NOVEL ENDOTHELIAL CELL CADHERIN LIKE MOLECULE

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Cadherins are cell surface proteins which subserve calcium-dependent cell- cell adhesion; they are responsible for many critical events in development and are modulated in important disease states including malignancy. A novel cadherin-like protein has been cloned from endothelial cells using a strategy designed to detect cDNAs containing trinucleotide repeats. The trinucleotide repeat, (CTG)5, falls within the open reading frame. Expansion of repeats such as this in other cDNAs has been implicated recently as the basis for several diseases. Overlapping endothelial cell cDNAs, corresponding to 4 kb of sequence, contain a single open reading frame with a predicted protein of 882 amino acids. Sequence analysis reveals that the protein contains 6 cadherin-like extracellular domains but it is otherwise not related to any previously identified protein. The mRNA for this protein is approximately 4.5 kb long and is expressed in a wide variety of adult human tissues. The gene for this protein has been localized to chromosome 1p12. The proposed work will study the adhesion function of this novel protein. Molecular cloning methods will be used to generate altered protein molecules in order to map the functionally important domains of this protein and to relate them to other studies on classical cadherins. Additionally, various techniques will be used to map the distribution of the protein (via Western blotting and immunohistochemistry, using antibodies to be developed) and its mRNA (via Northern blotting and in situ hybridization) in a wide variety of normal, abnormal and developing human tissues. These experiments are designed to investigate the function of this novel endothelial cell protein with probable adhesive capacity and to properly place it within the scheme of endothelial cell function in normal tissue and in disease states.