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4. Data from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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5. Supplementary Figure 6 from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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6. Supplementary Figure 4 from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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7. Supplementary Table S3 from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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8. Supplementary Figure 7 from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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9. Supplementary Methods from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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10. Supplementary Figure Legends from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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11. Supplementary Figure 3 from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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12. Supplementary Figure 1 from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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13. Supplementary Figure 5 from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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14. Supplementary Figure 2 from RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, primary, Fell, Stuart M., primary, Sobrado, Veronica R., primary, Hemmer, Marie C., primary, Ramsköld, Daniel, primary, Hellman, Ulf, primary, Sandberg, Rickard, primary, Kenchappa, Rajappa S., primary, Martinson, Tommy, primary, Johnsen, John I., primary, Kogner, Per, primary, and Schlisio, Susanne, primary

Published
2023
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15. Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA

Author

Fell, Stuart M., primary, Li, Shuijie, additional, Wallis, Karin, additional, Kock, Anna, additional, Surova, Olga, additional, Rraklli, Vilma, additional, Höfig, Carolin S., additional, Li, Wenyu, additional, Mittag, Jens, additional, Henriksson, Marie Arsenian, additional, Kenchappa, Rajappa S., additional, Holmberg, Johan, additional, Kogner, Per, additional, and Schlisio, Susanne, additional

Published
2017
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16. EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance.

Author

Shuijie Li, Rodriguez, Javier, Wenyu Li, Bullova, Petra, Fell, Stuart M., Surova, Olga, Westerlund, Isabelle, Topcic, Danijal, Bergsland, Maria, Stenman, Adam, Muhr, Jonas, Nistér, Monica, Holmberg, Johan, Juhlin, C. Christofer, Larsson, Catharina, von Kriegsheim, Alex, Kaelin Jr., William G., and Schlisio, Susanne

Subjects
MUTANT proteins, CANCER chemotherapy, PHEOCHROMOCYTOMA
Abstract

Despite the discovery of the oxygen-sensitive regulation of HIFα by the von Hippel–Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline VHL mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFα. While type 1, 2A, and 2B VHL mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα. Here, we identified an oxygen-sensitive function of VHL that is abolished by VHL type 2C mutations. We found that BIM-EL, a proapoptotic BH3-only protein, is hydroxylated by EglN3 and subsequently bound by VHL. VHL mutants fail to bind hydroxylated BIM-EL, regardless of whether they have the ability to bind hydroxylated HIFα or not. VHL binding inhibits BIM-EL phosphorylation by extracellular signal-related kinase (ERK) on serine 69. This causes BIM-EL to escape from proteasomal degradation, allowing it to enhance EglN3-induced apoptosis. BIM-EL was rapidly degraded in cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen, leading to enhanced cell survival and chemotherapy resistance. Combination therapy using ERK inhibitors, however, resensitizes VHL- and EglN3-deficient cells that are otherwise cisplatin-resistant. [ABSTRACT FROM AUTHOR]

Published
2019
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17. The 1p36 Tumor Suppressor KIF 1B beta Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis

Author

Li, Shuijie, Fell, Stuart M., Surova, Olga, Smedler, Erik, Wallis, Karin, Chen, Zhi Xiong, Hellman, Ulf, Johnsen, John Inge, Martinsson, Tommy, Kenchappa, Rajappa S., Uhlen, Per, Kogner, Per, Schlisio, Susanne, Li, Shuijie, Fell, Stuart M., Surova, Olga, Smedler, Erik, Wallis, Karin, Chen, Zhi Xiong, Hellman, Ulf, Johnsen, John Inge, Martinsson, Tommy, Kenchappa, Rajappa S., Uhlen, Per, Kogner, Per, and Schlisio, Susanne

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.

Published
2016
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18. The 1p36 Tumor Suppressor KIF 1Bβ Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis

Author

Li, Shuijie, primary, Fell, Stuart M., additional, Surova, Olga, additional, Smedler, Erik, additional, Wallis, Karin, additional, Chen, Zhi Xiong, additional, Hellman, Ulf, additional, Johnsen, John Inge, additional, Martinsson, Tommy, additional, Kenchappa, Rajappa S., additional, Uhlén, Per, additional, Kogner, Per, additional, and Schlisio, Susanne, additional

Published
2016
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19. RNA helicase A is a downstream mediator of KIF1Bβ tumor-suppressor function in neuroblastoma

Author

Chen, Zhi Xiong, Wallis, Karin, Fell, Stuart M, Sobrado, Veronica R, Hemmer, Marie C, Ramsköld, Daniel, Hellman, Ulf, Sandberg, Rickard, Kenchappa, Rajappa S, Martinson, Tommy, Johnsen, John I, Kogner, Per, Schlisio, Susanne, Chen, Zhi Xiong, Wallis, Karin, Fell, Stuart M, Sobrado, Veronica R, Hemmer, Marie C, Ramsköld, Daniel, Hellman, Ulf, Sandberg, Rickard, Kenchappa, Rajappa S, Martinson, Tommy, Johnsen, John I, Kogner, Per, and Schlisio, Susanne

Abstract

UNLABELLED: 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. SIGNIFICANCE: 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.

Published
2014
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20. RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Author

Chen, Zhi Xiong, primary, Wallis, Karin, additional, Fell, Stuart M., additional, Sobrado, Veronica R., additional, Hemmer, Marie C., additional, Ramsköld, Daniel, additional, Hellman, Ulf, additional, Sandberg, Rickard, additional, Kenchappa, Rajappa S., additional, Martinson, Tommy, additional, Johnsen, John I., additional, Kogner, Per, additional, and Schlisio, Susanne, additional

Published
2014
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21. The 2-oxoglutarate analog 3-oxoglutarate decreases normoxic hypoxia-inducible factor-1α in cancer cells, induces cell death, and reduces tumor xenograft growth

Author

Koivunen, Peppi, Fell, Stuart M, Lu, Wenyun, Rabinowitz, Joshua D, Kung, Andrew L, and Schlisio, Susanne

Subjects
cancer, EGLN, HIF, hypoxia, 3-oxoglutarate, prolyl hydroxylase
Abstract

The cellular response to hypoxia is primarily regulated by the hypoxia-inducible factors (HIFs). HIF-1α is also a major mediator of tumor physiology, and its abundance is correlated with therapeutic resistance in a broad range of cancers. Accumulation of HIF-1α under hypoxia is mainly controlled by the oxygen-sensing HIF prolyl 4-hydroxylases (EGLNs, also known as PHDs). Here, we identified a high level of normoxic HIF-1α protein in various cancer cell lines. EGLNs require oxygen and 2-oxoglutarate for enzymatic activity. We tested the ability of several cell-permeable 2-oxoglutarate analogs to regulate the abundance of HIF-1α protein. We identified 3-oxoglutarate as a potent regulator of HIF-1α in normoxic conditions. In contrast to 2-oxoglutarate, 3-oxoglutarate decreased the abundance of HIF-1α protein in several cancer cell lines in normoxia and diminished HIF-1α levels independent of EGLN enzymatic activity. Furthermore, we observed that 3-oxoglutarate was detrimental to cancer cell survival. We show that esterified 3-oxoglutarate, in combination with the cancer chemotherapeutic drug vincristine, induces apoptosis and inhibits tumor growth in vitro and in vivo. Our data imply that a novel treatment strategy targeting HIF-1α in combination with the use of existing cytotoxic agents could serve as potent, future antitumor chemotherapies.

Published
2016
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