TY  - 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 . .

TY  - JOUR
AU  - Yalcin, Safak
AU  - Marinković, 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/123456789/377
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. The EMBO Journal (2010) 29, 4118-4131. doi: 10.1038/emboj.2010.292; Published online 26 November 2010
PB  - Wiley, Hoboken
T2  - 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 Marinković, 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. The EMBO Journal (2010) 29, 4118-4131. doi: 10.1038/emboj.2010.292; Published online 26 November 2010",
publisher = "Wiley, Hoboken",
journal = "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., Marinković, 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 Embo Journal
Wiley, Hoboken., 29(24), 4118-4131.
https://doi.org/10.1038/emboj.2010.292

Yalcin S, Marinković 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 Embo Journal. 2010;29(24):4118-4131.
doi:10.1038/emboj.2010.292 .

Yalcin, Safak, Marinković, 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 Embo Journal, 29, no. 24 (2010):4118-4131,
https://doi.org/10.1038/emboj.2010.292 . .

TY  - JOUR
AU  - Yalcin, Safak
AU  - Zhang, Xin
AU  - Luciano, Julia P.
AU  - Mungamuri, Sathish Kumar
AU  - Marinković, Dragan
AU  - Vercherat, Cecile
AU  - Sarkar, Abby
AU  - Grisotto, Marcos
AU  - Taneja, Reshma
AU  - Ghaffari, Saghi
PY  - 2008
UR  - http://rfasper.fasper.bg.ac.rs/handle/123456789/193
AB  - Unchecked accumulation of reactive oxygen species (ROS) compromises maintenance of hematopoietic stem cells. Regulation of ROS by the tumor suppressor protein ataxia telangiectasia mutated (ATM) is critical for preserving the hematopoietic stem cell pool. In this study we demonstrate that the Foxo3 member of the Forkhead Box O (FoxO) family of transcription factors is essential for normal ATM expression. In addition, we show that loss of Foxo3 leads to defects in hematopoietic stem cells, and these defects result from an overaccumulation of ROS. Foxo3 suppression of ROS in hematopoietic stem cells is mediated partly by regulation of ATM expression. We identify ROS-independent modulations of ATM and p16(INK4a) and ROS-mediated activation of p53/p21(CIP1/WAF1/Sdi1) tumor suppressor pathways as major contributors to Foxo3-null hematopoietic stem cells defects. Our studies demonstrate that Foxo3 represses ROS in part via regulation of ATM and that this repression is required for maintenance of the hematopoietic stem cell pool.
PB  - Amer Soc Biochemistry Molecular Biology Inc, Bethesda
T2  - Journal of Biological Chemistry
T1  - Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells
EP  - 25705
IS  - 37
SP  - 25692
VL  - 283
DO  - 10.1074/jbc.M800517200
ER  - 

@article{
author = "Yalcin, Safak and Zhang, Xin and Luciano, Julia P. and Mungamuri, Sathish Kumar and Marinković, Dragan and Vercherat, Cecile and Sarkar, Abby and Grisotto, Marcos and Taneja, Reshma and Ghaffari, Saghi",
year = "2008",
abstract = "Unchecked accumulation of reactive oxygen species (ROS) compromises maintenance of hematopoietic stem cells. Regulation of ROS by the tumor suppressor protein ataxia telangiectasia mutated (ATM) is critical for preserving the hematopoietic stem cell pool. In this study we demonstrate that the Foxo3 member of the Forkhead Box O (FoxO) family of transcription factors is essential for normal ATM expression. In addition, we show that loss of Foxo3 leads to defects in hematopoietic stem cells, and these defects result from an overaccumulation of ROS. Foxo3 suppression of ROS in hematopoietic stem cells is mediated partly by regulation of ATM expression. We identify ROS-independent modulations of ATM and p16(INK4a) and ROS-mediated activation of p53/p21(CIP1/WAF1/Sdi1) tumor suppressor pathways as major contributors to Foxo3-null hematopoietic stem cells defects. Our studies demonstrate that Foxo3 represses ROS in part via regulation of ATM and that this repression is required for maintenance of the hematopoietic stem cell pool.",
publisher = "Amer Soc Biochemistry Molecular Biology Inc, Bethesda",
journal = "Journal of Biological Chemistry",
title = "Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells",
pages = "25705-25692",
number = "37",
volume = "283",
doi = "10.1074/jbc.M800517200"
}

Yalcin, S., Zhang, X., Luciano, J. P., Mungamuri, S. K., Marinković, D., Vercherat, C., Sarkar, A., Grisotto, M., Taneja, R.,& Ghaffari, S.. (2008). Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. in Journal of Biological Chemistry
Amer Soc Biochemistry Molecular Biology Inc, Bethesda., 283(37), 25692-25705.
https://doi.org/10.1074/jbc.M800517200

Yalcin S, Zhang X, Luciano JP, Mungamuri SK, Marinković D, Vercherat C, Sarkar A, Grisotto M, Taneja R, Ghaffari S. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. in Journal of Biological Chemistry. 2008;283(37):25692-25705.
doi:10.1074/jbc.M800517200 .

