Metastasis, the spread of tumors in the body is a pathophysiological process of profound importance in Cancer research, because much of the lethality from malignant neoplasrns is attributed directly to their ability to develop metastases in distant organs. Recognition and cell-cell interaction between tumor and normal host cells, lead to the formation of multi-cell emboli in the circulation a process directly related to the development of metastases. The role of the carbohydrate-binding protein galecUn- 3 in this process is now established. Galectin-3 [a.k.a. CBP-35, Mac-2, RL-29, L-29, hL-31, mL-34 and LBL) is a member of the newly designated gene family i.e., gal.Ctin, composed of at least eight members. Galectin-3 is a chimenc gene product with monomer subunit of 30,000 daltons, composed of three distinct structural motifs, a short NH2- origin preceding an amino half- domain containing Gly-X-Y tandem repeats characteristic of collagens and a caIboxy-terminal half which encompasses the N- acetyllactosamine (GalI3-4GlcNac)-binding site. Galectin-3 is an unusual protein. In that it is localized and function in different cell linages in the cytoplasm, cell membrane nucleus and the extracellular milieu and undergoes for function a non-ovalent homodimerization. Galectin-3 has distinct functions and recognition sites involving different cell lineages at different developmental and pathological stages including cell growth, apoptosis- resistance, adhesion, differentiation, inflammation, transformation, invasion and metastasis. However, direct evidence in support of a particular function(s) proposed for galectin-3 are only now emerging through the identification of its interacting ligands and structural motifs. Based on the progress and the findings obtained during the current funding period, we will continue to investigate, in order to understand in more detail, the structural4unctional relationship of galectin-3 as it relates to cellular localization, cell growth, apoptosis-resistance, cell-cell recognition, adhesion and hematogenous spread of tumor cells. To this end we propose the following: i) To study the expression, cellulardistribub.on and structural-functional relationship of recombinant wild type and mutants (point and deletion) of galectin-3, and elucidate the 3-D structure by X-ray crystallography. 2) To identify-the cell surface receptor-ligand of galectin-3. 3) To determine the functional role of galectin-3 in apoptosis. 4) To establish the significance of the degradation of galectin-3 by matrix metalloproteinases for invasion and metastasis. It is expected that the results to be obtained from this study will provide a better understanding of galectin-3 and its interacting ligands in tumor progression and metastasis, and will further to the developments of specific reagents for the detection and interventions in these processes.
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