We describe the dynamic intracellular localization of Drosophila
Pendulin and its role in the control of cell proliferation.
Pendulin is a new member of a superfamily of
proteins which contains Armadillo (Arm) repeats and displays extensive sequence similarities with the Srp1
protein from yeast, with RAG-1 interacting
proteins from humans, and with the
importin protein from Xenopus. Almost the entire
polypeptide chain of
Pendulin is composed of degenerate tandem repeats of approximately 42
amino acids each. A short NH2-terminal domain contains adjacent consensus sequences for nuclear localization and cdc2
kinase phosphorylation. The subcellular distribution of
Pendulin is dependent on the phase of cell cycle. During interphase,
Pendulin protein is exclusively found in the cytoplasm of embryonic cells. At the transition between G2 and M-phase,
Pendulin rapidly translocates into the nuclei where it is distributed throughout the nucleoplasm and the areas around the chromosomes. In the larval CNS,
Pendulin is predominantly expressed in the dividing neuroblasts, where it undergoes the same cell cycle-dependent redistribution as in embryos.
Pendulin is encoded by the oho31 locus and is expressed both maternally and zygotically. We describe the phenotypes of recessive lethal mutations in the oho31 gene that result in a massive decrease or loss of zygotic
Pendulin expression. Hematopoietic cells of mutant larvae overproliferate and form melanotic
tumors, suggesting 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 and the CNS of the larvae. This phenotype shows that
Pendulin is required for normal growth regulation. Based on the structure of the
protein, we propose that
Pendulin may serve as an adaptor molecule to form complexes with other
proteins. The sequence similarity with
importin indicates that
Pendulin may play a role in the nuclear import of karyophilic
proteins and some of these may be required for the normal transmission and function of proliferative signals in the cells.