Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms by which interferon-alpha (IFN-alpha) mediates its anti-leukemic effects in chronic myelogenous leukemia (CML) cells are not known. We determined whether p38 MAPK is activated by IFN-alpha in BCR-ABL-expressing cells and whether its function is required for the generation of growth inhibitory responses. IFN-alpha treatment induced phosphorylation/activation of p38 in the IFN-alpha-sensitive KT-1 cell line, but not in IFN-alpha-resistant K562 cells. Consistent with this, IFN-alpha treatment of KT-1 (but not K562) cells induced activation of the small GTPase Rac1, which functions as an upstream regulator of p38. In addition, IFN-alpha-dependent phosphorylation/activation of p38 was induced by treatment of primary granulocytes isolated from the peripheral blood of patients with CML. To define the functional role of the Rac1/p38 MAPK pathway in IFN-alpha signaling, the effects of pharmacological inhibition of p38 on the induction of IFN-alpha responses were determined. Treatment of KT-1 cells with the p38-specific inhibitors SB203580 and SB202190 reversed the growth inhibitory effects of IFN-alpha. On the other hand, the MEK kinase inhibitor PD098059 had no effects, further demonstrating the specificity of these findings. To directly determine the significance of IFN-alpha-dependent activation of p38 in the induction of the anti-leukemic effects of IFN-alpha, we evaluated the effects of p38 inhibition on leukemic colony formation in bone marrow samples of patients with CML. IFN-alpha inhibited leukemic granulocyte/macrophage colony formation in a dose-dependent manner, whereas concomitant treatment with p38 inhibitors reversed such an inhibition. Thus, the Rac1/p38 MAPK pathway is activated by IFN-alpha in BCR-ABL-expressing cells and appears to play a key role in the generation of the growth inhibitory effects of IFN-alpha in CML cells.
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PMID:The p38 MAPK pathway mediates the growth inhibitory effects of interferon-alpha in BCR-ABL-expressing cells. 1135 67

The BCR/ABL fusion tyrosine kinase activates various intracellular signaling pathways, thus causing chronic myeloid leukemia (CML). Here we demonstrate that the inducible expression of BCR/ABL in a murine hematopoietic cell line, TonB210, leads to the activation of the Ras family small GTPase Rap1, which is inhibited by the ABL kinase inhibitor imatinib. The Rap1 activity in a CML cell line, K562, was also inhibited by imatinib. Inhibition of Rap1 activation by a dominant negative mutant of Rap1, Rap1-N17, or SPA-1 inhibited the BCR/ABL-induced activation of Elk-1. BCR/ABL also activated in a kinase activity-dependent manner the B-Raf kinase, which is an effector molecule of Rap1 and a potent activator of the MEK/Erk/Elk-1 signaling pathway. Together, these data suggest that, in addition to the well-established Ras/Raf-1 pathway, BCR/ABL activates the alternative signaling pathway involving Rap1 and B-Raf to activate Erk, which may play important roles in leukemogenesis.
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PMID:BCR/ABL activates Rap1 and B-Raf to stimulate the MEK/Erk signaling pathway in hematopoietic cells. 1559 48

The Bcr/Abl oncoprotein is directly responsible for the development of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia in humans. The adapter protein Crkl is one of the most prominently tyrosine-phosphorylated substrates of Bcr/Abl in cells and tissues isolated from such patients. The guanine nucleotide exchange factor for the small GTPase Rap1, C3G, binds constitutively to Crkl. Here, we report that Crkl mediates the formation of protein complexes that include C3G and Bcr/Abl. These complexes contain highly elevated levels of tyrosine-phosphorylated C3G and P130Cas, a scaffolding protein. Moreover, the presence of Rap1 further promoted tyrosine phosphorylation of C3G and Cas. Co-expression of Crkl and C3G with Bcr/Abl generated increased levels of activated Rap1. In addition, lysates from leukemic cells of P190 BCR/ABL transgenic mice and of the myelogenous leukemia cell line K562 contained tyrosine-phosphorylated C3G and activated Rap1. These data suggest a role for C3G-mediated Rap1 activation in Bcr/Abl-induced leukemia development.
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PMID:Interaction of Bcr/Abl with C3G, an exchange factor for the small GTPase Rap1, through the adapter protein Crkl. 1598 36

