Browsing by Subject "Rho GTPase"

Now showing 1 - 3 of 3
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    Genetic variants in the genes encoding rho GTPases and related regulators predict cutaneous melanoma-specific survival
    (Wiley, 2017-08-15) Liu, Shun; Wang, Yanru; Xue, William; Liu, Hongliang; Xu, Yinghui; Shi, Qiong; Wu, Wenting; Zhu, Dakai; Amos, Christopher I.; Fang, Shenying; Lee, Jeffrey E.; Hyslop, Terry; Li, Yi; Han, Jiali; Wei, Qingyi; Epidemiology, School of Public Health
    Rho GTPases control cell division, motility, adhesion, vesicular trafficking and phagocytosis, which may affect progression and/or prognosis of cancers. Here, we investigated associations between genetic variants of Rho GTPases-related genes and cutaneous melanoma-specific survival (CMSS) by re-analyzing a published melanoma genome-wide association study (GWAS) and validating the results in another melanoma GWAS. In the single-locus analysis of 36,018 SNPs in 129 Rho-related genes, 427 SNPs were significantly associated with CMSS (p < 0.050 and false-positive report probability <0.2) in the discovery dataset, and five SNPs were replicated in the validation dataset. Among these, four SNPs (i.e., RHOU rs10916352 G > C, ARHGAP22 rs3851552 T > C, ARHGAP44 rs72635537 C > T and ARHGEF10 rs7826362 A > T) were independently predictive of CMSS (a meta-analysis derived p = 9.04 × 10-4 , 9.58 × 10-4 , 1.21 × 10-4 and 8.47 × 10-4 , respectively). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had markedly reduced CMSS in both discovery dataset and validation dataset (ptrend =1.47 × 10-7 and 3.12 × 10-5 ). The model including the NUGs and clinical variables demonstrated a significant improvement in predicting the five-year CMSS. Moreover, rs10916352C and rs3851552C alleles were significantly associated with an increased mRNA expression levels of RHOU (p = 1.8 × 10-6 ) and ARHGAP22 (p = 5.0 × 10-6 ), respectively. These results may provide promising prognostic biomarkers for CM personalized management and treatment.
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    Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils
    (2006-12) Szczur, Kathleen; Xu, Haiming; Atkinson, Simon J; Zheng, Yi; Filippi, Marie-Dominique
    Neutrophil transmigration into tissue is a multiple-step process that results from a coordinated rearrangement of the cytoskeleton and adhesion complexes. Assembly and disassembly of actin and adhesion structures dictate motility behavior, while polarity and gradient sensing provide directionality to the cell movement. Here, using mice deficient in the CDC42 regulator CDC42 GTPase-activating protein (CDC42GAP), we demonstrate that CDC42 activity separately regulates neutrophil motility and directionality. CDC42GAP–/– neutrophils showed increased motility, while directed migration was defective. Podosome-like structures present at the leading edge in wild-type neutrophils were significantly reduced in CDC42GAP–/– cells. CDC42GAP–/– neutrophils also showed increased lateral and tail filopodia-like formation, and excess membrane protrusions. We further suggest that CDC42GAP-mediated extracellular signal–regulated kinase (ERK) activity regulates motility associated with podosome-like structures at the cell leading edge, while CDC42GAP-induced p38MAPK phosphorylation regulates directed migration by antagonizing filopodia assembly. Overall, this study reveals that CDC42 activity regulates both motility and directionality in neutrophils, but via distinct mitogen-activated protein kinase (MAPK) pathways.
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    RhoA/Rho kinase (ROCK) alters fetuin-A uptake and regulates calcification in bovine vascular smooth muscle cells (BVSMC)
    (2010-09) Chen, Neal X; Chen, Xianming; O'Neill, Kalisha D; Atkinson, Simon J; Moe, Sharon M
    RhoA/Rho kinases (ROCK) play a critical role in vascular smooth muscle cell (VSMC) actin cytoskeleton organization, differentiation, and function and are implicated in the pathogenesis of cardiovascular disease. We have previously determined that an important step in the regulation of calcification is fetuin-A endocytosis, a process that is dependent on changes in the cytoskeleton, which, in turn, is known to be affected by the RhoA/ROCK signaling pathway. In the present study, bovine VSMC (BVSMC) were treated with the ROCK inhibitor Y-27632 or transfected with ROCK small interfering (si) RNA to knock down ROCK expression. Both conditions resulted in reduced actin stress fibers and increased Cy5-labeled fetuin-A uptake. Inhibition of ROCK by Y-27632 or siRNA also significantly increased BVSMC alkaline phosphatase (ALP) activity and calcification of BVSMC and rat aorta organ cultures. Cells were then incubated in calcification media in the presence or absence of Y-27632 and matrix vesicles (MV) isolated by collagenase digestion. These MV, isolated from BVSMC incubated with Y-27632, had increased ALP activity and increased ability of MV to subsequently calcify collagen by 66%. In contrast, activation of RhoA, which is upstream of ROCK, by transfecting plasmids encoding the dominant active Rho GTPase mutant (Rho-L63) led to decreased fetuin-A uptake and reduced calcification in BVSMC. These results demonstrate that the RhoA/ROCK signaling pathway is an important negative regulator of vascular calcification.