The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor.

Schlisio S, Kenchappa RS, Vredeveld LC, George RE, Stewart R, Greulich H, Shahriari K, Nguyen NV, Pigny P, Dahia PL, Pomeroy SL, Maris JM, Look AT, Meyerson M, Peeper DS, Carter BD, Kaelin WG
Genes Dev. 2008 22 (7): 884-93

PMID: 18334619 · PMCID: PMC2279200 · DOI:10.1101/gad.1648608

VHL, NF-1, c-Ret, and Succinate Dehydrogenase Subunits B and D act on a developmental apoptotic pathway that is activated when nerve growth factor (NGF) becomes limiting for neuronal progenitor cells and requires the EglN3 prolyl hydroxylase as a downstream effector. Germline mutations of these genes cause familial pheochromocytoma and other neural crest-derived tumors. Using an unbiased shRNA screen we found that the kinesin KIF1Bbeta acts downstream from EglN3 and is both necessary and sufficient for neuronal apoptosis when NGF becomes limiting. KIF1Bbeta maps to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors including neuroblastomas. We identified inherited loss-of-function KIF1Bbeta missense mutations in neuroblastomas and pheochromocytomas and an acquired loss-of-function mutation in a medulloblastoma, arguing that KIF1Bbeta is a pathogenic target of these deletions.

MeSH Terms (28)

Animals Animals, Newborn Apoptosis Cells, Cultured Child Chromosome Mapping Chromosomes, Mammalian DNA-Binding Proteins HeLa Cells Humans Hypoxia-Inducible Factor-Proline Dioxygenases Immediate-Early Proteins Immunoblotting Kinesin Medulloblastoma Mice Mice, Knockout Models, Biological Mutation, Missense Nerve Tissue Proteins Neuroblastoma Neurons PC12 Cells Pheochromocytoma Procollagen-Proline Dioxygenase Rats RNA Interference Tumor Suppressor Proteins

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