Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR
(2013) In BMC Cancer 13.- Abstract
- Background: The t(6;9)(p23;q34) chromosomal translocation is found in 1% of acute myeloid leukemia and encodes the fusion protein DEK-NUP214 (formerly DEK-CAN) with largely uncharacterized functions. Methods: We expressed DEK-NUP214 in the myeloid cell lines U937 and PL-21 and studied the effects on cellular functions. Results: In this study, we demonstrate that expression of DEK-NUP214 increases cellular proliferation. Western blot analysis revealed elevated levels of one of the key proteins regulating proliferation, the mechanistic target of rapamycin, mTOR. This conferred increased mTORC1 but not mTORC2 activity, as determined by the phosphorylation of their substrates, p70 S6 kinase and Akt. The functional importance of the mTOR... (More)
- Background: The t(6;9)(p23;q34) chromosomal translocation is found in 1% of acute myeloid leukemia and encodes the fusion protein DEK-NUP214 (formerly DEK-CAN) with largely uncharacterized functions. Methods: We expressed DEK-NUP214 in the myeloid cell lines U937 and PL-21 and studied the effects on cellular functions. Results: In this study, we demonstrate that expression of DEK-NUP214 increases cellular proliferation. Western blot analysis revealed elevated levels of one of the key proteins regulating proliferation, the mechanistic target of rapamycin, mTOR. This conferred increased mTORC1 but not mTORC2 activity, as determined by the phosphorylation of their substrates, p70 S6 kinase and Akt. The functional importance of the mTOR upregulation was determined by assaying the downstream cellular processes; protein synthesis and glucose metabolism. A global translation assay revealed a substantial increase in the translation rate and a metabolic assay detected a shift from glycolysis to oxidative phosphorylation, as determined by a reduction in lactate production without a concomitant decrease in glucose consumption. Both these effects are in concordance with increased mTORC1 activity. Treatment with the mTORC1 inhibitor everolimus (RAD001) selectively reversed the DEK-NUP214-induced proliferation, demonstrating that the effect is mTOR-dependent. Conclusions: Our study shows that the DEK-NUP214 fusion gene increases proliferation by upregulation of mTOR, suggesting that patients with leukemias carrying DEK-NUP214 may benefit from treatment with mTOR inhibitors. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4172540
- author
- Sandén, Carl LU ; Ageberg, Malin LU ; Petersson, Jessica LU ; Lennartsson, Andreas and Gullberg, Urban LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Acute myeloid leukemia, DEK-NUP214, DEK-CAN, Fusion gene, Proliferation, mTOR, Everolimus
- in
- BMC Cancer
- volume
- 13
- article number
- 440
- publisher
- BioMed Central (BMC)
- external identifiers
-
- wos:000325080000002
- scopus:84884733616
- pmid:24073922
- ISSN
- 1471-2407
- DOI
- 10.1186/1471-2407-13-440
- language
- English
- LU publication?
- yes
- id
- 1ef0102d-d90f-4133-9750-e4125882bae4 (old id 4172540)
- date added to LUP
- 2016-04-01 14:04:43
- date last changed
- 2022-03-21 22:05:40
@article{1ef0102d-d90f-4133-9750-e4125882bae4, abstract = {{Background: The t(6;9)(p23;q34) chromosomal translocation is found in 1% of acute myeloid leukemia and encodes the fusion protein DEK-NUP214 (formerly DEK-CAN) with largely uncharacterized functions. Methods: We expressed DEK-NUP214 in the myeloid cell lines U937 and PL-21 and studied the effects on cellular functions. Results: In this study, we demonstrate that expression of DEK-NUP214 increases cellular proliferation. Western blot analysis revealed elevated levels of one of the key proteins regulating proliferation, the mechanistic target of rapamycin, mTOR. This conferred increased mTORC1 but not mTORC2 activity, as determined by the phosphorylation of their substrates, p70 S6 kinase and Akt. The functional importance of the mTOR upregulation was determined by assaying the downstream cellular processes; protein synthesis and glucose metabolism. A global translation assay revealed a substantial increase in the translation rate and a metabolic assay detected a shift from glycolysis to oxidative phosphorylation, as determined by a reduction in lactate production without a concomitant decrease in glucose consumption. Both these effects are in concordance with increased mTORC1 activity. Treatment with the mTORC1 inhibitor everolimus (RAD001) selectively reversed the DEK-NUP214-induced proliferation, demonstrating that the effect is mTOR-dependent. Conclusions: Our study shows that the DEK-NUP214 fusion gene increases proliferation by upregulation of mTOR, suggesting that patients with leukemias carrying DEK-NUP214 may benefit from treatment with mTOR inhibitors.}}, author = {{Sandén, Carl and Ageberg, Malin and Petersson, Jessica and Lennartsson, Andreas and Gullberg, Urban}}, issn = {{1471-2407}}, keywords = {{Acute myeloid leukemia; DEK-NUP214; DEK-CAN; Fusion gene; Proliferation; mTOR; Everolimus}}, language = {{eng}}, publisher = {{BioMed Central (BMC)}}, series = {{BMC Cancer}}, title = {{Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR}}, url = {{https://lup.lub.lu.se/search/files/3763952/4253774}}, doi = {{10.1186/1471-2407-13-440}}, volume = {{13}}, year = {{2013}}, }