Abstract
Inherited KIF1B loss-of-function mutations in neuroblastomas and pheochromocytomas implicate the kinesin KIF1B as a 1p36.2 tumor suppressor. However, the mechanism of tumor suppression is unknown. We found that KIF1B isoform β (KIF1Bβ) interacts with RNA helicase A (DHX9), causing nuclear accumulation of DHX9, followed by subsequent induction of the proapoptotic XIAP-associated factor 1 (XAF1) and, consequently, apoptosis. Pheochromocytoma and neuroblastoma arise from neural crest progenitors that compete for growth factors such as nerve growth factor (NGF) during development. KIF1Bβ is required for developmental apoptosis induced by competition for NGF. We show that DHX9 is induced by and required for apoptosis stimulated by NGF deprivation. Moreover, neuroblastomas with chromosomal deletion of 1p36 exhibit loss of KIF1Bβ expression and impaired DHX9 nuclear localization, implicating the loss of DHX9 nuclear activity in neuroblastoma pathogenesis. KIF1Bβ has neuroblastoma tumor-suppressor properties and promotes and requires nuclear-localized DHX9 for its apoptotic function by activating XAF1 expression. Loss of KIF1Bβ alters subcellular localization of DHX9 and diminishes NGF dependence of sympathetic neurons, leading to reduced culling of neural progenitors, and, therefore, might predispose to tumor formation.
Highlights
During development of the peripheral nervous system, neural progenitor cells depend on and compete for growth factors, such as nerve growth factor (NGF)
KIF1B isoform β (KIF1Bβ) was previously characterized as a potential 1p36 tumor-suppressor gene that mediates neuronal apoptosis when NGF is limiting in the developing nervous system [5, 11, 12]
We identified the RNA helicase DHX9 as an interacting partner of KIF1Bβ and found that DHX9 is necessary for KIF1Bβ to induce apoptosis and is required for apoptosis when NGF is limiting
Summary
During development of the peripheral nervous system, neural progenitor cells depend on and compete for growth factors, such as nerve growth factor (NGF). Mutations affecting NGF-dependent neuronal survival have been associated with sympathetic nervous system tumors such as neuroblastoma and later-developing malignancies of neural crest origin, such as paraganglioma and pheochromocytoma [1,2,3,4,5]. Germline mutations associated with paragangliomas and pheochromocytomas (VHL, RET, NF1, and SDHB/C/D) are thought to define a pathway that is activated when NGF is limiting, leading to apoptosis mediated by the EGLN3 prolyl hydroxylase [4]. Failure to properly cull the neuronal progenitor cells during development might predispose to neoplastic transformation [2, 6].
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