| 1. |
|
|
| 2. |
- Fell, SM, et al.
(författare)
-
Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA
- 2017
-
Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 31:10, s. 1036-1053
-
Tidskriftsartikel (refereegranskat)abstract
- We recently identified pathogenic KIF1Bβ mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted KIF1Bβ in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bβ is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA. Moreover, pathogenic KIF1Bβ mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both KIF1Bβ-deficient mouse neuroblasts and human neuroblastomas that lack KIF1Bβ. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1Bβ independent of MYCN amplification and the loss of genes neighboring KIF1B on chromosome 1p36. Thus, defective precursor cell differentiation, a common trait of aggressive childhood malignancies, is a pathogenic effect of KIF1Bβ loss in neuroblastomas. Furthermore, neuropathy-associated KIF1Bβ mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration.
|
|
| 3. |
|
|
| 4. |
- Li, S. J., et al.
(författare)
-
The 1p36 Tumor Suppressor KIF 1B beta Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis
- 2016
-
Ingår i: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 36:2, s. 164-178
-
Tidskriftsartikel (refereegranskat)abstract
- KIF1B beta is a candidate 1p36 tumor suppressor that regulates apoptosis in the developing sympathetic nervous system. We found that KIF1B beta activates the Ca2+-dependent phosphatase calcineurin (CN) by stabilizing the CN-calmodulin complex, relieving enzymatic autoinhibition and enabling CN substrate recognition. CN is the key mediator of cellular responses to Ca2+ signals and its deregulation is implicated in cancer, cardiac, neurodegenerative, and immune disease. We show that KIF1B beta affects mitochondria! dynamics through CN-dependent dephosphorylation of Dynamin-related protein 1 (DRP1), causing mitochondria! fission and apoptosis. Furthermore, KIF1B beta actuates recognition of all known CN substrates, implying a general mechanism for KIF1B beta in Ca2+ signaling and how Ca2+-dependent signaling is executed by CN. Pathogenic KIF1B beta mutations previously identified in neuroblastomas and pheochromocytomas all fail to activate CN or stimulate DRP1 dephosphorylation. Importantly, KIF1B beta and DRP1 are silenced in 1p36 hemizygous-deleted neuroblastomas, indicating that deregulation of calcineurin and mitochondria! dynamics contributes to high-risk and poor-prognosis neuroblastoma.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Westerlund, I, et al.
(författare)
-
Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression
- 2017
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 114:30, s. E6137-E6146
-
Tidskriftsartikel (refereegranskat)abstract
- High-risk neuroblastoma remains a therapeutic challenge, and adjuvant retinoic acid (RA) treatment shows poor efficacy. We demonstrate that combined treatment with 5-Aza-deoxycytidine (AZA) and RA impedes neuroblastoma growth and induces a transcriptional response characterized by high levels of the HIF2α transcription factor. This approach targets high-risk neuroblastoma that responds poorly to RA. In addition, genome-wide analysis of treated tumors and patient data links HIF2α to tumor suppression, which is supported by a HIF2α-specific small molecule inhibitor-mediated block of the tumor response to AZA+RA treatment.
|
|
| 10. |
|
|
