Treatment by design in leukemia, a meeting report, Philadelphia, Pennsylvania, December 2002

Larson, Richard A.; Gq, Daley; Schiffer, CA; Porcu, Pierluigi; Ch, Pui; Jp, Marie; Ls, Steelman; Fe, Bertrand; McCubrey, James A.

doi:10.1038/sj.leu.2403156

Cited by 8 publications

(5 citation statements)

References 183 publications

(164 reference statements)

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“…BCR-ABL activates the Ras/Raf/MEK/ERK, JAK/STAT and PI3K/Akt signal transduction pathways, which results in a proliferative effect. [451][452][453][454][455][456][457][458][459][460][461][462][463][464] BCR-ABL-transformed cells display hyperactivity of Ras, Raf and JAK/STAT. This could occur by multiple mechanisms, by BCR-ABL activating these pathways directly, or by the induction of autocrine cytokines, which in turn activate these pathways.…”

Section: Figure 16mentioning

confidence: 99%

“…[451][452][453][454][455][456][457][458][459][460][461][462][463][464] The BCR-ABL oncoprotein induces a proliferative effect, while full transformation requires additional genetic events (translocation of other oncogenes, for example, AML1/ EVI1, AML/ETO, NuP98/HOXA) that block differentiation. 451 Over the past few years, it has been discovered that BCR-ABL also has effects on pre-existing cellular signaling circuits. BCR-ABL activates the Ras/Raf/MEK/ERK, JAK/STAT and PI3K/Akt signal transduction pathways, which results in a proliferative effect.…”

Section: Figure 16mentioning

confidence: 99%

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JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis

et al. 2004

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Section: Figure 16mentioning

confidence: 99%

Section: Figure 16mentioning

confidence: 99%

JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis

et al. 2004

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“…27,35 Even though more recent studies have attributed the anti-apoptotic effects of Raf signaling to MEK/ERK-independent pathways, MEK/ERK also contributes to prosurvival signals transduced by Raf. [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] Anti-apoptotic signals initiated by the Raf/MEK/ERK pathway are mainly transcription-dependent mechanisms which involve transcription factors including CREB, c-Myc, Ets and AP-1. 14 The Raf/MEK/ERK pathway couples signals from cell surface receptors to these transcription factors and therefore modulate the expression of genes that regulate cell cycle progression and cell survival.…”

Section: Discussionmentioning

confidence: 99%

“…Cdks, cyclins, CKIs, cytokines, growth factors, apoptosis prevention, (e.g., Bcl-2, Bcl-XL, Fas-L, Mcl-1) and caspases. [57][58][59][60][61][62][63][64] However, it was suggested that the Raf signaling-induced transcription factor activation is cell type specific and may also depend on the differentiation state of the cells. 14 In this paper, we demonstrated that activation of B-Raf in FDC-P1 murine hematopoietic cells induced the expression of proapoptotic Bad molecule.…”

Section: Discussionmentioning

confidence: 99%

B-Raf and Insulin Synergistically Prevent Apoptosis and Induce Cell Cycle Progression in Hematopoietic Cell

Shelton

Chang²,

Lee

et al. 2004

Cell Cycle

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FDC-P1 hematopoietic cells were conditionally transformed to grow in response to ∆B Raf:ER, ∆Raf-1:ER or ∆A-Raf:ER in which the hormone binding domain of the estrogen receptor (ER) was linked to the N-terminal truncated (∆) Raf genes. When these cells were deprived of IL-3 or β-estradiol for 24 hrs, they exited the cell cycle and underwent apoptosis. FD/∆Raf-1:ER and FD/∆A-Raf:ER, but not FD/∆B-Raf:ER cells, were readily induced to re-enter the cell cycle after addition of β-estradiol or IL-3. Deprived FD/∆Raf-1:ER, but not FD/∆B-Raf:ER cells, expressed activated forms of MEK1 and ERK after β-estradiol or IL-3 stimulation. Insulin or β-estradiol alone did not induce FD/∆B-Raf:ER cells to re-enter the cell cycle, whereas cell cycle entry was observed upon their co-addition. Apoptosis was prevented in FD/∆B-Raf:ER cells when they were cultured in the presence of IL-3 or β-estradiol, whereas they underwent apoptosis in their absence. Insulin by itself did not prevent apoptosis, however, upon ∆B-Raf:ER or ∆Raf-1:ER activation and addition of insulin, more than an additive effect was observed in both lines indicating that these pathways synergized to prevent apoptosis. Raf isoforms differ in their abilities to control apoptosis and cell cycle progression, and B-Raf requires insulin-activated pathways for full antiapoptotic and proliferative activity.

