The Experts below are selected from a list of 144 Experts worldwide ranked by ideXlab platform
Brigitte Bauvois - One of the best experts on this subject based on the ideXlab platform.
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p70s6 kinase is a target of the novel proteasome inhibitor 3 3 diamino 4 methoxyflavone during apoptosis in human myeloid tumor cells
Biochimica et Biophysica Acta, 2013Co-Authors: Marion Piedfer, Sandrine Bouchet, Ruoping Tang, Christian Billard, Daniel Dauzonne, Brigitte BauvoisAbstract:Abstract Acute myeloid leukemia (AML) is a deadly disease characterized by the clonal expansion and accumulation of hematopoietic stem cells arrested at various stages of development. Clinical research efforts are currently focusing on targeted therapies that induce apoptosis in AML cells. Herein, the effects and mechanisms of the novel flavone 3,3′-diamino-4′-methoxyflavone (DD1) on AML cell dysfunction were investigated in AML cells (monoblast U937, Myelomonocyte OCI-AML3, promyelocyte NB4, myeloblast HL-60) and blood samples from patients with AML. The administration of DD1 inhibited proliferation and induced death of AML cell lines and reduced the clonogenic activity of AML, but not normal, blood cells. The flavone's apoptotic action in U937 cells was associated with recruitment of mitochondria, Bax activation, Bad dephosphorylation (at Ser 136 ), activation of caspases -8, -9, and -3 and cleavage of the caspase substrate PARP-1. DD1 induced a marked decrease in (i) Thr 389 -phosphorylation and (ii) protein levels of the caspase-3 substrate P70 ribosomal S6 kinase (P70S6K, known for its ability to phosphorylate Bad). Caspase-dependent apoptosis and P70S6K degradation were simultaneously prevented by the caspase inhibitors. Importantly, DD1 was shown to directly inhibit the proteasome's chymotrypsin-like activity in U937 cells. Apoptotic activity of the proteasome inhibitor bortezomib was also related to Bax activation and P70S6K downregulation. Accordingly, DD1 failed to induce P70S6K cleavage, Bax stimulation and apoptosis in K562 cells resistant to bortezomib. These results indicate that DD1 has the potential to eradicate AML cells and support a critical role for Bax and P70S6K in DD1-mediated proteasome inhibition and apoptosis of leukemia cells.
Daniel Dauzonne - One of the best experts on this subject based on the ideXlab platform.
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p70s6 kinase is a target of the novel proteasome inhibitor 3 3 diamino 4 methoxyflavone during apoptosis in human myeloid tumor cells
Biochimica et Biophysica Acta, 2013Co-Authors: Marion Piedfer, Sandrine Bouchet, Ruoping Tang, Christian Billard, Daniel Dauzonne, Brigitte BauvoisAbstract:Abstract Acute myeloid leukemia (AML) is a deadly disease characterized by the clonal expansion and accumulation of hematopoietic stem cells arrested at various stages of development. Clinical research efforts are currently focusing on targeted therapies that induce apoptosis in AML cells. Herein, the effects and mechanisms of the novel flavone 3,3′-diamino-4′-methoxyflavone (DD1) on AML cell dysfunction were investigated in AML cells (monoblast U937, Myelomonocyte OCI-AML3, promyelocyte NB4, myeloblast HL-60) and blood samples from patients with AML. The administration of DD1 inhibited proliferation and induced death of AML cell lines and reduced the clonogenic activity of AML, but not normal, blood cells. The flavone's apoptotic action in U937 cells was associated with recruitment of mitochondria, Bax activation, Bad dephosphorylation (at Ser 136 ), activation of caspases -8, -9, and -3 and cleavage of the caspase substrate PARP-1. DD1 induced a marked decrease in (i) Thr 389 -phosphorylation and (ii) protein levels of the caspase-3 substrate P70 ribosomal S6 kinase (P70S6K, known for its ability to phosphorylate Bad). Caspase-dependent apoptosis and P70S6K degradation were simultaneously prevented by the caspase inhibitors. Importantly, DD1 was shown to directly inhibit the proteasome's chymotrypsin-like activity in U937 cells. Apoptotic activity of the proteasome inhibitor bortezomib was also related to Bax activation and P70S6K downregulation. Accordingly, DD1 failed to induce P70S6K cleavage, Bax stimulation and apoptosis in K562 cells resistant to bortezomib. These results indicate that DD1 has the potential to eradicate AML cells and support a critical role for Bax and P70S6K in DD1-mediated proteasome inhibition and apoptosis of leukemia cells.
