The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor.
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.
Schlisio
Susanne
S
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kenchappa
Rajappa S
RS
Vredeveld
Liesbeth C W
LC
George
Rani E
RE
Stewart
Rodney
R
Greulich
Heidi
H
Shahriari
Kristina
K
Nguyen
Nguyen V
NV
Pigny
Pascal
P
Dahia
Patricia L
PL
Pomeroy
Scott L
SL
Maris
John M
JM
Look
A Thomas
AT
Meyerson
Matthew
M
Peeper
Daniel S
DS
Carter
Bruce D
BD
Kaelin
William G
WG
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002478:Cells, Cultured; D002648:Child; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000235:genetics / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase; D034622:RNA Interference; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; C490398:Kif1b protein, mouse; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D016547:Kinesins