Rap1, a member of the Ras superfamily, regulates cytoskeletal changes in lower eukaryots and integrin-mediated adhesion in hematopoietic cells. Sustained activation of Rap1 in mouse hematopoietic stem cells causes expansion of hematopoietic progenitors, followed by a myeloproliferative disorder mimicking chronic myeloid leukemia. Moreover, these mice develop a B-cell lymphoproliferative disorder resembling chronic lymphocytic leukemia. Here, we used HEK 293 cells as a tool to examine the molecular effects of Rap1. We observed that a constitutively active Rap1 mutant localized predominantly in the nucleus. Nuclear localization of endogenous Rap1-GTP was also detected upon physiologic activation. A potential consequence of nuclear localization of Rap1-GTP is the regulation of gene expression. We used a high throughput proteomic approach to identify gene products potentially modulated by Rap1-GTP. Out of 1000 proteins examined, 64 proteins were upregulated and 66 proteins were downregulated. The differentially expressed gene products belong to cytoskeletal regulator proteins, signaling molecules, transcription factors, viability regulators, and protein transporters. This analysis provides the first fingerprint of gene product expression regulated by Rap1 and may contribute to our understanding of malignant transformation mechanisms regulated by this small GTPase.
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PMID:Active Rap1, a small GTPase that induces malignant transformation of hematopoietic progenitors, localizes in the nucleus and regulates protein expression. 1748 43

The Bcr/Abl oncogene is responsible for the development of Ph-chromosome positive acute lymphoblastic leukemia and chronic myelogenous leukemia in humans. Previous studies demonstrated that Bcr/Abl expression is associated with elevated levels of activated Rap1, a small GTPase. Levels of activated Rap1 are determined by a balance between GTPase activating and G-nucleotide exchange factor activity. We show that Bcr/Abl forms a protein-protein complex with Spa-1, a GTPase activating protein for Rap1, both in COS-1 cells as well as in primary lymphoblastic leukemia cells from a transgenic P190 BCR/ABL mouse model. The interaction between Spa-1 and P190 did not affect the tyrosine kinase activity of P190, nor did Spa-1 become phosphorylated on tyrosine as a result of the interaction. P190 and Spa-1 co-localized to peripheral actin structures in primary lymphoblasts and expression of Spa-1 in the leukemic lymphoblasts decreased the migration of these cells. The binding of Bcr/Abl to Spa-1 may cause aberrant subcellular location of Spa-1 and affect migration of these cells.
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PMID:Bcr/Abl P190 interaction with Spa-1, a GTPase activating protein for the small GTPase Rap1. 1881 51

BCR/ABL is a well-known activator of multiple signaling pathways. RalA, a Ras downstream signaling molecule and a small GTPase, plays an important role in Bcr-Abl-induced leukemogenesis but the exact mechanism remains elusive. Here, we show that RalA GTPase activity is commonly high in chronic myelogenous leukemia (CML) cell lines and patient samples. Overexpression of RalA results in malignant transformation and progression, and induces resistance to imatinib (IM) in BaF3 and K562 cell lines. RalA reduced survival and led to IM resistance in a xenografted mouse model. Ablation of RalA by either siRNA or miR-181a, a RalA targeting microRNA, attenuated the malignant phenotypes in K562 cells. RBC8, a selective Ral inhibitor, enhanced the inhibitory effects of IM in K562, KCL22 and BaF3-P210 cells. Interestingly, the phospho-specific protein microarray assay revealed that multiple phosphorylation signal proteins were decreased by RalA inhibition, including SAPK, JNK, SRC, VEGFR2, P38 MAPK, c-Kit, JunB, and Keratin18. Among them, P38 MAPK and SAPK/JNK are Ras downstream signaling kinases. Taken together, RalA GTPase might be an important oncogene activating the Ras-related signaling pathway in CML.
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PMID:RalA, a GTPase targeted by miR-181a, promotes transformation and progression by activating the Ras-related signaling pathway in chronic myelogenous leukemia. 2696 92