Dose-dependent effects of Bcr-Abl in cell line models of different stages of chronic myeloid leukemia

Barnes, David; Schultheis, Beate; Adedeji, Simisade; Melo, Junia V.

doi:10.1038/sj.onc.1208796

Cited by 69 publications

(65 citation statements)

References 36 publications

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“…The discrepancy may also be caused by other differences in experimental conditions, such as the presence or absence of hematopoietic cytokines, because BCR/ABL was reported to inhibit cell adhesion induced by hematopoietic cytokines and growth factors (Bhatia et al, 2001). Consistent with this, in a very recent study by Barnes et al (2005), BCR/ABL increased adhesion of IL-3-dependent 32D cell line in a dose-dependent manner in the absence of IL-3 but had an inhibitory effect on IL-3-induced adhesion in a dose-independent manner. Thus, as compared with parental cells, adhesion of 32D cells expressing BCR/ABL at low levels was either increased or reduced in the absence or presence of IL-3, respectively.…”

Section: Rap1 Activation By Bcr/abl and Il-3mentioning

confidence: 86%

BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion

et al. 2006

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Section: Rap1 Activation By Bcr/abl and Il-3mentioning

confidence: 86%

BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion

et al. 2006

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“…In particular, gradual decreases in Dok-1 levels were observed with increasing levels of p210 bcr-abl . As discussed below, this could have significant functional implications, as the expression levels of p210 bcr-abl increase with CML progression (3,25). Thus, Dok-1 levels are expected to decrease as the disease progresses.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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Cellular transformation induced by oncogenic tyrosine kinases is a multistep process involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinasemediated cell transformation. Findings that its loss facilitates transformation induced by oncogenic tyrosine kinases suggest that Dok-1 inactivation could constitute an intermediate step in oncogenesis driven by these oncoproteins. However, whether Dok-1 is subject to regulation by oncogenic tyrosine kinases remained unknown. In this study, we show that oncogenic tyrosine kinases, including p210 bcr-abl and oncogenic forms of Src, downregulate Dok-1 by targeting it for degradation through the ubiquitin-proteasome pathway. This process is dependent on the tyrosine kinase activity of the oncoproteins and is mediated primarily by lysine-dependent polyubiquitination of Dok-1. Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is more pronounced in the context of a Dok-1 mutant that is largely refractory to oncogenic tyrosine kinase-induced degradation. Our findings suggest that proteasome-mediated downregulation of Dok-1 is a key mechanism by which oncogenic tyrosine kinases overcome the inhibitory effect of Dok-1 on cellular transformation and tumor progression.Protein tyrosine kinases (PTKs), of which more than 90 are encoded by the human genome, are key regulators of intracellular signal transduction pathways that control a variety of cellular processes, such as proliferation, differentiation, survival, cell movement, and cytoskeletal organization (46,52). Under physiological conditions, the activity of these kinases, including receptor and cytoplasmic PTKs, is tightly controlled to maintain cell and tissue homeostasis. However, when deregulated, due to, for example, mutations, gene amplifications, or impaired deactivation of the PTK, this control is lost, leading to aberrant downstream signaling, which can result in malignant transformation. To date, deregulation of more than 50 human PTKs has been implicated in the pathogenesis of various solid tumors and hematologic malignancies (2, 7, 36).Significant progress has been made toward unraveling the mechanisms of oncogenic activation of PTKs. Also, numerous studies have identified key signaling molecules and pathways that are activated by oncogenic tyrosine kinases (OTKs) and participate in mediating their effects on malignant transformation (45,55,57,71,72,75). However, besides triggering positive signaling events, OTKs also need to overcome negative regulatory constraints to drive tumor initiation and/or progression (7,24,42,57). These include, for instance, constraints brought about by tumor suppressors or inhibitory molecules that counteract the signaling activity triggered by the OTKs (17, 69). The nature of these "negative regulators" and, import...

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“…In fact, along with other frequent genetic and molecular abnormalities (e.g. double Ph 1 chromosome, p53 inactivation) (Johansson et al, 2002), increased expression and activity of the BCR/ABL oncoprotein is frequently observed during CML disease progression and in blast crisis CML (Elmaagacli et al, 2000;Jamieson et al, 2004;Barnes et al, 2005b), and sustained BCR/ABL expression in myeloid progenitor cell lines induces phenotypic changes (i.e. differentiation arrest) characteristic of CML-BC .…”

Section: CML Bcr/abl and Imatinibmentioning

confidence: 99%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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Dose-dependent effects of Bcr-Abl in cell line models of different stages of chronic myeloid leukemia

Cited by 69 publications

References 36 publications

BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion

BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

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