BCR and its mutants, the reciprocal t(9;22)-associated ABL/BCR fusion proteins, differentially regulate the cytoskeleton and cell motility

Zheng, Xiao; Güller, Saskia; Beissert, Tim; Puccetti, Elena; Ruthardt, Martin

doi:10.1186/1471-2407-6-262

Cited by 14 publications

(16 citation statements)

References 28 publications

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“…The Bcr protein serves as a negative regulator of Rac1 (28), and its overexpression results in the formation of stress fibers due to its effect on small GTPases, suggesting a potential role for Bcr in cell motility (52). The robust Bcr repression that we observed in miR-K6-5-transfected cells ( Fig.…”

Section: Discussionsupporting

confidence: 48%

Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Repress Breakpoint Cluster Region Protein Expression, Enhance Rac1 Activity, and Increase In Vitro Angiogenesis

Ramalingam

Happel

Ziegelbauer

2015

J Virol

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Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a gammaherpesvirus that is associated with AIDS-associated KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD) (1, 2). KSHV infects primarily cells of endothelial cell or B-cell origin and persists in either a latent phase, during which only a few viral genes are expressed, or a lytic phase, where the full repertoire of viral genes is expressed and infectious virions are released. During latent infection, KSHV also expresses 12 pre-microRNAs (premiRNAs) that are processed to yield ϳ20 mature miRNAs (3-6). miRNAs are ϳ22-nucleotide-long RNAs that typically bind with imperfect complementarity to the 3= untranslated regions (UTRs) of mRNAs and cause translational repression and mRNA degradation (7). The KSHV miRNAs are believed to be involved in repressing numerous targets that are involved in immune evasion (MICB) (8), apoptosis (BCLAF1, TWEAKR, and caspase 3) (9-11), lytic reactivation (RTA) (12, 13), angiogenesis (THBS1) (14), transcription repression (BACH1) (15,16), and cell signaling (p21, IB, and SMAD5) (17)(18)(19).Previously, we reported a microarray-based expression profiling approach to identify cellular mRNAs that are downregulated in the presence of KSHV miRNAs (11). From this array, we identified BCLAF1 (11), TWEAKR (9), and IRAK1 and MyD88 (20) as cellular targets of KSHV miRNAs. In this report, we identify the breakpoint cluster region (Bcr) mRNA and RacGAP1 as cellular targets of the KSHV miRNA miR-K12-6-5p (miR-K6-5).Bcr was originally identified as a fusion partner of Bcr-Abl, which is the fusion protein that is associated with most forms of chronic myelogenous leukemia (CML) and acute lymphocytic leukemias (ALLs) (21). Bcr by itself has been suggested to act as a tumor suppressor (22). Bcr interferes with the ␤-catenin-Tcf4

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Section: Discussionsupporting

confidence: 48%

Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Repress Breakpoint Cluster Region Protein Expression, Enhance Rac1 Activity, and Increase In Vitro Angiogenesis

Ramalingam

Happel

Ziegelbauer

2015

J Virol

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“…Furthermore, both ABL/BCRs inhibit Rho activation, which may contribute to the increase in stem cell capacity [11].…”

Section: Discussionmentioning

confidence: 99%

Reciprocal t(9;22) ABL/BCR Fusion Proteins: Leukemogenic Potential and Effects on B Cell Commitment