Yalcin, Safak, Zhang, Xin, Luciano, Julia P., Mungamuri, Sathish Kumar, Marinković, Dragan, Vercherat, Cecile, Sarkar, Abby, Grisotto, Marcos, Taneja, Reshma, Ghaffari, Saghi, "Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells" in Journal of Biological Chemistry, 283, no. 37 (2008):25692-25705,
https://doi.org/10.1074/jbc.M800517200 . .

TY  - CONF
AU  - Yalcin, Safak
AU  - Mungamuri, Sathish Kumar
AU  - Marinković, Dragan
AU  - Zhang, Xin
AU  - Tong, Wei
AU  - Cullen, Dana
AU  - Ghaffari, Saghi
PY  - 2008
UR  - http://rfasper.fasper.bg.ac.rs/handle/123456789/206
PB  - Amer Soc Hematology, Washington
C3  - Blood
T1  - Oxidative Stress-Mediated Activation of AKT/mTOR Signaling Pathway Leads to Myeloproliferative Syndrome in FoxO3 Null Mice: A Role for Lnk Adaptor Protein
EP  - 193
IS  - 11
SP  - 192
VL  - 112
UR  - https://hdl.handle.net/21.15107/rcub_rfasper_206
ER  - 

@conference{
author = "Yalcin, Safak and Mungamuri, Sathish Kumar and Marinković, Dragan and Zhang, Xin and Tong, Wei and Cullen, Dana and Ghaffari, Saghi",
year = "2008",
publisher = "Amer Soc Hematology, Washington",
journal = "Blood",
title = "Oxidative Stress-Mediated Activation of AKT/mTOR Signaling Pathway Leads to Myeloproliferative Syndrome in FoxO3 Null Mice: A Role for Lnk Adaptor Protein",
pages = "193-192",
number = "11",
volume = "112",
url = "https://hdl.handle.net/21.15107/rcub_rfasper_206"
}

Yalcin, S., Mungamuri, S. K., Marinković, D., Zhang, X., Tong, W., Cullen, D.,& Ghaffari, S.. (2008). Oxidative Stress-Mediated Activation of AKT/mTOR Signaling Pathway Leads to Myeloproliferative Syndrome in FoxO3 Null Mice: A Role for Lnk Adaptor Protein. in Blood
Amer Soc Hematology, Washington., 112(11), 192-193.
https://hdl.handle.net/21.15107/rcub_rfasper_206

Yalcin S, Mungamuri SK, Marinković D, Zhang X, Tong W, Cullen D, Ghaffari S. Oxidative Stress-Mediated Activation of AKT/mTOR Signaling Pathway Leads to Myeloproliferative Syndrome in FoxO3 Null Mice: A Role for Lnk Adaptor Protein. in Blood. 2008;112(11):192-193.
https://hdl.handle.net/21.15107/rcub_rfasper_206 .

Yalcin, Safak, Mungamuri, Sathish Kumar, Marinković, Dragan, Zhang, Xin, Tong, Wei, Cullen, Dana, Ghaffari, Saghi, "Oxidative Stress-Mediated Activation of AKT/mTOR Signaling Pathway Leads to Myeloproliferative Syndrome in FoxO3 Null Mice: A Role for Lnk Adaptor Protein" in Blood, 112, no. 11 (2008):192-193,
https://hdl.handle.net/21.15107/rcub_rfasper_206 .

