PENDULIN, A DROSOPHILA PROTEIN WITH CELL CYCLE-DEPENDENT NUCLEAR-LOCALIZATION, IS REQUIRED FOR NORMAL-CELL PROLIFERATION

We describe the dynamic intracellular localization of Drosophila Pendu lin and its role in the control of cell proliferation. Pendulin is a n ew member of a superfamily of proteins which contains Armadillo (Arm) repeats and displays extensive sequence similarities with the Srp1 pro tein from yeast, with RAG-1 interacting proteins from humans, and with the importin protein from Xenopus. Almost the entire polypeptide chai n of Pendulin is composed of degenerate tandem repeats of similar to 4 2 amino acids each. A short NH2-terminal domain contains adjacent cons ensus sequences for nuclear localization and cdc2 kinase phosphorylati on. The subcellular distribution of Pendulin is dependent on the phase of cell cycle. During interphase, Pendulin protein is exclusively fou nd in the cytoplasm of embryonic cells. At the transition between G2 a nd M-phase, Pendulin rapidly translocates into the nuclei where it is distributed throughout the nucleoplasm and the areas around the chromo somes. In the larval CNS, Pendulin is predominantly expressed in the d ividing neuroblasts, where it undergoes the same cell cycle-dependent redistribution as in embryos. Pendulin is encoded by the oho31 locus a nd is expressed both maternally and zygotically. We describe the pheno types of recessive lethal mutations in the oho31 gene that result in a massive decrease or loss of zygotic Pendulin expression. Hematopoieti c cells of mutant larvae overproliferate and form melanotic tumors, su ggesting that Pendulin normally acts as a blood cell tumor suppressor. In contrast, growth and proliferation in imaginal tissues are reduced and irregular, resulting in abnormal development of imaginal discs an d the CNS of the larvae. This phenotype shows that Pendulin is require d for normal growth regulation. Based on the structure of the protein, we propose that Pendulin may serve as an adaptor molecule to form com plexes with other proteins. The sequence similarity with importin indi cates that Pendulin may play a role in the nuclear import of karyophil ic proteins and some of these may be required for the normal transmiss ion and function of proliferative signals in the cells.