Activation of ERK1/2 by ΔRaf-1 : ER* represses Bim expression independently of the JNK or PI3K pathways

Weston, Claire R.; Balmanno, Kathryn; Chalmers, Claire J.; Hadfield, Kathryn; Molton, Sarah A; Ley, Rebecca; Wagner, Erwin F.; Cook, Simon J.

doi:10.1038/sj.onc.1206261

Cited by 162 publications

(217 citation statements)

References 49 publications

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“…However, the most striking phenotype is the resistance of both B and T cells to cytokine deprivation. 12 Indeed, Bim is expressed de novo following withdrawal of survival factors from haematopoietic cell lines, 12,17 primary sympathetic neurons, 18,19 osteoclasts 20 and fibroblasts 21 (Figure 2a-c). This is consistent with the observation that cell death following withdrawal of cytokines requires new gene expression in many cell types.…”

Section: Bim As a Sensor Of Survival Factors And Trophic Supportmentioning

confidence: 99%

“…22 The PI3K-PKB-FOXO pathway may operate to repress Bim in many other cell types including lymphocytes 17 and fibroblasts. 21 In addition, pharmacological inhibitors of the ERK1/2 MAP kinase pathway also induce Bim mRNA and protein levels in fibroblasts 21 and breast epithelial cells, 23,24 though the precise mechanism is not presently known. The ERK1/2 pathway does not act via the PI3K pathway to repress Bim, 21 but whether it acts independently of the FOXO transcription factors or decreases mRNA stability remains to be seen.…”

Section: Bim As a Sensor Of Survival Factors And Trophic Supportmentioning

confidence: 99%

“…21 In addition, pharmacological inhibitors of the ERK1/2 MAP kinase pathway also induce Bim mRNA and protein levels in fibroblasts 21 and breast epithelial cells, 23,24 though the precise mechanism is not presently known. The ERK1/2 pathway does not act via the PI3K pathway to repress Bim, 21 but whether it acts independently of the FOXO transcription factors or decreases mRNA stability remains to be seen. Expression of Bim following withdrawal of NGF from primary sympathetic neurons 18,19 may require AP-1 since an interfering mutant of c-Jun reduced the expression of Bim mRNA and protein.…”

Section: Bim As a Sensor Of Survival Factors And Trophic Supportmentioning

confidence: 99%

“…18 Subsequently, it has been shown that CEP-1347, a mixed-lineage kinase-3 inhibitor, prevents activation of JNK, the induction of Bim and reduces the apoptotic response to NGF withdrawal. 25,26 This mode of regulation may be confined to neuronal cell types since c-Jun is not required for Bim expression in fibroblasts 21 and JNK activation is not a ubiquitous response to withdrawal of survival factors.…”

Section: Bim As a Sensor Of Survival Factors And Trophic Supportmentioning

confidence: 99%

“…Subsequent studies in fibroblasts, using the conditional kinase DRaf-1:ER*, confirmed that selective activation of the ERK1/2 pathway was sufficient to promote the phosphorylation of Bim EL at multiple sites but did not apparently influence the phosphorylation of Bim S or Bim L . 21 However, the real complexity of Bim EL phosphorylation first became apparent after metabolic labelling and 2-D gel analysis in the IL-2-dependent Bal17 cell line. 28 This revealed that Bim EL was phosphorylated on four serine residues in viable cells and that withdrawal of IL-2 caused the loss of at least two of these phosphorylation sites prior to the onset of apoptosis, suggesting that there might be a causal relationship between de-phosphorylation of Bim EL and apoptosis following withdrawal of IL-2.…”