TY  - JOUR
AU  - Marinković, Dragan
AU  - Zhang, Xin
AU  - Yalcin, Safak
AU  - Luciano, Julia P.
AU  - Brugnara, Carlo
AU  - Huber, Tara
AU  - Ghaffari, Saghi
PY  - 2007
UR  - http://rfasper.fasper.bg.ac.rs/handle/123456789/118
AB  - Erythroid cells accumulate hemoglobin as they mature and as a result are highly prone to oxidative damage. However, mechanisms of transcriptional control of antioxidant defense in erythroid cells have thus far been poorly characterized. We observed that animals deficient in the forkhead box O3 (Foxo3) transcription factor died rapidly when exposed to erythroid oxidative stress-induced conditions, while wild-type mice showed no decreased viability. In view of this striking finding, we investigated the potential role of Foxo3 in the regulation of ROS in erythropoiesis. Foxo3 expression, nuclear localization, and transcriptional activity were all enhanced during normal erythroid cell maturation. Foxo3-deficient erythrocytes exhibited decreased expression of ROS scavenging enzymes and had a ROS-mediated shortened lifespan and evidence of oxidative damage. Furthermore, loss of Foxo3 induced mitotic arrest in erythroid precursor cells, leading to a significant decrease in the rate of in vivo erythroid maturation. We identified ROS-mediated upregulation of P21(CIP1/WAF1/Sdi1) (also known as Cdkn1a) as a major contributor to the interference with cell cycle progression in Foxo3-deficient erythroid precursor cells. These findings establish an essential nonredundant function for Foxo3 in the regulation of oxidative stress, cell cycle, maturation, and lifespan of erythroid cells. These results may have an impact on the understanding of human disorders in which ROS play a role.
PB  - Amer Soc Clinical Investigation Inc, Ann Arbor
T2  - Journal of Clinical Investigation
T1  - Foxo3 is required for the regulation of oxidative stress in erythropoiesis
EP  - 2144
IS  - 8
SP  - 2133
VL  - 117
DO  - 10.1172/JCI31807
ER  - 

@article{
author = "Marinković, Dragan and Zhang, Xin and Yalcin, Safak and Luciano, Julia P. and Brugnara, Carlo and Huber, Tara and Ghaffari, Saghi",
year = "2007",
abstract = "Erythroid cells accumulate hemoglobin as they mature and as a result are highly prone to oxidative damage. However, mechanisms of transcriptional control of antioxidant defense in erythroid cells have thus far been poorly characterized. We observed that animals deficient in the forkhead box O3 (Foxo3) transcription factor died rapidly when exposed to erythroid oxidative stress-induced conditions, while wild-type mice showed no decreased viability. In view of this striking finding, we investigated the potential role of Foxo3 in the regulation of ROS in erythropoiesis. Foxo3 expression, nuclear localization, and transcriptional activity were all enhanced during normal erythroid cell maturation. Foxo3-deficient erythrocytes exhibited decreased expression of ROS scavenging enzymes and had a ROS-mediated shortened lifespan and evidence of oxidative damage. Furthermore, loss of Foxo3 induced mitotic arrest in erythroid precursor cells, leading to a significant decrease in the rate of in vivo erythroid maturation. We identified ROS-mediated upregulation of P21(CIP1/WAF1/Sdi1) (also known as Cdkn1a) as a major contributor to the interference with cell cycle progression in Foxo3-deficient erythroid precursor cells. These findings establish an essential nonredundant function for Foxo3 in the regulation of oxidative stress, cell cycle, maturation, and lifespan of erythroid cells. These results may have an impact on the understanding of human disorders in which ROS play a role.",
publisher = "Amer Soc Clinical Investigation Inc, Ann Arbor",
journal = "Journal of Clinical Investigation",
title = "Foxo3 is required for the regulation of oxidative stress in erythropoiesis",
pages = "2144-2133",
number = "8",
volume = "117",
doi = "10.1172/JCI31807"
}

Marinković, D., Zhang, X., Yalcin, S., Luciano, J. P., Brugnara, C., Huber, T.,& Ghaffari, S.. (2007). Foxo3 is required for the regulation of oxidative stress in erythropoiesis. in Journal of Clinical Investigation
Amer Soc Clinical Investigation Inc, Ann Arbor., 117(8), 2133-2144.
https://doi.org/10.1172/JCI31807

Marinković D, Zhang X, Yalcin S, Luciano JP, Brugnara C, Huber T, Ghaffari S. Foxo3 is required for the regulation of oxidative stress in erythropoiesis. in Journal of Clinical Investigation. 2007;117(8):2133-2144.
doi:10.1172/JCI31807 .

Marinković, Dragan, Zhang, Xin, Yalcin, Safak, Luciano, Julia P., Brugnara, Carlo, Huber, Tara, Ghaffari, Saghi, "Foxo3 is required for the regulation of oxidative stress in erythropoiesis" in Journal of Clinical Investigation, 117, no. 8 (2007):2133-2144,
https://doi.org/10.1172/JCI31807 . .