KIF1Bβ Functions as a Haploinsufficient Tumor Suppressor Gene Mapped to Chromosome 1p36.2 by Inducing Apoptotic Cell DeathS

Deletion of the distal region of chromosome 1 frequently occurs in a variety of human cancers, including aggressive neuroblastoma. Previously, we have identified a 500-kb homozygously deleted region at chromosome 1p36.2 harboring at least six genes in a neuroblastoma-derived cell line NB1/C201. Among them, only KIF1B β, a member of the kinesin superfamily proteins, induced apoptotic cell death. These results prompted us to address whether KIF1B β could be a tumor suppressor gene mapped to chromosome 1p36 in neuroblastoma. Hemizygous deletion of KIF1B β in primary neuroblastomas was significantly correlated with advanced stages ( p = 0.0013) and MYCN amplification ( p < 0.001), whereas the mutation rate of the KIF1B β gene was infrequent. Although KIF1B β allelic loss was significantly associated with a decrease in KIF1B β mRNA levels, its promoter region was not hypermethylated. Additionally, expression of KIF1B β was markedly down-regulated in advanced stages of tumors ( p < 0.001). Enforced expression of KIF1B β resulted in an induction of apoptotic cell death in association with an increase in the number of cells entered into the G 2 /M phase of the cell cycle, whereas its knockdown by either short interfering RNA or by a genetic suppressor element led to an accelerated cell proliferation or enhanced tumor formation in nude mice, respectively. Furthermore, we demonstrated that the rod region unique to KIF1B β is critical for the induction of apoptotic cell death in a p53-independent manner. Thus, KIF1B β may act as a haploinsufficient tumor suppressor, and its allelic loss may be involved in the pathogenesis of neuroblastoma and other cancers.