et al. 2009

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Backgroundt(9;22) is a balanced translocation, and the chromosome 22 breakpoints (Philadelphia chromosome – Ph+) determine formation of different fusion genes that are associated with either Ph+ acute lymphatic leukemia (Ph+ ALL) or chronic myeloid leukemia (CML). The “minor” breakpoint in Ph+ ALL encodes p185BCR/ABL from der22 and p96ABL/BCR from der9. The “major” breakpoint in CML encodes p210BCR/ABL and p40ABL/BCR. Herein, we investigated the leukemogenic potential of the der9-associated p96ABL/BCR and p40ABL/BCR fusion proteins and their roles in the lineage commitment of hematopoietic stem cells in comparison to BCR/ABL.MethodologyAll t(9;22) derived proteins were retrovirally expressed in murine hematopoietic stem cells (SL cells) and human umbilical cord blood cells (UCBC). Stem cell potential was determined by replating efficiency, colony forming - spleen and competitive repopulating assays. The leukemic potential of the ABL/BCR fusion proteins was assessed by in a transduction/transplantation model. Effects on the lineage commitment and differentiation were investigated by culturing the cells under conditions driving either myeloid or lymphoid commitment. Expression of key factors of the B-cell differentiation and components of the preB-cell receptor were determined by qRT-PCR.Principal FindingsBoth p96ABL/BCR and p40ABL/BCR increased proliferation of early progenitors and the short term stem cell capacity of SL-cells and exhibited own leukemogenic potential. Interestingly, BCR/ABL gave origin exclusively to a myeloid phenotype independently from the culture conditions whereas p96ABL/BCR and to a minor extent p40ABL/BCR forced the B-cell commitment of SL-cells and UCBC.Conclusions/SignificanceOur here presented data establish the reciprocal ABL/BCR fusion proteins as second oncogenes encoded by the t(9;22) in addition to BCR/ABL and suggest that ABL/BCR contribute to the determination of the leukemic phenotype through their influence on the lineage commitment.

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“…All of them can be regulated by DH domain contained in Bcr-Abl [53,54] or by the domain with GAP activity which is present in the complementary fusion protein Abl-Bcr detectable in the majority of patients with CML and in all ALL patients [55]. The best explored members of this family are RhoA, which induces stress fiber formation and is responsible for actomyosin contractility in non-muscle cells, Rac1, which is required for lamellipodia formation and dynamic assembly of focal adhesions, and Cdc42, which regulates filopodia formation, directional migration and cell polarity.…”

Section: Scheme 1 Perturbations Of Rhoa and Rac Signaling In CML Cellsmentioning

confidence: 99%

Rho-Signaling Pathways in Chronic Myelogenous Leukemia

Kuželová

Hrkal²

2008

CHDDT

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Chronic myelogenous leukemia (CML) is a hematological malignancy that is characteristic by as expansion of myeloid cells and their premature release into the circulation. The molecular cause of CML is the fusion oncoprotein Bcr-Abl whose constitutive tyrosine-kinase (TK) activity maintains enhanced signaling through multiple signal transduction pathways and confers proliferative and survival advantage to CML cells. These effects can be largely suppressed by TK inhibitor Imatinib mesylate, currently the leading drug in CML treatment. However, Bcr-Abl contains also additional functional domains, in particular a DBL homology (DH) domain with guanine-exchange function (GEF) which can activate small GTPases of Rho family and a Src-homology3 (SH3) domain which recruits other proteins with GEF activity. Bcr-Abl affects among others the RhoA/ROCK/LIM/cofilin pathway that regulates the actin cytoskeleton assembly and thereby the cellular adhesion and migration. This review deals in detail with the known points of interference between Bcr-Abl and Rho kinase pathways and with the effects of Imatinib mesylate on Rho signaling and cell adhesion to the extracellular matrix (ECM) components. The potential protein targets related to Bcr-Abl non-kinase activity are discussed.

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BCR and its mutants, the reciprocal t(9;22)-associated ABL/BCR fusion proteins, differentially regulate the cytoskeleton and cell motility

Cited by 14 publications

References 28 publications

Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Repress Breakpoint Cluster Region Protein Expression, Enhance Rac1 Activity, and Increase In Vitro Angiogenesis

Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Repress Breakpoint Cluster Region Protein Expression, Enhance Rac1 Activity, and Increase In Vitro Angiogenesis

Reciprocal t(9;22) ABL/BCR Fusion Proteins: Leukemogenic Potential and Effects on B Cell Commitment

Rho-Signaling Pathways in Chronic Myelogenous Leukemia

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