Rac GTPases as key regulators of p210-BCR-ABL-dependent leukemogenesis

Thomas, Emily K.; Cancelas, José A.; Zheng, Yi; Williams, David A.

doi:10.1038/leu.2008.71

Cited by 58 publications

(55 citation statements)

References 65 publications

(60 reference statements)

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“…As with previous studies (37)(38)(39)(40)56), treatment of MDA-MB-468 cells with NSC23766 also induced cleavage and activation of caspase-3 and caspase-8 (Fig. 3C).…”

Section: Discussionsupporting

confidence: 57%

“…36). Repression of Rac1 activity by NSC23766 diminished Rac-dependent cell proliferation of PC3 prostate cancer line (36) and leukemia cell lines both in vitro and in vivo (37)(38)(39)(40); it also inhibited cell migration of several breast cancer cell lines (41) and induced apoptosis in leukemia (37)(38)(39)(40) and glioma (42) cell lines. Increasing evidence shows that Tiam1 and Trio are overexpressed in different types of human tumors (18)(19)(20), including human breast (42) carcinomas, which is believed to contribute to Rac1 hyperactivity.…”

Section: Introductionmentioning

confidence: 99%

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Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

Yoshida

Zhang

Rosado

et al. 2010

Molecular Cancer Therapeutics

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Rac1 GTPase regulates a variety of signaling pathways that are implicated in malignant phenotypes. Here, we show that selective inhibition of Rac1 activity by the pharmacologic inhibitor NSC23766 suppressed cell growth in a panel of human breast cancer cell lines, whereas it had little toxicity to normal mammary epithelial cells. NSC23766 elicits its cytotoxicity via two distinct mechanisms in a cell line-dependent manner: induction of G 1 cell cycle arrest in cell lines (MDA-MB-231, MCF7, and T47D) that express retinoblastoma (Rb) protein or apoptosis in Rb-deficient MDA-MB-468 cells. In MDA-MB-231 cells, Rac1 inhibition induced G 1 cell cycle arrest through downregulation of cyclin D1 and subsequent dephosphorylation/inactivation of Rb. By contrast, MDA-MB-468 cells underwent substantial apoptosis that was associated with loss of antiapoptotic proteins survivin and X-linked inhibitor of apoptosis protein (XIAP). Rac1 knockdown by RNAi interference confirmed the specificity of NSC23766 and requirement for Rac1 in the regulation of cyclin D1, survivin, and XIAP in breast cancer cells. Further, NF-κB, but not c-Jun NH 2 -terminal kinase or p38 pathways, mediates the survival signal from Rac1. Overall, our results indicate that Rac1 plays a central role in breast cancer cell survival through regulation of NF-κB-dependent gene products. Mol Cancer Ther; 9(6); 1657-68. ©2010 AACR.

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“…As with previous studies (37)(38)(39)(40)56), treatment of MDA-MB-468 cells with NSC23766 also induced cleavage and activation of caspase-3 and caspase-8 (Fig. 3C).…”

Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

Yoshida

Zhang

Rosado

et al. 2010

Molecular Cancer Therapeutics

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“…In addition to inhibiting IRF-4's DNA binding, IBP has been shown to function as an activator for Rac (38,39). It has been shown that Rac1 and Rac2 are key regulators of leukemogenesis induced by BCR/ABL (40). Thus, IRF-4 interaction with IBP may play a role in suppressing BCR/ABL transformation.…”

Section: Discussionmentioning

confidence: 99%

IRF-4 Suppresses BCR/ABL Transformation of Myeloid Cells in a DNA Binding-independent Manner

Ren

2012

Journal of Biological Chemistry

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Background: IRF-4 functions both as an oncoprotein and as a tumor suppressor in different cell context. Results: We found that IRF-4 inhibits BCR/ABL transformation of myeloid cells independent of its DNA binding and nuclear localization. Conclusion:The oncogenic and tumor suppressor functions of IRF-4 involve distinct pathways. Significance: The studies help to develop improved therapies for malignancies involving IRF-4.

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“…2 show that Sos1 silencing results in alteration of macrophage cytoskeleton dynamics similar to those reported in cells where Abl, or Src-family kinases, were deficient or inhibited (14,15,18). The established relation among Abl, Src, and Rac in different cell context (17,28,36,(40)(41)(42)(43) prompted experiments to address whether Sos1 silencing affects Rac activation.…”

Section: Sos1 Regulates Cytoskeleton Dynamics In Macrophagesmentioning

confidence: 99%

Sos1 Regulates Macrophage Podosome Assembly and Macrophage Invasive Capacity

Baruzzi

Remelli

Lorenzetto

et al. 2015

The Journal of Immunology

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Podosomes are protrusive structures implicated in macrophage extracellular matrix degradation and three-dimensional migration through cell barriers and the interstitium. Podosome formation and assembly are regulated by cytoskeleton remodeling requiring cytoplasmic tyrosine kinases of the Src and the Abl families. Considering that Abl has been reported to phosphorylate the guanine nucleotide exchange factor Sos1, eliciting its Rac-guanine nucleotide exchange factor activity, and Rac regulates podosome formation in myeloid cells and invadopodia formation in cancer cells, we addressed whether Sos1 is implicated in podosome formation and function in macrophages. We found that ectopically expressed Abl or the Src kinase Fgr phosphorylate Sos1, and the Src kinases Hck and Fgr are required for Abl and Sos1 phosphorylation and Abl/Sos1 interaction in macrophages. Sos1 localizes to podosomes in both murine and human macrophages, and its silencing by small interfering RNA results in disassembly of murine macrophage podosomes and a marked reduction of GTP loading on Rac. Matrix degradative capacity, three-dimensional migration through Matrigel, and transmigration through an endothelial cell monolayer of Sos1-silenced macrophages were inhibited. In addition, Sos1- or Abl-silenced macrophages, or macrophages treated with the selective Abl inhibitor imatinib mesylate had a reduced capability to migrate into breast tumor spheroids, the majority of cells remaining at the margin and the outer layers of the spheroid itself. Because of the established role of Src and Abl kinases to regulate also invadopodia formation in cancer cells, our findings suggest that targeting the Src/Abl/Sos1/Rac pathway may represent a double-edged sword to control both cancer-invasive capacities and cancer-related inflammation.

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Rac GTPases as key regulators of p210-BCR-ABL-dependent leukemogenesis

Cited by 58 publications

References 65 publications

Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

IRF-4 Suppresses BCR/ABL Transformation of Myeloid Cells in a DNA Binding-independent Manner

Sos1 Regulates Macrophage Podosome Assembly and Macrophage Invasive Capacity

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