Overexpression of Rac1 in leukemia patients and its role in leukemia cell migration and growth

Wang, Jiying; Rao, Qing; Wang, Min; Wei, Hui; Xing, Haiyan; Liu, Huan; Wang, Yanzhong; Tang, Kejing; Peng, Leiwen; Tian, Zheng; Wang, Jianxiang

doi:10.1016/j.bbrc.2009.06.125

Cited by 35 publications

(35 citation statements)

References 17 publications

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“…Instead, overexpression of RAC1 has been reported in colorectal, pancreatic, breast, and testicular cancers and in various leukemias (5)(6)(7). Additionally, a self-activating splice variant of RAC1, RAC1b, was shown to be overexpressed in breast cancer and lung cancer and is thought to mediate the epithelial-mesenchymal transition in lung epithelial cells (8)(9)(10).…”

Section: F28lmentioning

confidence: 99%

RAC1 ^P29S is a spontaneously activating cancer-associated GTPase

Davis¹,

Ha²,

Holman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

154

151

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RAC1 is a small, Ras-related GTPase that was recently reported to harbor a recurrent UV-induced signature mutation in melanoma, resulting in substitution of P29 to serine (RAC1 P29S ), ranking this the third most frequently occurring gain-of-function mutation in melanoma. Although the Ras family GTPases are mutated in about 30% of all cancers, mutations in the Rho family GTPases have rarely been observed. In this study, we demonstrate that unlike oncogenic Ras proteins, which are primarily activated by mutations that eliminate GTPase activity, the activated melanoma RAC1 P29S protein maintains intrinsic GTP hydrolysis and is spontaneously activated by substantially increased inherent GDP/GTP nucleotide exchange. Determination and comparison of crystal structures for activated RAC1 GTPases suggest that RAC1 F28L-a known spontaneously activated RAC1 mutant-and RAC1P29S are self-activated in distinct fashions. Moreover, the mechanism of RAC1 P29S and RAC1 F28L activation differs from the common oncogenic mutations found in Ras-like GTPases that abrogate GTP hydrolysis. The melanoma RAC1 P29Sgain-of-function point mutation therefore represents a previously undescribed class of cancer-related GTPase activity.cancer | cell signaling | x-ray crystallography | cytoskeleton | GEF-independent GTPase exchange R AC1, the Ras-related small GTPase belonging to the Rho family, functions as a binary molecular switch cycling between an inactive GDP-bound "OFF" state and an active GTP-bound "ON" state (1). Its activity is responsible for the regulation of diverse cellular behaviors including NADPH oxidase activation, formation of cortical actin-containing membrane ruffles and lamellipodia, and induction of gene expression programs (2). Accordingly, these functions are tightly controlled through RAC1 lipidation, subcellular localization, protein expression levels, and Rho GDP-dissociation inhibitor (Rho GDI) interactions. In addition, as a GTPase, RAC1 is turned ON by guanine nucleotide exchange factors (GEFs) and is turned OFF by GTPase activating proteins (GAPs) that facilitate GDP/GTP nucleotide exchange and GTP hydrolysis, respectively. Once this regulation is compromised, RAC1 activity is implicated in various steps of oncogenesis including initiation, progression, invasion, and metastasis (3, 4).In contrast to Ras, RAC1 has rarely been identified as significantly mutated in cancer. Instead, overexpression of RAC1 has been reported in colorectal, pancreatic, breast, and testicular cancers and in various leukemias (5-7). Additionally, a self-activating splice variant of RAC1, RAC1b, was shown to be overexpressed in breast cancer and lung cancer and is thought to mediate the epithelial-mesenchymal transition in lung epithelial cells (8-10). Furthermore, aberrant activation of upstream regulators of RAC1, particularly in the DBL family of GEFs specific for RAC1 (e.g., TIAM1, PREX1, and ECT2), have been implicated in various cancers (11). Although increased GDP→GTP nucleotide exchange in RAC1 (dependent or independent of GEFs) is...

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Section: F28lmentioning

confidence: 99%

RAC1 ^P29S is a spontaneously activating cancer-associated GTPase

Davis¹,

Ha²,

Holman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

154

151

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show abstract

“…Several lines of evidence support a link between Rac1 and carcinogenesis, and Rac1 activity has been implicated in cancer initiation, progression, invasion, and metastasis (Ellenbroek and Collard, 2007; Vega and Ridley, 2008). Overexpression of Rac1 has been reported in colorectal, pancreatic, and breast cancers as well as in various leukaemias (Fritz et al , 1999; Schnelzer et al , 2000; Wang et al , 2009; Wertheimer et al , 2012). Therefore, it is important to understand the involvement of SNTA1 in Rac1 activation and its effects on downstream signalling, such as ROS generation and cell migration.…”

