Rac2 expression and mutation in human brain tumors

Hwang, Shiuh-Lin; Lieu, Ann-Shung; Chang, Jan-Gowth; Cheng, Tsung Chieh; Cheng, Chi-Yun; Lee, K.-S.; Lin, Chih-Lung; Howng, Shen-Long; Hong, Yi‐Ren

doi:10.1007/s00701-005-0515-5

Cited by 25 publications

(14 citation statements)

References 22 publications

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“…Mutation analysis of the coding regions of RAC2 and CHIBBY by SSCP analysis and direct sequencing did not reveal any mutations despite their relatively high frequency of loss. However, these results are in accordance with observation by Hwang et al (2005) where a low frequency [15.4% (2/13)] of RAC2 mutations was observed in malignant astrocytomas, despite a high incidence (58%) of decreased expression. Similarly, no mutations were seen for CHIBBY in colorectal carcinoma (Gad et al, 2004;Schuierer et al, 2006).…”

Section: Discussionsupporting

confidence: 93%

Real‐time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12‐q13

Karakoula

Suárez-Merino

Ward

et al. 2008

Genes Chromosomes & Cancer

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Loss of chromosome 22 and gain of 1q are the most frequent genomic aberrations in ependymomas, indicating that genes mapping to these regions are critical in their pathogenesis. Using real-time quantitative PCR, we measured relative copy numbers of 10 genes mapping to 22q12.3-q13.33 and 10 genes at 1q21-32 in a series of 47 pediatric intracranial ependymomas. Loss of one or more of the genes on 22 was detected in 81% of cases, with RAC2 and C22ORF2 at 22q12-q13.1 being deleted most frequently in 38% and 32% of ependymoma samples, respectively. Combined analysis of quantitative-PCR with methylation-specific PCR and bisulphite sequencing revealed a high rate (>60% ependymoma) of transcriptional inactivation of C22ORF2, indicating its potential importance in the development of pediatric ependymomas. Increase of relative copy numbers of at least one gene on 1q were detected in 61% of cases, with TPR at 1q25 displaying relative copy number gains in 38% of cases. Patient age was identified as a significant adverse prognostic factor, as a significantly shorter overall survival time (P = 0.0056) was observed in patients <2 years of age compared with patients who were >2 years of age. Loss of RAC2 at 22q13 or amplification of TPR at 1q25 was significantly associated with shorter overall survival in these younger patients (P = 0.0492 and P = < 0.0001, respectively). This study identifies candidate target genes within 1q and 22q that are potentially important in the pathogenesis of intracranial pediatric ependymomas.

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Section: Discussionsupporting

confidence: 93%

Real‐time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12‐q13

Karakoula

Suárez-Merino

Ward

et al. 2008

Genes Chromosomes & Cancer

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“…27 However, recent studies have shown that Rac2 is expressed at low levels in most brain tumours and gastric cancer tissues, suggesting that there is a strong relationship between Rac2 and tumorigenesis. 20,21 Western blot and RT-PCR in the present study revealed that the expression of Rac2 protein and mRNA was significantly upregulated in DADS-induced apoptotic HL-60 cells compared with untreated cells. To further investigate this, we inhibited Rac2 expression using siRNA.…”

Section: Discussionmentioning

confidence: 76%

“…Recent studies have shown that Rac2 is expressed at low levels in most brain tumours and gastric cancer tissues. 20,21 The main factor inducing ROS production is NADPH oxidase. Reactive oxygen species can trigger a variety of signal transduction pathways, ultimately causing a variety of responses, such as cell proliferation, differentiation and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Role of Ras‐related C3 botulinum toxin substrate 2 (Rac2), NADPH oxidase and reactive oxygen species in diallyl disulphide‐induced apoptosis of human leukaemia HL‐60 cells

Liang

Tan

et al. 2010

Clin Exp Pharma Physio

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1. Diallyl disulphide (DADS) has potential as a chemopreventive and therapeutic agent. Previous studies have reported that Ras-related C3 botulinum toxin substrate 2 (Rac2), a regulatory subunit of the NADPH oxidase complex, is upregulated in DADS-induced apoptosis in human leukaemia HL-60 cells. The aim of the present study was to investigate the role of Rac2, NADPH oxidase and reactive oxygen species (ROS) in DADS-induced apoptosis. 2. Expression of the Rac2 gene along with that of five other genes of NADPH oxidase subunits were in HL-60 cells measured by Sybergreen quantitative real-time polymerase chain reaction. RNA interference was used to test the effect of Rac2. Protein expression was evaluated using western blot analysis and ROS levels were measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA) fluorescence. DNA fragmentation and flow cytometry analysis were used to detect apoptotic cells. 3. Levels of Rac2 gene and protein were significantly upregulated and NADPH oxidase was activated in DADS-induced apoptosis. Pretreatment of HL-60 cells with small interfering (si) RNAs to inhibit Rac2 blocked DADS-induced apoptosis. Diallyl disulphide-induced intracellular ROS production was increased in phorbol myristate acetate-stimulated cells, but decreased in Rac2 siRNA-treated cells. In Rac2 siRNA-treated cells, activator protein-1 and caspase 3 levels decreased, c-myc protein levels were increased and p38 protein levels were unchanged compared with Rac2-competent, DADS-treated cells. 4. These results demonstrate that NADPH oxidase is the main source of DADS-induced ROS. In addition, Rac2 selectively activates the c-Jun N-terminal kinase pathway, but not the p38 pathway, in DADS-induced apoptosis. So, Rac2, NADPH oxidase and ROS have a critical role in DADS-induced apoptosis in human leukaemia HL-60 cells.

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“…Increasing evidence suggests a regulating role for Rho GTPases in cadherin and b-catenin families (Wildenberg et al, 2006). Mutations in Rac GTPases have also been found in many human brain tumors (Hwang et al, 2005).…”

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confidence: 99%

A novel role of Rac1 GTPase in JCV T-antigen-mediated β-catenin stabilization

2007

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Wnt signaling follows canonical and non-canonical pathways to regulate a variety of processes during cellular homeostasis and development. The large T-antigen (T-Ag) of the human neurotropic JC virus, has been shown to modulate the Wnt-signaling pathway via interaction with b-catenin, one of the most important components of the canonical Wnt pathway. Here, we have identified an alternative non-canonical pathway that allows T-Ag to recruit Rac1 for stabilizing b-catenin by inhibiting its ubiquitin-dependent proteasomal degradation. We demonstrate that inhibition of Rac1 by its dominant negative mutant, RacN17, abrogates T-Ag-mediated stabilization of b-catenin yet exhibits no impact on the transcriptional activity of b-catenin. Results from immunocytochemistry revealed that together with T-Ag, a pool of b-catenin appears at the cell surface, particularly at the membrane ruffles where active Rac1 is positioned. Interestingly, cooperativity between T-Ag and b-catenin leads to activation of Rac1, which in turn, stimulates its association with b-catenin. These observations unravel the interplay between b-catenin and Rac1 that is initiated by T-Ag and results in stabilization of b-catenin and its presence in cell membrane ruffles.

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Rac2 expression and mutation in human brain tumors

Cited by 25 publications

References 22 publications

Real‐time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12‐q13

Real‐time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12‐q13

Role of Ras‐related C3 botulinum toxin substrate 2 (Rac2), NADPH oxidase and reactive oxygen species in diallyl disulphide‐induced apoptosis of human leukaemia HL‐60 cells

A novel role of Rac1 GTPase in JCV T-antigen-mediated β-catenin stabilization

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