Marion Piedfer - One of the best experts on this subject based on the ideXlab platform.
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p70s6 kinase is a target of the novel proteasome inhibitor 3 3 diamino 4 methoxyflavone during apoptosis in human myeloid tumor cells
Biochimica et Biophysica Acta, 2013Co-Authors: Marion Piedfer, Sandrine Bouchet, Ruoping Tang, Christian Billard, Daniel Dauzonne, Brigitte BauvoisAbstract:Abstract Acute myeloid leukemia (AML) is a deadly disease characterized by the clonal expansion and accumulation of hematopoietic stem cells arrested at various stages of development. Clinical research efforts are currently focusing on targeted therapies that induce apoptosis in AML cells. Herein, the effects and mechanisms of the novel flavone 3,3′-diamino-4′-methoxyflavone (DD1) on AML cell dysfunction were investigated in AML cells (monoblast U937, Myelomonocyte OCI-AML3, promyelocyte NB4, myeloblast HL-60) and blood samples from patients with AML. The administration of DD1 inhibited proliferation and induced death of AML cell lines and reduced the clonogenic activity of AML, but not normal, blood cells. The flavone's apoptotic action in U937 cells was associated with recruitment of mitochondria, Bax activation, Bad dephosphorylation (at Ser 136 ), activation of caspases -8, -9, and -3 and cleavage of the caspase substrate PARP-1. DD1 induced a marked decrease in (i) Thr 389 -phosphorylation and (ii) protein levels of the caspase-3 substrate P70 ribosomal S6 kinase (P70S6K, known for its ability to phosphorylate Bad). Caspase-dependent apoptosis and P70S6K degradation were simultaneously prevented by the caspase inhibitors. Importantly, DD1 was shown to directly inhibit the proteasome's chymotrypsin-like activity in U937 cells. Apoptotic activity of the proteasome inhibitor bortezomib was also related to Bax activation and P70S6K downregulation. Accordingly, DD1 failed to induce P70S6K cleavage, Bax stimulation and apoptosis in K562 cells resistant to bortezomib. These results indicate that DD1 has the potential to eradicate AML cells and support a critical role for Bax and P70S6K in DD1-mediated proteasome inhibition and apoptosis of leukemia cells.
Masashi Sanada - One of the best experts on this subject based on the ideXlab platform.
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acquired expression of cblq367p in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia
Blood, 2017Co-Authors: Yuichiro Nakata, Takeshi Ueda, Akiko Nagamachi, Norimasa Yamasaki, Kenichiro Ikeda, Yasuyuki Sera, Keiyo Takubo, Akinori Kanai, Hideaki Oda, Masashi SanadaAbstract:Abstract Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by uncontrolled proliferation of dysplastic Myelomonocytes and frequent progression to acute myeloid leukemia (AML). We identified mutations in the Cbl gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutant Cbl in CMML pathogenesis, we generated conditional knockin mice for Cbl that express wild-type Cbl in a steady state and inducibly express CblQ367P, a CMML-associated Cbl mutant. CblQ367P mice exhibited sustained proliferation of Myelomonocytes, multilineage dysplasia, and splenomegaly, which are the hallmarks of CMML. The phosphatidylinositol 3-kinase (PI3K)-AKT and JAK-STAT pathways were constitutively activated in CblQ367P hematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine-chemokine receptor activity. Gem, a gene encoding a GTPase that is upregulated by CblQ367P, enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition, Evi1, a gene encoding a transcription factor, was found to cooperate with CblQ367P and progress CMML to AML. Furthermore, targeted inhibition for the PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity of CblQ367P-bearing CMML cells. Our findings provide insights into the molecular mechanisms underlying mutant Cbl-induced CMML and propose a possible molecular targeting therapy for mutant Cbl-carrying CMML patients.
