Bcl-xL and Mcl-1 are involved in prevention of in vitro apoptosis in rat late-stage erythroblasts derived from bone marrow

Asano, Hitoshi; Fukunaga, Satoki; Deguchi, Yoshihito; Kawamura, Satoshi; Inaba, Mutsumi

doi:10.2131/jts.37.23

Cited by 9 publications

(4 citation statements)

References 28 publications

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“…Moreover, anti-apoptotic Bcl2l1/Bcl-xL, Mcl1, Trib3 and pro-apoptotic Nix (coexpressed with Bcl-xL during erythroid maturation) were not upregulated in KIT D816V cells (Figures 4a and b, Supplementary Figure 4A). 21,[37][38][39][40] Alongside, downregulation of Bad and Bid was impaired (Figure 4a). These data show that continuous Kit signaling perturbs induction of the transcriptional program associated with terminal erythroid maturation and interferes with regulation of key mediators of cell cycle control, cell death and survival, thereby leading to continued proliferation and elevated apoptosis during terminal differentiation.…”

Section: Kitmentioning

confidence: 98%

Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver

et al. 2014

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Signaling by the stem cell factor receptor Kit in hematopoietic stem and progenitor cells is functionally associated with the regulation of cellular proliferation, differentiation and survival. Expression of the receptor is downregulated upon terminal differentiation in most lineages, including red blood cell terminal maturation, suggesting that omission of Kit transduced signals is a prerequisite for the differentiation process to occur. However, the molecular mechanisms by which Kit signaling preserves the undifferentiated state of progenitor cells are not yet characterized in detail. In this study, we generated a mouse model for inducible expression of a Kit receptor carrying an activating mutation and studied its effects on fetal liver hematopoiesis. We found that sustained Kit signaling leads to expansion of erythroid precursors and interferes with terminal maturation beyond the erythroblast stage. Primary KIT D816V erythroblasts stimulated to differentiate fail to exit cell cycle and show elevated rates of apoptosis because of insufficient induction of survival factors. They further retain expression of progenitor cell associated factors c-Myc, c-Myb and GATA-2 and inefficiently upregulate erythroid transcription factors GATA-1, Klf1 and Tal1. In KIT D816V erythroblasts we found constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, elevated expression of the src kinase family member Lyn and impaired Akt activation in response to erythropoietin. We demonstrate that the block in differentiation is partially rescued by MAPK inhibition, and completely rescued by the multikinase inhibitor Dasatinib. These results show that a crosstalk between Kit and erythropoietin receptor signaling cascades exists and that continuous Kit signaling, partly mediated by the MAPK pathway, interferes with this crosstalk. Erythroid cell proliferation, differentiation and survival are tightly regulated to ensure supply of the organism with sufficient numbers of red blood cells. Regulation of these processes is governed by two major signaling receptors, the stem cell factor (SCF) receptor Kit and the erythropoietin receptor (EpoR). Kit is expressed in hematopoietic stem and progenitor cells and becomes downregulated upon differentiation of colony-forming unit erythroid cells.1 EpoR gets upregulated after erythroid commitment and is expressed until later erythroblast stages. Both receptors are essential for erythroid development, as Kit or EpoR-deficient mice die in utero because of impaired fetal liver erythropoiesis.3,4 The roles of Kit and EpoR in erythropoiesis are partially overlapping and signal integration after co-stimulation results in proliferative synergy and enhanced survival. [5][6][7] However, Kit has been attributed a primary role in proliferation, 8,9 whereas EpoR has its main role in mediating differentiation and survival.

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Section: Kitmentioning

confidence: 98%

Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver

et al. 2014

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“…Mcl-1 expression, just like Bcl-xL expression, is highly induced under conditions that are conducive to survival and by differentiation signals from cytokines and growth factors [11,12]. Mitogen-activated protein kinase (MAPK)-phosphatidylinositol-3 (PI3K)- and Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-dependent pathways have all been implicated in the stimulation of Mcl-1 transcription, acting via specific transcription factor response elements in the Mcl-1 gene promoter [13-15].…”

