DROSOPHILA LETHAL(2)GIANT LARVAE TUMOR-SUPPRESSOR PROTEIN IS A COMPONENT OF THE CYTOSKELETON

Tumor suppressor genes act as recessive determinants of cancer. In Dro sophila these genes play a role in normal development and are essentia l for regulating cell growth and differentiation. Mutations in the gen e, lethal(2)giant larvae, l(2)gl, besides causing malignant tumors in the brain and imaginal discs, generate developmental defects in a numb er of other tissues. Much of the uncertainty regarding the function of the l(2)gl gene product, p127, results from a lack of knowledge as to the precise location of this protein in the cell. We have investigate d the cellular and subcellular localization of p127, using confocal an d electron microscopy as well as biochemical and cell fractionation pr ocedures. Our analyses indicate that p127 is located entirely within t he cell in both the cytoplasm and bound to the inner face of lateral c ell membranes in regions of cell junctions. On the membrane, p127 can form large aggregates which are resistant to solubilization by nonioni c detergents, indicating that p127 is participating in a cytoskeletal matrix. These findings suggest that the changes in cell shape and the loss of apical-basal polarity observed in tumorous tissues are a direc t result of alterations in the cytoskeleton organization caused by l(2 )gl inactivation and also suggest that p127 is involved in a cytoskele tal-based intercellular communication system directing cell differenti ation.