Mutations in the β-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain

Inactivation of both alleles of the fruit fly D. melanogaster brain tumor (brat) gene results in the production of a tumor-like neoplasm in the larval brain, and lethality in the Larval third instar and pupal stages. We cloned the brat gene from a transposon-tagged allele and identified its gene product. hr nt encodes for an 1037 amino acid protein with an N-terminal B-box1 zinc finger followed ba a B-box2 zinc finger, a coiled-coil domain, and a C-terminal beta-propeller domain with six blades. All these motifs are known to mediate protein-protein interactions. Sequence analysis of four br at alleles revealed that all of them are mutated at the beta-propeller domain. The clustering of mutations in this domain strongly suggests that it has a crucial role in the normal function of Brat, and defines a novel protein motif involved in tumor suppression activity. The brat gene is expressed in the embryonic central and peripheral nervous systems including the embryonic brain. In third instar larva br nt expression was detected in the Larval central nervous sa stem including the brain and the ventral ganglion, in two glands - the ring gland and the salivary gland, and in parts of the foregut - the gastric caecae and the proventriculus. A second brat-like gene was found in D, melanogaster, and homologs were identified in the nematode, mouse, rat, and human. Accumulated data suggests that Brat may regulate proliferation and differentiation by secretion/transport mediated processes.