Rationale: The intercalated disc (ID) is a highly specialized cell-cell contact structure that ensures mechanical and electric coupling of contracting cardiomyocytes. Recently, the ID has been recognized to be a hot spot of cardiac disease, in particular inherited cardiomyopathy. Objective: Given its complex structure and function we hypothesized that important molecular constituents of the ID still remain unknown. Methods and Results: Using a bioinformatics screen, we discovered and cloned a previously uncharacterized 54 kDa cardiac protein which we termed Myozap (Myocardium-enriched zonula occludens-1-associated protein). Myozap is strongly expressed in the heart and lung. In cardiac tissue it localized to the ID and directly binds to desmoplakin and zonula occludens- Key Words: myocytes Ⅲ cardiac Ⅲ cardiomyopathies Ⅲ serum response factor A unique morphological feature of cardiac muscle is the intercalated disc (ID), a highly specialized cell-cell contact structure that connects individual cardiomyocytes. Several independent substructures of the ID have been distinguished, including (1) desmosomes, which link the intermediate filament apparatus of the cell, (2) fasciae adhaerentes, to which the actomyosin filament bundles are attached, and (3) gap junctions, which allow free movement of ions and small molecules between adjacent cardiomyocytes. Together, these structures form a network of proteins which ensure mechanical and electric coupling of contracting cardiomyocytes ("functional syncytium") (reviewed elsewhere 1 ). Recently, immunoelectron microscopy and biochemical studies have revealed that major constituents of the desmosomes such as desmoplakin, plakophilin-2 and the cadherins can also be detected in adherens junctions. 2 Correspondingly, typical components of adherens and gap junctions were found to colocalize with desmosomal molecules. 3 Thus, it has been proposed that in the heart these specialized cell-cell contact structures are merged in an "area composita." 2,4 Given the critical importance of the intercalated disc for cardiac integrity and function, it is perhaps not surprising that the ID has become a hot spot of inherited cardiac disease. In particular, arrhythmogenic right ventricular cardiomyopathy (ARVC), has been coined a "desmosome cardiomyopathy," 5 Original received May 26, 2009; resubmission received November 15, 2009; revised resubmission received December 30, 2009; accepted January 11, 2010. From the Department of Internal Medicine III (T.S.S., D.F., C.R., R.W., S.J., W. MethodsExperimental procedures for cloning and the subsequent bioinformatics, Northern blot analysis and radioactive in situ hybridization, the generation of a Myozap-specific antiserum and western blot analyses, immunofluorescence and immunoelectron microscopy, yeast 2-hybrid assays, tissue culture, immunoprecipitations, reporter gene assays as well as zebrafish injection procedures, and fractional shortening measurement are provided in the expanded Methods section in the Online Data Supplement, avail...
Mice expressing a transgene encoding the transcription factor NF-E2 in hematopoietic cells exhibit features of myeloproliferative neoplasms, including thrombocytosis, Epo-independent colony formation, stem and progenitor cell overabundance, leukocytosis, and progression to acute myeloid leukemia.
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