Mcl-1 is a common target of stem cell factor and interleukin-5 for apoptosis prevention activity via MEK/MAPK and PI-3K/Akt pathways

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1764-1771 ◽  
Author(s):  
Huei-Mei Huang ◽  
Chang-Jen Huang ◽  
Jeffrey Jong-Young Yen
Keyword(s):  
Stem Cell ◽  
Signaling Pathways ◽  
Stem Cell Factor ◽  
Early Stage ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 5 ◽  
Mitogen Activated Protein ◽  
Highly Correlated ◽  
Cytokine Stimulation

Stem cell factor (SCF) has been suggested as essential for optimal production of various hematopoietic lineages mainly because of its apoptosis prevention function when it costimulates with other cytokines. However, the underlying mechanism of this synergism of apoptosis prevention is largely unknown. The present study examined the expression of some Bcl-2 family members, including Bcl-2, Bcl-XL, Mcl-1, and Bax, in response to cytokine stimulation in TF-1 and JYTF-1 cells in which SCF costimulation is differentially required for optimal proliferation. The results revealed that only the expression of Mcl-1 highly correlated with the antiapoptotic activity of interleukin-5 (IL-5) and the synergistic effect of SCF. In TF-1 cells, the defect of IL-5 in apoptosis suppression and Mcl-1 induction was associated with the incapability to highly phosphorylate Janus kinases (JAK1, JAK2), signal transducer and activator of transcription-5 (STAT5), mitogen-activated protein kinase (MAPK), and Akt/PKB, whereas SCF costimulation restored the potent phosphorylation of MAPK and Akt/PKB, but not STAT5. The importance of MAPK and Akt/PKB signaling pathways in regulating the expression of Mcl-1 and cell survival was further supported by the observation that inhibition of MEK by PD98059 or phosphatidylinositol-3 kinase (PI-3K) by LY294002 independently resulted in the reduction of Mcl-1 expression and loss of cell viability. Therefore, the data suggest that Mcl-1 is a common antiapoptotic target of both early-stage cytokine SCF and late-stage cytokine IL-5. Both MEK/MAPK and PI-3K/Akt signaling pathways are essential in the regulation of Mcl-1 expression and apoptosis prevention.

Mcl-1 is a common target of stem cell factor and interleukin-5 for apoptosis prevention activity via MEK/MAPK and PI-3K/Akt pathways

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1764-1771 ◽  
Author(s):  
Huei-Mei Huang ◽  
Chang-Jen Huang ◽  
Jeffrey Jong-Young Yen
Keyword(s):  
Stem Cell ◽  
Signaling Pathways ◽  
Stem Cell Factor ◽  
Early Stage ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 5 ◽  
Mitogen Activated Protein ◽  
Highly Correlated ◽  
Cytokine Stimulation

Abstract Stem cell factor (SCF) has been suggested as essential for optimal production of various hematopoietic lineages mainly because of its apoptosis prevention function when it costimulates with other cytokines. However, the underlying mechanism of this synergism of apoptosis prevention is largely unknown. The present study examined the expression of some Bcl-2 family members, including Bcl-2, Bcl-XL, Mcl-1, and Bax, in response to cytokine stimulation in TF-1 and JYTF-1 cells in which SCF costimulation is differentially required for optimal proliferation. The results revealed that only the expression of Mcl-1 highly correlated with the antiapoptotic activity of interleukin-5 (IL-5) and the synergistic effect of SCF. In TF-1 cells, the defect of IL-5 in apoptosis suppression and Mcl-1 induction was associated with the incapability to highly phosphorylate Janus kinases (JAK1, JAK2), signal transducer and activator of transcription-5 (STAT5), mitogen-activated protein kinase (MAPK), and Akt/PKB, whereas SCF costimulation restored the potent phosphorylation of MAPK and Akt/PKB, but not STAT5. The importance of MAPK and Akt/PKB signaling pathways in regulating the expression of Mcl-1 and cell survival was further supported by the observation that inhibition of MEK by PD98059 or phosphatidylinositol-3 kinase (PI-3K) by LY294002 independently resulted in the reduction of Mcl-1 expression and loss of cell viability. Therefore, the data suggest that Mcl-1 is a common antiapoptotic target of both early-stage cytokine SCF and late-stage cytokine IL-5. Both MEK/MAPK and PI-3K/Akt signaling pathways are essential in the regulation of Mcl-1 expression and apoptosis prevention.

scholarly journals Effect of Urban Particulate Matter on Vocal Fold Fibrosis through the MAPK/NF-κB Signaling Pathway

2020 ◽  
Vol 21 (18) ◽  
pp. 6643
Author(s):  
Ho-Ryun Won ◽  
Seung-Nam Jung ◽  
Min-Kyung Yeo ◽  
Shinae Yi ◽  
Lihua Liu ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Signaling Pathways ◽  
Vocal Fold ◽  
Animal Experiments ◽  
Vocal Folds ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Histological Evaluation ◽  
Mitogen Activated Protein