Section: Phosphorylation Of Bim El By Erk1/2mentioning

confidence: 99%

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Regulatory phosphorylation of Bim: sorting out the ERK from the JNK

et al. 2005

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Section: Bim As a Sensor Of Survival Factors And Trophic Supportmentioning

confidence: 99%

Section: Bim As a Sensor Of Survival Factors And Trophic Supportmentioning

confidence: 99%

Section: Bim As a Sensor Of Survival Factors And Trophic Supportmentioning

confidence: 99%

Section: Bim As a Sensor Of Survival Factors And Trophic Supportmentioning

confidence: 99%

Section: Phosphorylation Of Bim El By Erk1/2mentioning

confidence: 99%

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Regulatory phosphorylation of Bim: sorting out the ERK from the JNK

et al. 2005

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Capitalizing on paradoxical activation of the mitogen‐activated protein kinase pathway for treatment of Imatinib‐resistant mast cell leukemia

Wilhelm

Toledo

Simons

et al. 2022

Hematological Oncology

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Prevention of fatal side effects during cancer therapy of cancer patients with high‐dosed pharmacological inhibitors is to date a major challenge. Moreover, the development of drug resistance poses severe problems for the treatment of patients with leukemia or solid tumors. Particularly drug‐mediated dimerization of RAF kinases can be the cause of acquired resistance, also called “paradoxical activation.” In the present work we re‐analyzed the effects of different tyrosine kinase inhibitors (TKIs) on the proliferation, metabolic activity, and survival of the Imatinib‐resistant, KIT V560G, D816V‐expressing human mast cell (MC) leukemia (MCL) cell line HMC‐1.2. We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway. Indeed, these TKIs caused BRAF‐CRAF dimerization, resulting in ERK1/2 activation. The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC‐1.2 proliferation, metabolic activity, and induced apoptotic cell death. Effectiveness of this drug combination was recapitulated in the human KIT D816V MC line ROSAKIT D816V and in KIT D816V hematopoietic progenitors obtained from patient‐derived induced pluripotent stem cells (iPS cells) and systemic mastocytosis patient samples. In conclusion, mutated KIT‐driven Imatinib resistance and possible TKI‐induced paradoxical activation can be efficiently overcome by a low concentration Ponatinib and Trametinib co‐treatment, potentially reducing the negative side effects associated with MCL therapy.

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Vitamin D Control of Hematopoietic Cell Differentiation and Leukemia

Studzinski

Harrison

Wang

et al. 2015

J of Cellular Biochemistry

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It is now well known that in the mammalian body vitamin D is converted by successive hydroxylations to 1,25-dihydroxyvitamin D (1,25D), a steroid-like hormone with pleiotropic properties. These include important contributions to the control of cell proliferation, survival and differentiation, as well as the regulation of immune responses in disease. Here, we present recent advances in current understanding of the role of 1,25D in myelopoiesis and lymphopoiesis, and the potential of 1,25D and analogs (vitamin D derivatives; VDDs) for the control of hematopoietic malignancies. The reasons for the unimpressive results of most clinical studies of the therapeutic effects of VDDs in leukemia and related diseases may include the lack of a precise rationale for the conduct of these studies. Further, clinical trials to date have generally used extremely heterogeneous patient populations and, in many cases, small numbers of patients, generally without controls. Although low calcemic VDDs have been used and combined with agents that can increase the leukemia cell killing or differentiation effects in acute leukemias, the sequencing of agents used for combination therapy should to be more clearly delineated. Most importantly, it is recommended that in future clinical trials the rationale for the basis of the enhancing action of drug combinations should be clearly articulated and the effects on anticancer immunity should also be evaluated.

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Activation of ERK1/2 by ΔRaf-1 : ER* represses Bim expression independently of the JNK or PI3K pathways

Cited by 162 publications

References 49 publications

Regulatory phosphorylation of Bim: sorting out the ERK from the JNK

Regulatory phosphorylation of Bim: sorting out the ERK from the JNK

Capitalizing on paradoxical activation of the mitogen‐activated protein kinase pathway for treatment of Imatinib‐resistant mast cell leukemia

Vitamin D Control of Hematopoietic Cell Differentiation and Leukemia

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