ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice
Аутори
Yalcin, SafakMarinkovic, Dragan
Mungamuri, Sathish Kumar
Zhang, Xin
Tong, Wei
Sellers, Rani
Ghaffari, Saghi
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Reactive oxygen species (ROS) participate in normal intracellular signalling and in many diseases including cancer and aging, although the associated mechanisms are not fully understood. Forkhead Box O (FoxO) 3 transcription factor regulates levels of ROS concentrations, and is essential for maintenance of hematopoietic stem cells. Here, we show that loss of Foxo3 causes a myeloproliferative syndrome with splenomegaly and increased hematopoietic progenitors (HPs) that are hypersensitive to cytokines. These mutant HPs contain increased ROS, overactive intracellular signalling through the AKT/mammalian target of rapamycin signalling pathway and relative deficiency of Lnk, a negative regulator of cytokine receptor signalling. In vivo treatment with ROS scavenger N-acetyl-cysteine corrects these biochemical abnormalities and relieves the myeloproliferation. Moreover, enforced expression of Lnk by retroviral transfer corrects the abnormal expansion of Foxo3(-/-) HPs in vivo. Our combined re...sults show that loss of Foxo3 causes increased ROS accumulation in HPs. In turn, this inhibits Lnk expression that contributes to exaggerated cytokine responses that lead to myeloproliferation. Our findings could explain the mechanisms by which mutations that alter Foxo3 function induce malignancy. More generally, the work illustrates how deregulated ROS may contribute to malignant progression.
Кључне речи:
oxO / Lnk; mTOR / myeloproliferation / ROSИзвор:
The EMBO Journal, 2010, 29, 24, 4118-4131Издавач:
- The EMBO Journal
DOI: 10.1038/emboj.2010.292
ISSN: 0261-4189; Electronic: 1460-2075
WoS: 000285407200008
[ Google Scholar ]Институција/група
rFASPERTY - JOUR AU - Yalcin, Safak AU - Marinkovic, Dragan AU - Mungamuri, Sathish Kumar AU - Zhang, Xin AU - Tong, Wei AU - Sellers, Rani AU - Ghaffari, Saghi PY - 2010 UR - http://rfasper.fasper.bg.ac.rs/handle/123456789/5178 AB - Reactive oxygen species (ROS) participate in normal intracellular signalling and in many diseases including cancer and aging, although the associated mechanisms are not fully understood. Forkhead Box O (FoxO) 3 transcription factor regulates levels of ROS concentrations, and is essential for maintenance of hematopoietic stem cells. Here, we show that loss of Foxo3 causes a myeloproliferative syndrome with splenomegaly and increased hematopoietic progenitors (HPs) that are hypersensitive to cytokines. These mutant HPs contain increased ROS, overactive intracellular signalling through the AKT/mammalian target of rapamycin signalling pathway and relative deficiency of Lnk, a negative regulator of cytokine receptor signalling. In vivo treatment with ROS scavenger N-acetyl-cysteine corrects these biochemical abnormalities and relieves the myeloproliferation. Moreover, enforced expression of Lnk by retroviral transfer corrects the abnormal expansion of Foxo3(-/-) HPs in vivo. Our combined results show that loss of Foxo3 causes increased ROS accumulation in HPs. In turn, this inhibits Lnk expression that contributes to exaggerated cytokine responses that lead to myeloproliferation. Our findings could explain the mechanisms by which mutations that alter Foxo3 function induce malignancy. More generally, the work illustrates how deregulated ROS may contribute to malignant progression. PB - The EMBO Journal T2 - The EMBO Journal T1 - ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice EP - 4131 IS - 24 SP - 4118 VL - 29 DO - 10.1038/emboj.2010.292 ER -
@article{ author = "Yalcin, Safak and Marinkovic, Dragan and Mungamuri, Sathish Kumar and Zhang, Xin and Tong, Wei and Sellers, Rani and Ghaffari, Saghi", year = "2010", abstract = "Reactive oxygen species (ROS) participate in normal intracellular signalling and in many diseases including cancer and aging, although the associated mechanisms are not fully understood. Forkhead Box O (FoxO) 3 transcription factor regulates levels of ROS concentrations, and is essential for maintenance of hematopoietic stem cells. Here, we show that loss of Foxo3 causes a myeloproliferative syndrome with splenomegaly and increased hematopoietic progenitors (HPs) that are hypersensitive to cytokines. These mutant HPs contain increased ROS, overactive intracellular signalling through the AKT/mammalian target of rapamycin signalling pathway and relative deficiency of Lnk, a negative regulator of cytokine receptor signalling. In vivo treatment with ROS scavenger N-acetyl-cysteine corrects these biochemical abnormalities and relieves the myeloproliferation. Moreover, enforced expression of Lnk by retroviral transfer corrects the abnormal expansion of Foxo3(-/-) HPs in vivo. Our combined results show that loss of Foxo3 causes increased ROS accumulation in HPs. In turn, this inhibits Lnk expression that contributes to exaggerated cytokine responses that lead to myeloproliferation. Our findings could explain the mechanisms by which mutations that alter Foxo3 function induce malignancy. More generally, the work illustrates how deregulated ROS may contribute to malignant progression.", publisher = "The EMBO Journal", journal = "The EMBO Journal", title = "ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice", pages = "4131-4118", number = "24", volume = "29", doi = "10.1038/emboj.2010.292" }
Yalcin, S., Marinkovic, D., Mungamuri, S. K., Zhang, X., Tong, W., Sellers, R.,& Ghaffari, S.. (2010). ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice. in The EMBO Journal The EMBO Journal., 29(24), 4118-4131. https://doi.org/10.1038/emboj.2010.292
Yalcin S, Marinkovic D, Mungamuri SK, Zhang X, Tong W, Sellers R, Ghaffari S. ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice. in The EMBO Journal. 2010;29(24):4118-4131. doi:10.1038/emboj.2010.292 .
Yalcin, Safak, Marinkovic, Dragan, Mungamuri, Sathish Kumar, Zhang, Xin, Tong, Wei, Sellers, Rani, Ghaffari, Saghi, "ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice" in The EMBO Journal, 29, no. 24 (2010):4118-4131, https://doi.org/10.1038/emboj.2010.292 . .