Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma

B. A. Jacobson; A. De; M. G. Kratzke; M. R. Patel; J. Jay-Dixon; B. A. Whitson; A. A. Sadiq; P. B. Bitterman; V. A. Polunovsky; R. A. Kratzke

doi:10.1038/sj.bjc.6605184

Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma

B. A. Jacobson, A. De, M. G. Kratzke, M. R. Patel, J. Jay-Dixon, B. A. Whitson, A. A. Sadiq, P. B. Bitterman, V. A. Polunovsky, R. A. Kratzke

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Abstract

Background: Insulin-like growth factor (IGF)-I signalling stimulates proliferation, survival, and invasion in malignant mesothelioma and other tumour types. Studies have found that tumourigenesis is linked to dysregulation of cap-dependent protein translation. Methods: The effect of IGF stimulation on cap-mediated translation activation in mesothelioma cell lines was studied using binding assays to a synthetic 7-methyl GTP-cap analogue. In addition, cap-mediated translation was genetically repressed in these cells with a dominant active motive of 4E-BP1.Results: In most mesothelioma cell lines, IGF-I stimulation resulted in a hyperphosphorylation-mediated inactivation of 4E-BP1 compared with that in normal mesothelial cells. An inhibitor of Akt diminished IGF-I-mediated phosphorylation of 4E-BP1, whereas inhibiting MAPK signalling had no such effect. IGF-I stimulation resulted in the activation of the cap-mediated translation complex as indicated by an increased eIF4GeIF4E ratio in cap-affinity assays. Akt inhibition reversed the eIF4GeIF4E ratio. Mesothelioma cells transfected with an activated 4E-BP1 protein (4E-BP1 ^A37A46) were resistant to IGF-I-mediated growth, motility, and colony formation. In a murine xenograft model, mesothelioma cells expressing the dominant active 4E-BP1^A37A46 repressor protein showed abrogated tumourigenicity compared with control tumours. Conclusion: IGF-I signalling in mesothelioma cells drives cell proliferation, motility, and tumourigenesis through its ability to activate cap-mediated protein translation complex through PI3KAktmTOR signalling.

Original language	English (US)
Pages (from-to)	424-431
Number of pages	8
Journal	British Journal of Cancer
Volume	101
Issue number	3
DOIs	https://doi.org/10.1038/sj.bjc.6605184
State	Published - Aug 4 2009

Bibliographical note

Funding Information:
We thank Douglas Yee and Deepali Sachdev for their helpful advice and comments. We thank Michael Franklin for editorial assistance with this article. This work is supported in part by a grant from the Mesothelioma Applied Research Foundation (RAK).

Keywords

4E-BP1
Cap-dependent
EIF4E
EIF4F
IGF-I
Translation

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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@article{a335f0da478e4be19add0a5aee4da966,

title = "Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma",

abstract = "Background: Insulin-like growth factor (IGF)-I signalling stimulates proliferation, survival, and invasion in malignant mesothelioma and other tumour types. Studies have found that tumourigenesis is linked to dysregulation of cap-dependent protein translation. Methods: The effect of IGF stimulation on cap-mediated translation activation in mesothelioma cell lines was studied using binding assays to a synthetic 7-methyl GTP-cap analogue. In addition, cap-mediated translation was genetically repressed in these cells with a dominant active motive of 4E-BP1.Results: In most mesothelioma cell lines, IGF-I stimulation resulted in a hyperphosphorylation-mediated inactivation of 4E-BP1 compared with that in normal mesothelial cells. An inhibitor of Akt diminished IGF-I-mediated phosphorylation of 4E-BP1, whereas inhibiting MAPK signalling had no such effect. IGF-I stimulation resulted in the activation of the cap-mediated translation complex as indicated by an increased eIF4GeIF4E ratio in cap-affinity assays. Akt inhibition reversed the eIF4GeIF4E ratio. Mesothelioma cells transfected with an activated 4E-BP1 protein (4E-BP1 A37A46) were resistant to IGF-I-mediated growth, motility, and colony formation. In a murine xenograft model, mesothelioma cells expressing the dominant active 4E-BP1A37A46 repressor protein showed abrogated tumourigenicity compared with control tumours. Conclusion: IGF-I signalling in mesothelioma cells drives cell proliferation, motility, and tumourigenesis through its ability to activate cap-mediated protein translation complex through PI3KAktmTOR signalling.",

keywords = "4E-BP1, Cap-dependent, EIF4E, EIF4F, IGF-I, Translation",

author = "Jacobson, {B. A.} and A. De and Kratzke, {M. G.} and Patel, {M. R.} and J. Jay-Dixon and Whitson, {B. A.} and Sadiq, {A. A.} and Bitterman, {P. B.} and Polunovsky, {V. A.} and Kratzke, {R. A.}",

note = "Funding Information: We thank Douglas Yee and Deepali Sachdev for their helpful advice and comments. We thank Michael Franklin for editorial assistance with this article. This work is supported in part by a grant from the Mesothelioma Applied Research Foundation (RAK).",

year = "2009",

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doi = "10.1038/sj.bjc.6605184",

language = "English (US)",

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T1 - Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma

AU - Jacobson, B. A.