Section: Introductionmentioning

confidence: 99%

The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition

et al. 2012

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BackgroundIt has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. Mcl-1 is a critical survival protein in a variety of cell lineages and is critically regulated via ubiquitination.MethodsThe Mcl-1, Bcl-xL and USP9X expression patterns in human lung and colon adenocarcinomas were evaluated via immunohistochemistry. Interaction between USP9X and Mcl-1 was demonstrated by immunoprecipitation-western blotting. The protein expression profiles of Mcl-1, Bcl-xL and USP9X in multiple cancer cell lines were determined by western blotting. Annexin-V staining and cleaved PARP western blotting were used to assay for apoptosis. The cellular toxicities after various treatments were measured via the XTT assay.ResultsIn our current analysis of colon and lung cancer samples, we demonstrate that Mcl-1 and Bcl-xL are overexpressed and also co-exist in many tumors and that the expression levels of both genes correlate with the clinical staging. The downregulation of Mcl-1 or Bcl-xL via RNAi was found to increase the sensitivity of the tumor cells to chemotherapy. Furthermore, our analyses revealed that USP9X expression correlates with that of Mcl-1 in human cancer tissue samples. We additionally found that the USP9X inhibitor WP1130 promotes Mcl-1 degradation and increases tumor cell sensitivity to chemotherapies. Moreover, the combination of WP1130 and ABT-737, a well-documented Bcl-xL inhibitor, demonstrated a chemotherapeutic synergy and promoted apoptosis in different tumor cells.ConclusionMcl-1, Bcl-xL and USP9X overexpression are tumor survival mechanisms protective against chemotherapy. USP9X inhibition increases tumor cell sensitivity to various chemotherapeutic agents including Bcl-2/Bcl-xL inhibitors.

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“…EPO/EPOR binding upregulates Bcl-xl expression via inhibition of caspase activities, thus resulting in the protection of erythroid cells from apoptosis [ 33 , 34 ]. A rat study showed that EPO stimulation resulted in reduced apoptotic cells death of late-stage erythroblast accompanied by decreased caspase-3 and caspase-9 activities and upregulated the Bcl-xl mRNA, resulting in decreases in the mRNA ratios of Bak, Bax, Bad, to Bcl-xl, which is indicative of the induction of apoptosis through mitochondrial pathway in rat late-stage cultured erythroblasts derived from bone marrow [ 35 ] and Bcl-xl and Mcl expression increase and Bid, Bax, and Bim decrease in bone marrow-derived definitive erythroblasts [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

PI3K-Akt Signal Transduction Molecules Maybe Involved in Downregulation of Erythroblasts Apoptosis and Perifosine Increased Its Apoptosis in Chronic Mountain Sickness

Zhao

et al. 2017

Med Sci Monit

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BackgroundChronic mountain sickness (CMS) has a higher incidence in the plateau region. The one of its principal characters is excessive erythrocytosis. The PI3K-Akt pathway plays an important role in the process of erythropoiesis, and could downregulate apoptosis by regulating apoptosis-related molecules. In this paper, we explored the change in apoptosis of erythroblasts and the effect of the PI3K-Akt signal pathway on erythroblasts apoptosis in CMS.Material/MethodsA total of 22 CMS and 20 non-CMS participants were involved in this study. Bone marrow mononuclear cells were cultured and treated with celecoxib and perifosine in vitro for 72 hours. The apoptotic rate, the mRNA expressions of Akt, Bcl-xl, and caspase-9, and the protein expressions of Akt, p-Akt, Bcl-xl, and caspase-9 were determined by flow cytometry, quantitative RT-PCR, and western-blot technique.ResultsThe apoptotic rate of cultured erythroblasts was lower in the CMS group than in the non-CMS group. It was increased after perifosine intervention. The mRNA and protein expressions of Akt and Bcl-xl were higher and caspase-9 was lower in the CMS group than the non-CMS group. Perifosine induced decreased Bcl-xl mRNA and proteins and p-Akt proteins, and increased caspase-9 mRNA and proteins in vitro. In the CMS group, the hemoglobin concentration was correlated with apoptotic rate negatively and with Bcl-xl mRNA positively in erythroblasts; the erythroblasts apoptotic rate was negatively associated with the Akt mRNA and Bcl-xl mRNA.ConclusionThe erythroblasts apoptosis was downregulated and the PI3K-Akt signal pathway appeared to be involved in the mechanism of decreased erythroblasts apoptosis in CMS.

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Bcl-xL and Mcl-1 are involved in prevention of in vitro apoptosis in rat late-stage erythroblasts derived from bone marrow

Cited by 9 publications

References 28 publications

Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver

Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver

The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition

PI3K-Akt Signal Transduction Molecules Maybe Involved in Downregulation of Erythroblasts Apoptosis and Perifosine Increased Its Apoptosis in Chronic Mountain Sickness

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