Tumor-associated antigens on the cell surface serve as potential targets for the host's immune system and may be important in establishing or maintaining malignant phenotype of the tumor cell. The long-term objective of this research is to understand the genetic mechanisms by which the tumor cell regulates expression of its cell-surface antigens. To accomplish this, we will study several normal and tumor-associated antigens of murine lymphomas to define and understand the mechanism of action of the genes critical in the regulation of their expression on the cell surface. The general approach is to isolate somatic cell mutants showing abnormal cell surface expression of particular cell surface molecules and characterizing the defects in molecular terms. The Thy-1 and T200 glycoproteins are being characterized in detail. Eight complementation classes of Thy-1-mutants have been isolated; one, defining a critical post-translational step in Thy-1 glycoprotein biosynthesis, has been characterized in detail. A second has been shown to represent mutants in the Thy-1 structural gene, and several mutants have been analyzed at the nucleic acid level. A third class has properties expected of a regulatory mutation and is being studied at the nucleic acid level. This mutant class acts in a transdominant manner to extinguish Thy-1 glycoprotein expression and mRNA in somatic cell hybrids to wild-type Thy-1+lymphomas. A series of T200-mutants has also been isolated and T200+revertants of them have been obtained. These mutants and revertants are being studied at the protein and nucleic acid levels. Finally, hybrids between Thy-1+and Thy-1-cell lines are being studied to identify genes which may regulate antigen expression during differentiation. Several gene dosage-dependent regulatory circuits have been identified. Studies are being carried out to determine whether regulation acts at the level of gene transcription. (AG)