Members of the armadillo (arm) repeat family of proteins are implicated in tumorigenesis, embryonic development, and maintenance of tissue integrity. We have cloned cDNA for a novel human arm repeat protein, ALEX1, encoding 453 amino acids. ALEX1 shares significant homology with uncharacterized ORF KIAA0512 and putative protein product of unknown mRNA (GenBank AF211175), designated here as ALEX2 and ALEX3, respectively. The genes encoding ALEX1, ALEX2 and ALEX3 co-localize to the same region in Xq21.33-q22.2. ALEX1 and ALEX2 transcripts are found in all human tissues examined except peripheral blood leukocytes. Expression of ALEX1 and ALEX2 mRNA is lost or significantly reduced in human lung, prostate, colon, pancreas, and ovarian carcinomas and also in cell lines established from different human carcinomas. These genes are, however, normally expressed in cell lines derived from other types of tumors, e.g., sarcomas, neuroblastomas, and gliomas. We speculate that ALEX genes may play a role in suppression of tumors originating hom epithelial tissue,i.e., carcinomas.