Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation

Gu, Yi; Siefring, Jamie E.; Wang, L.; Chae, Hee-Don; Bailey, Jeff; Zheng, Yi

doi:10.1038/sj.onc.1209427

Cited by 8 publications

(6 citation statements)

References 45 publications

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“…L61Rac1 expression or rac1 knock-out also induces primary MEF apoptosis (36); this effect of L61Rac1 was somewhat unexpected, as a body of literature has suggested that it might act to promote survival rather than apoptosis (10). The pro-apoptosis activity of constitutively active Rac1 in MEFs is consistent with our observations in a number of primary cell types, including the hematopoietic stem/progenitors (41). Moreover, we found that Rac1 gain or loss of activity leads to premature cell senescence of primary MEFs.…”

Section: Discussionsupporting

confidence: 78%

“…1A). Anti-Rac1 antibody appears to be highly specific toward endogenous Rac1 because it did not detect Rac2 or Rac3 in various Rac1 Ϫ/Ϫ blood lineages or Rac3 in Rac1 Ϫ/Ϫ mouse forebrain (data not shown) (9,40,41). The cells were passaged every 3 days following a 3T3 subculture schedule in standard MEF medium, and population doubling was quantified over a 12-day period (passages 4 -7).…”

Section: Rac1 Gain or Loss Of Activity Results In Impaired Cell Prolimentioning

confidence: 99%

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Rac1 GTPase Regulates Cell Genomic Stability and Senescence

Debidda

Williams

Zheng

2006

Journal of Biological Chemistry

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The Rho family small GTPase Rac1 has been shown to play multiple roles in cell regulation, including actin cytoskeleton organization, transcriptional activation, microtubule dynamics, and endocytosis. Here, we report a novel role of Rac1 in regulating genomic stability and cell senescence. We observed in primary mouse embryonic fibroblasts that deletion of rac1 by gene targeting, as well as expression of the constitutively active Rac1 mutant L61Rac1, led to decreased cell growth that was associated with altered cell cycle progression at both G 1 /S and G 2 /M phases, increased apoptosis, and premature senescence. The senescence induction by either loss or gain of Rac1 activity was due at least in part to an increase in cellular reactive oxygen species (ROS). rac1 gene deletion caused a compensatory upregulation of a closely related family member, Rac3, in mouse embryonic fibroblasts, the activity of which induced ROS production independently of Rac1. Furthermore, the Rac1-regulated ROS production and senescence correlated with the extent of DNA damage in the Rac1 ؊/؊ and L61Rac1 cells. Treatment of these cells with a ROS inhibitor inhibited phospho-H2AX-positive nuclear focus formation. Finally, phospho-Ser 15 p53 was significantly increased in L61Rac1 and Rac1 ؊/؊ cells, and genetic deletion of p53 from these cells readily reversed the senescence phenotype, indicating that Rac1 is functionally dependent on p53 in regulating cell senescence. Taken together, our results show that Rac1 activity serves as a regulator of cell senescence through modulation of cellular ROS, genomic stability, and p53 activity.

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Section: Discussionsupporting

confidence: 78%

Section: Rac1 Gain or Loss Of Activity Results In Impaired Cell Prolimentioning

confidence: 99%

Rac1 GTPase Regulates Cell Genomic Stability and Senescence

Debidda

Williams

Zheng

2006

Journal of Biological Chemistry

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“…While Vav1 was shown to protect Jurkat T cells from Fas-mediated apoptosis by promoting Bcl-2 transcription through its GEF activity [46], Gu et al, demonstrated that oncogenic Vav1, which is constitutively active as a GEF, induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation [58]. Thus, it is conceivable that in non-hematopoietic cancer cells wild-type Vav1 might function in a similar fashion to oncogenic Vav1 in hematopoietic cells due to its constitutive activation by various aberrantly functional signaling cascades.…”

Section: Discussionmentioning

confidence: 99%

Vav1 Fine Tunes p53 Control of Apoptosis versus Proliferation in Breast Cancer

Sebban¹,

Farago²,

Gashai³

et al. 2013

PLoS ONE

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Vav1 functions as a signal transducer protein in the hematopoietic system, where it is exclusively expressed. Vav1 was recently implicated in several human cancers, including lung, pancreatic and neuroblasoma. In this study, we analyzed the expression and function of Vav1 in human breast tumors and breast cancer cell lines. Immunohistochemical analysis of primary human breast carcinomas indicated that Vav1 is expressed in 62% of 65 tumors tested and is correlated positively with estrogen receptor expression. Based on published gene profiling of 50 breast cancer cell lines, several Vav1-expressing cell lines were identified. RT-PCR confirmed Vav1 mRNA expression in several of these cell lines, yet no detectable levels of Vav1 protein were observed due to cbl-c proteasomal degradation. We used two of these lines, MCF-7 (Vav1 mRNA negative) and AU565 (Vav1 mRNA positive), to explore the effect of Vav1 expression on breast cell phenotype and function. Vav1 expression had opposite effects on function in these two lines: it reduced proliferation and enhanced cell death in MCF-7 cells but enhanced proliferation in AU565 cells. Consistent with these findings, transcriptome analysis revealed an increase in expression of proliferation-related genes in Vav1-expressing AU565 cells compared to controls, and an increase in apoptosis-related genes in Vav1-expressing MCF-7 cells compared with controls. TUNEL and γ-H2AX foci assays confirmed that expression of Vav1 increased apoptosis in MCF-7 cells but not AU565 cells and shRNA experiments revealed that p53 is required for this pro-apoptotic effect of Vav1 in these cells. These results highlight for the first time the potential role of Vav1 as an oncogenic stress activator in cancer and the p53 dependence of its pro-apoptotic effect in breast cells.