AU - De, A.

AU - Kratzke, M. G.

AU - Patel, M. R.

AU - Jay-Dixon, J.

AU - Whitson, B. A.

AU - Sadiq, A. A.

AU - Bitterman, P. B.

AU - Polunovsky, V. A.

AU - Kratzke, R. A.

N1 - Funding Information: We thank Douglas Yee and Deepali Sachdev for their helpful advice and comments. We thank Michael Franklin for editorial assistance with this article. This work is supported in part by a grant from the Mesothelioma Applied Research Foundation (RAK).

PY - 2009/8/4

Y1 - 2009/8/4

N2 - Background: Insulin-like growth factor (IGF)-I signalling stimulates proliferation, survival, and invasion in malignant mesothelioma and other tumour types. Studies have found that tumourigenesis is linked to dysregulation of cap-dependent protein translation. Methods: The effect of IGF stimulation on cap-mediated translation activation in mesothelioma cell lines was studied using binding assays to a synthetic 7-methyl GTP-cap analogue. In addition, cap-mediated translation was genetically repressed in these cells with a dominant active motive of 4E-BP1.Results: In most mesothelioma cell lines, IGF-I stimulation resulted in a hyperphosphorylation-mediated inactivation of 4E-BP1 compared with that in normal mesothelial cells. An inhibitor of Akt diminished IGF-I-mediated phosphorylation of 4E-BP1, whereas inhibiting MAPK signalling had no such effect. IGF-I stimulation resulted in the activation of the cap-mediated translation complex as indicated by an increased eIF4GeIF4E ratio in cap-affinity assays. Akt inhibition reversed the eIF4GeIF4E ratio. Mesothelioma cells transfected with an activated 4E-BP1 protein (4E-BP1 A37A46) were resistant to IGF-I-mediated growth, motility, and colony formation. In a murine xenograft model, mesothelioma cells expressing the dominant active 4E-BP1A37A46 repressor protein showed abrogated tumourigenicity compared with control tumours. Conclusion: IGF-I signalling in mesothelioma cells drives cell proliferation, motility, and tumourigenesis through its ability to activate cap-mediated protein translation complex through PI3KAktmTOR signalling.

AB - Background: Insulin-like growth factor (IGF)-I signalling stimulates proliferation, survival, and invasion in malignant mesothelioma and other tumour types. Studies have found that tumourigenesis is linked to dysregulation of cap-dependent protein translation. Methods: The effect of IGF stimulation on cap-mediated translation activation in mesothelioma cell lines was studied using binding assays to a synthetic 7-methyl GTP-cap analogue. In addition, cap-mediated translation was genetically repressed in these cells with a dominant active motive of 4E-BP1.Results: In most mesothelioma cell lines, IGF-I stimulation resulted in a hyperphosphorylation-mediated inactivation of 4E-BP1 compared with that in normal mesothelial cells. An inhibitor of Akt diminished IGF-I-mediated phosphorylation of 4E-BP1, whereas inhibiting MAPK signalling had no such effect. IGF-I stimulation resulted in the activation of the cap-mediated translation complex as indicated by an increased eIF4GeIF4E ratio in cap-affinity assays. Akt inhibition reversed the eIF4GeIF4E ratio. Mesothelioma cells transfected with an activated 4E-BP1 protein (4E-BP1 A37A46) were resistant to IGF-I-mediated growth, motility, and colony formation. In a murine xenograft model, mesothelioma cells expressing the dominant active 4E-BP1A37A46 repressor protein showed abrogated tumourigenicity compared with control tumours. Conclusion: IGF-I signalling in mesothelioma cells drives cell proliferation, motility, and tumourigenesis through its ability to activate cap-mediated protein translation complex through PI3KAktmTOR signalling.

KW - 4E-BP1

KW - Cap-dependent

KW - EIF4E

KW - EIF4F

KW - IGF-I

KW - Translation

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Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma

Abstract

Bibliographical note

Keywords

UN SDGs

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