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acquired expression of cblq367p in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia
Blood, 2017Co-Authors: Yuichiro Nakata, Takeshi Ueda, Akiko Nagamachi, Norimasa Yamasaki, Kenichiro Ikeda, Yasuyuki Sera, Keiyo Takubo, Akinori Kanai, Hideaki Oda, Masashi SanadaAbstract:Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by uncontrolled proliferation of dysplastic Myelomonocytes and frequent progression to acute myeloid leukemia (AML). We identified mutations in the Cbl gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutant Cbl in CMML pathogenesis, we generated conditional knock-in mice for Cbl that express wild-type Cbl in a steady state and inducibly express Cbl Q367P , a CMML-associated Cbl mutant. Cbl Q367P mice exhibited sustained proliferation of Myelomonocytes, multilineage dysplasia, and splenomegaly, which are the hallmarks of CMML. The PI3K-AKT and JAK-STAT pathways were constitutively activated in Cbl Q367P hematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine–chemokine receptor activity. Gem , a gene encoding a GTPase that is upregulated by Cbl Q367P , enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition, Evi1 , a gene encoding a transcription factor, was found to cooperate with Cbl Q367P and progress CMML to AML. Furthermore, targeted inhibition for PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity of Cbl Q367P -bearing CMML cells. Our findings provide insights into the molecular mechanisms underlying mutant Cbl -induced CMML and propose a possible molecular-targeting therapy for mutant Cbl -carrying CMML patients.
Sandrine Bouchet - One of the best experts on this subject based on the ideXlab platform.
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p70s6 kinase is a target of the novel proteasome inhibitor 3 3 diamino 4 methoxyflavone during apoptosis in human myeloid tumor cells
Biochimica et Biophysica Acta, 2013Co-Authors: Marion Piedfer, Sandrine Bouchet, Ruoping Tang, Christian Billard, Daniel Dauzonne, Brigitte BauvoisAbstract:Abstract Acute myeloid leukemia (AML) is a deadly disease characterized by the clonal expansion and accumulation of hematopoietic stem cells arrested at various stages of development. Clinical research efforts are currently focusing on targeted therapies that induce apoptosis in AML cells. Herein, the effects and mechanisms of the novel flavone 3,3′-diamino-4′-methoxyflavone (DD1) on AML cell dysfunction were investigated in AML cells (monoblast U937, Myelomonocyte OCI-AML3, promyelocyte NB4, myeloblast HL-60) and blood samples from patients with AML. The administration of DD1 inhibited proliferation and induced death of AML cell lines and reduced the clonogenic activity of AML, but not normal, blood cells. The flavone's apoptotic action in U937 cells was associated with recruitment of mitochondria, Bax activation, Bad dephosphorylation (at Ser 136 ), activation of caspases -8, -9, and -3 and cleavage of the caspase substrate PARP-1. DD1 induced a marked decrease in (i) Thr 389 -phosphorylation and (ii) protein levels of the caspase-3 substrate P70 ribosomal S6 kinase (P70S6K, known for its ability to phosphorylate Bad). Caspase-dependent apoptosis and P70S6K degradation were simultaneously prevented by the caspase inhibitors. Importantly, DD1 was shown to directly inhibit the proteasome's chymotrypsin-like activity in U937 cells. Apoptotic activity of the proteasome inhibitor bortezomib was also related to Bax activation and P70S6K downregulation. Accordingly, DD1 failed to induce P70S6K cleavage, Bax stimulation and apoptosis in K562 cells resistant to bortezomib. These results indicate that DD1 has the potential to eradicate AML cells and support a critical role for Bax and P70S6K in DD1-mediated proteasome inhibition and apoptosis of leukemia cells.