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“…These receptors are comprised of a ligand-specific a-subunit, and a common b-subunit (b c ), which is essential for signal transduction (Kitamura et al, 1991;Sato et al, 1993;Ihle et al, 1995;Pritchard et al, 1995;Steelman et al, 1996;Blalock et al, 1999;McCubrey et al, 2000). After receptor ligation, the Shc protein becomes phosphorylated and forms a complex with the receptor (Larson et al, 2003;Steelman et al, 2004). Shc then recruits the Grb2/Sos complex to the b c chain, which subsequently results in Ras activation, leading to the stimulation of Raf and MEK and mobilization of the MAP (ERK) kinase cascade (Bosch et al, 1997;Blalock et al, 1999Blalock et al, , 2000aBlalock et al, , b, 2001Chang et al, 2003b, c).…”

Section: Introductionmentioning

confidence: 99%

Effects of a conditionally active v-ErbB and an EGF-R inhibitor on transformation of NIH-3T3 cells and abrogation of cytokine dependency of hematopoietic cells

et al. 2004

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Epidermal growth factor (EGF) and its cognate receptor (EGF-R) are often dysregulated in human neoplasia. Moreover, EGF-R-transformed cell lines have constitutive EGF-R activity, which makes elucidation of its effects difficult to determine. In the following studies, the effects of a novel conditionally activated form of EGF-R, v-ErbB:ER, on the morphological transformation of NIH-3T3 cells and the abrogation of hematopoietic cell cytokine dependence were investigated. The v-ErbB ES-4 oncogene was fused to the hormone binding domain of the estrogen receptor (ER). This construct, v-ErbB:ER, requires beta-estradiol or 4-OH tamoxifen for activation. v-ErbB:ER conditionally transformed NIH-3T3 cells and abrogated cytokine dependence of hematopoietic cells. Stimulation of v-ErbB:ER activity resulted in the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and Raf/MEK/ERK kinase cascades. To determine the importance of these signal transduction pathways, the conditionally transformed hematopoietic cells were treated with EGF-R, PI3K and MEK inhibitors. The EGF-R inhibitor AG1478 effectively inhibited MEK, ERK and Akt activation, and induced apoptosis when the cells were grown in response to v-ErbB:ER. Apoptosis was observed at 100- to 1000-fold lower concentrations of AG1478 when the cells were grown in response to v-ErbB:ER as opposed to IL-3. Furthermore, the parental, BCR-ABL- and Raf-transformed cells were only susceptible to the apoptosis-inducing effects of AG1478 at the highest concentrations demonstrating the specificity of these inhibitors. MEK or PI3K inhibitors suppressed ERK or Akt activation, respectively, and induced apoptosis in the v-ErbB:ER-responsive cells. However, MEK and PI3K inhibitors only induced apoptosis at 1000-fold higher concentrations than the EGFR inhibitor. This novel v-ErbB:ER construct and these conditionally transformed cell lines will be useful to further elucidate ErbB-mediated signal transduction and to determine the effectiveness of various inhibitors in targeting different aspects of EGF-R-mediated signal transduction and malignant transformation.

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Treatment by design in leukemia, a meeting report, Philadelphia, Pennsylvania, December 2002

Cited by 8 publications

References 183 publications

JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis

JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis

B-Raf and Insulin Synergistically Prevent Apoptosis and Induce Cell Cycle Progression in Hematopoietic Cell

Effects of a conditionally active v-ErbB and an EGF-R inhibitor on transformation of NIH-3T3 cells and abrogation of cytokine dependency of hematopoietic cells

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