mentioning

confidence: 99%

Role of SNTA1 in Rac1 activation, modulation of ROS generation, and migratory potential of human breast cancer cells

et al. 2014

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Background:Alpha-1-syntrophin (SNTA1) has been implicated in the activation of Rac1. However, the underlying mechanism has not yet been explored. Here, we show that a novel complex, involving SNTA1, P66shc, and Grb2 proteins, is involved in Rac1 activation.Methods:Co-immunoprecipitation assays were used to show the complex formation, while siRNAs and shRNAs were used to downregulate expression of these proteins. Various Rac1 activation assays and functional assays, such as migration assays, in vitro wound healing assays, cell proliferation assays, and ROS generation assays, were also performed.Results:The results showed a significant increase in activation of Rac1 when SNTA1 and P66shc were overexpressed, whereas depletion of SNTA1 and P66shc expression effectively reduced the levels of active Rac1. The results indicated a significant displacement of Sos1 protein from Grb2 when SNTA1 and P66shc are overexpressed in breast cancer cell lines, resulting in Sos1 predominantly forming a complex with Eps8 and E3b1. In addition, the SNTA1/P66shc-mediated Rac1 activation resulted in an increase in reactive oxygen species (ROS) production and migratory potential in human breast cancer cells.Conclusion:Together, our results present a possible mechanism of Rac1 activation involving SNTA1 and emphasise its role in ROS generation, cell migration, and acquisition of malignancy.

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“…The genes within this subnetwork are very substantially supported by literature with respect to their role in leukaemia. For instance, the gene RAC (which regulates a diverse array of cellular events) is referenced in [30,31] as having an effect on leukaemia. Other genes within the network are Rhoa (regulates the actin cytoskeleton in formation of stress fibers) in [32,33], Vav1 (plays a major role in development and activation of T-cell and B-cell blood cells) in [34] and IQGAP (regulates cell adhesion, morphology and motility) in [35].…”

Section: Resultsmentioning

confidence: 99%

Finding consistent disease subnetworks across microarray datasets

et al. 2011

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BackgroundWhile contemporary methods of microarray analysis are excellent tools for studying individual microarray datasets, they have a tendency to produce different results from different datasets of the same disease. We aim to solve this reproducibility problem by introducing a technique (SNet). SNet provides both quantitative and descriptive analysis of microarray datasets by identifying specific connected portions of pathways that are significant. We term such portions within pathways as “subnetworks”.ResultsWe tested SNet on independent datasets of several diseases, including childhood ALL, DMD and lung cancer. For each of these diseases, we obtained two independent microarray datasets produced by distinct labs on distinct platforms. In each case, our technique consistently produced almost the same list of significant nontrivial subnetworks from two independent sets of microarray data. The gene-level agreement of these significant subnetworks was between 51.18% to 93.01%. In contrast, when the same pairs of microarray datasets were analysed using GSEA, t-test and SAM, this percentage fell between 2.38% to 28.90% for GSEA, 49.60% tp 73.01% for t-test, and 49.96% to 81.25% for SAM. Furthermore, the genes selected using these existing methods did not form subnetworks of substantial size. Thus it is more probable that the subnetworks selected by our technique can provide the researcher with more descriptive information on the portions of the pathway actually affected by the disease.ConclusionsThese results clearly demonstrate that our technique generates significant subnetworks and genes that are more consistent and reproducible across datasets compared to the other popular methods available (GSEA, t-test and SAM). The large size of subnetworks which we generate indicates that they are generally more biologically significant (less likely to be spurious). In addition, we have chosen two sample subnetworks and validated them with references from biological literature. This shows that our algorithm is capable of generating descriptive biologically conclusions.

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Overexpression of Rac1 in leukemia patients and its role in leukemia cell migration and growth

Cited by 35 publications

References 17 publications

RAC1 ^P29S is a spontaneously activating cancer-associated GTPase

RAC1 ^P29S is a spontaneously activating cancer-associated GTPase

Role of SNTA1 in Rac1 activation, modulation of ROS generation, and migratory potential of human breast cancer cells

Finding consistent disease subnetworks across microarray datasets

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Overexpression of Rac1 in leukemia patients and its role in leukemia cell migration and growth

Cited by 35 publications

References 17 publications

RAC1 P29S is a spontaneously activating cancer-associated GTPase

RAC1 P29S is a spontaneously activating cancer-associated GTPase

Role of SNTA1 in Rac1 activation, modulation of ROS generation, and migratory potential of human breast cancer cells

Finding consistent disease subnetworks across microarray datasets

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RAC1 ^P29S is a spontaneously activating cancer-associated GTPase

RAC1 ^P29S is a spontaneously activating cancer-associated GTPase