1δ expression levels in tumor tissue of CRC patients as a prognostic biomarker. We show by quantitative RNA expression analyses that decreased CK1δ expression levels in tumor tissue predict prolonged survival rates. Random sampling of CK1δ stained tumor tissue indicates that CK1δ gene expression corresponds with CK1δ protein expression. Especially in low grade (grade 1, grade 2) and in UICC II/III classified tumors decreased CK1δ RNA levels correlate with significantly improved survival rates when the tumor was located in the right colon. We furthermore found gender-specific differences within these subgroups, revealing most significant increase in overall survival rates in male patients with tumors in right colon expressing low levels of CK1δ RNA. Results become even clearer, when only male patients over 50 years were considered. Together, these findings support the assumption that CK1δ might be a prognostic biomarker for CRC thereby providing an interesting drug target for the development of new therapy concepts.