Particulate matter (PM) is an environmental exposure factor that adversely affects human health. PM is a risk factor for various diseases. However, the mechanism by which PM affects the vocal folds (VF) has not yet been evaluated. Thus, we investigated the cytotoxic effects of PM on human vocal fold fibroblasts (hVFF) and the underlying signaling pathways. hVFF were isolated from human VF. The effect of PM on hVFF, and the underlying mechanism, were analyzed using Western blot, quantitative real-time polymerase chain reaction, and flow cytometry. In addition, a histological evaluation was performed in animal experiments. Cell proliferation decreased after the PM treatment. PM increased the expression of interleukin (IL)-6 and IL-1β. The generation of reactive oxygen species (ROS) in PM-treated hVFF and subsequent activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways were confirmed. Furthermore, PM increased the expression of fibrosis-related markers and induced the accumulation of collagen in the extracellular matrix. As a result, PM exposure significantly enhances the inflammatory response on VF through the ROS-mediated activation of the MAPK and NF-κB signaling pathways. In addition, PM promotes differentiation into myofibroblasts and induces fibrosis. These results suggest that PM triggers an inflammatory reaction through ROS production and causes VF fibrosis.

KIT exon 8 mutations associated with core-binding factor (CBF)–acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3319-3321 ◽  
Author(s):  
Tobias M. Kohl ◽  
Susanne Schnittger ◽  
Joachim W. Ellwart ◽  
Wolfgang Hiddemann ◽  
Karsten Spiekermann
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Myeloid Leukemia ◽  
Apoptotic Cell ◽  
Mitogen Activated Protein Kinase ◽  
Core Binding Factor ◽  
Binding Factor ◽  
Mitogen Activated Protein ◽  
Acute Myeloid

AbstractKIT exon 8 mutations are located in the extracellular portion of the receptor and are strongly associated with core-binding factor (CBF)-acute myeloid leukemia (AML). To characterize the functional role of these mutants, we analyzed the proproliferative and antiapoptotic potential of 3 KIT exon 8 mutations in interleukin 3 (IL-3)-dependent Ba/F3 cells. All KIT exon 8 mutants induced receptor hyperactivation in response to stem cell factor (SCF) stimulation in terms of proliferation and resistance toward apoptotic cell death. A representative KIT exon 8 mutant showed spontaneous receptor dimerization, phosphorylation of mitogen-activated protein kinase (MAPK), and conferred IL-3-independent growth to Ba/F3 cells. MAPK and phosphatidylinositol 3-kinase (PI3-kinase) activation was essential for the phenotype of this mutant. Additionally, imatinib inhibited proliferation of KIT exon 8 mutant-expressing Ba/F3 cells. Our data show that KIT exon 8 mutations represent gain-of-function mutations and might represent a new molecular target for treatment of CBF leukemias. (Blood. 2005;105:3319-3321)

scholarly journals Identification of Tyr-703 and Tyr-936 as the primary association sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor

1999 ◽  
Vol 341 (1) ◽  
pp. 211-216 ◽  
Author(s):  
Kerstin THÖMMES ◽  
Johan LENNARTSSON ◽  
Monika CARLBERG ◽  
Lars RÖNNSTRAND
Keyword(s):  
Stem Cell ◽  
Stem Cell Factor ◽  
Specific Binding ◽  
Mitogen Activated Protein Kinase ◽  
Adapter Protein ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Mitogen Activated Protein ◽  
Src Homology

In this paper we demonstrate the presence of two novel in vivo autophosphorylation sites in the c-Kit/stem cell factor receptor (c-Kit/SCFR): Tyr-703 in the kinase insert and Tyr-936 in the C-terminal tail. We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936. It is shown that the association occurs through the Src homology 2 (SH2) domains of Grb2 and Grb7. Binding of Grb2 to Tyr-703 in the c-Kit/SCFR provides a link to the Ras/mitogen-activated protein kinase pathway.

Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1330-1336 ◽  
Author(s):  
Christine Möller ◽  
Jessica Alfredsson ◽  
Maria Engström ◽  
Hanna Wootz ◽  
Zou Xiang ◽  
...  
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Protein Kinase ◽  
Cell Survival ◽  
Cell Apoptosis ◽  
Stem Cell Factor ◽  
Mitogen Activated Protein Kinase ◽  
Proapoptotic Protein ◽  
Mitogen Activated Protein

AbstractMast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl-2 [B-cell lymphoma-2] interacting modulator of cell death), a Bcl-2 homology 3 (BH3)–only proapoptotic protein. SCF induced a rapid and transient phosphorylation of Akt (protein kinase B) and FOXO3a. SCF treatment prevented up-regulation of Bim protein expression and led to increased Bim phosphorylation. Bim phosphorylation was inhibited by PD98059 and LY294002 treatment, suggesting the involvement of mitogen-activated protein kinase kinase/mitogen-activated protein kinase (MEK/MAPK) and phosphatidylinositol 3 (PI3)–kinase pathways in this process. Overexpression of phosphorylation-deficient FOXO3a caused an up-regulation of Bim and induced mast cell apoptosis even in the presence of SCF. Mast cell apoptosis induced by the phosphorylation-deficient FOXO3a was attenuated in bim–/– mast cells. Because apoptosis is abnormally reduced in bim–/– mast cells, these data provide evidence that Akt-mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells.

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