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“…36 Constitutive activation of Rac in primary HSC/Ps also induces apoptosis, similar to what is seen with Rac deficiency. 37 This effect of hyperactivated Rac signaling can be overcome by increased expression of Bcl-2 and Bcl-xL, such as occurs on loss of p53. 37 Interestingly, MLL-AF9 is among the MLL fusion proteins found to significantly downregulate the transcriptional activity of p53.…”

mentioning

confidence: 99%

“…37 This effect of hyperactivated Rac signaling can be overcome by increased expression of Bcl-2 and Bcl-xL, such as occurs on loss of p53. 37 Interestingly, MLL-AF9 is among the MLL fusion proteins found to significantly downregulate the transcriptional activity of p53. 38 We have confirmed that p53 signaling is muted in MA9 cells (F.-S.C. and J.C.M., unpublished observations, January 2009).…”

mentioning

confidence: 99%

Inhibition of Rac GTPase signaling and downstream prosurvival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia

Mizukawa¹,

Wei

Shrestha

et al. 2011

Blood

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The Rac family of small Rho GTPases coordinates diverse cellular functions in hematopoietic cells including adhesion, migration, cytoskeleton rearrangements, gene transcription, proliferation, and survival. The integrity of Rac signaling has also been found to critically regulate cellular functions in the initiation and maintenance of hematopoietic malignancies. Using an in vivo gene targeting approach, we demonstrate that Rac2, but not Rac1, is critical to the initiation of acute myeloid leukemia in a retroviral expression model of MLL-AF9 leukemogenesis. However, loss of either Rac1 or Rac2 is sufficient to impair survival and growth of the transformed MLL-AF9 leukemia. Rac2 is known to positively regulate expression of Bcl-2 family proteins toward a prosurvival balance. We demonstrate that disruption of downstream survival signaling through antiapoptotic Bcl-2 proteins is implicated in mediating the effects of Rac2 deficiency in MLL-AF9 leukemia. Indeed, overexpression of Bcl-xL is able to rescue the effects of Rac2 deficiency and MLL-AF9 cells are exquisitely sensitive to direct inhibition of Bcl-2 family proteins by the BH3-mimetic, ABT-737. Furthermore, concurrent exposure to NSC23766, a smallmolecule inhibitor of Rac activation, increases the apoptotic effect of ABT-737, indicating the Rac/Bcl-2 survival pathway may be targeted synergistically. (Blood. 2011;118(19):5235-5245) IntroductionThe pathway to aberrant self-renewal and survival in acute myeloid leukemia (AML) commonly begins with specific chromosomal lesions. In a recent study, rearrangement of the mixed-lineageleukemia (MLL) gene on chromosome 11q23 was the most prevalent chromosomal abnormality in pediatric AML, constituting 16% of all patients. 1 The most common MLL gene rearrangement, seen in 49% of all MLL-positive patients, involved a balanced translocation with the AF9 gene on chromosome 9, t(9;11)(p21-22; q23), producing the fusion protein MLL-AF9 (MA9). 1 AML with the MA9 fusion displays a myelomonocytic phenotype and is associated with intermediate prognostic risk. AF9 is one of several MLL fusion partners found to recruit a macromolecular complex involving positive transcription elongation factor B (pTEFb) and the histone methyltransferase DOT1L to the fusion protein with preserved DNA-binding domains at the MLL amino terminus. 2,3 This pTEFb/DOT1L complex results in aberrant transcription elongation and histone H3K79 methylation of MLL target genes leading to their overexpression. [4][5][6][7] Genetic, epigenetic, and signaling changes accumulate leading to leukemic transformation. Using retroviral vectors to express MA9 in hematopoietic stem and progenitor cells (HSC/Ps), we and others have been able to model the initiation and progression of AML in both xenograft and pure murine genetic models. [8][9][10][11][12] Rac GTPases have garnered interest as a therapeutic target in hematologic malignancies because of their central role in coordinating diverse cellular functions in response to stimuli within the cell microenvironment. [13][1...

show abstract

Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation

Cited by 8 publications

References 45 publications

Rac1 GTPase Regulates Cell Genomic Stability and Senescence

Rac1 GTPase Regulates Cell Genomic Stability and Senescence

Vav1 Fine Tunes p53 Control of Apoptosis versus Proliferation in Breast Cancer

Inhibition of Rac GTPase signaling and downstream prosurvival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia

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