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Bergom C.,Cancer Center | Bergom C.,Medical College of Wisconsin | Hauser A.D.,Cancer Center | Hauser A.D.,Medical College of Wisconsin | And 15 more authors.
Journal of Biological Chemistry | Year: 2016

The small GTPase DiRas1 has tumor-suppressive activities, unlike the oncogenic properties more common to small GTPases such as K-Ras and RhoA. Although DiRas1 has been found to be a tumor suppressor in gliomas and esophageal squamous cell carcinomas, the mechanisms by which it inhibits malignant phenotypes have not been fully determined. In this study, we demonstrate that DiRas1 binds toSmgGDS,a protein that promotes the activation of several oncogenic GTPases. In silico docking studies predict that DiRas1 binds to SmgGDS in a manner similar to other small GTPases. SmgGDS is a guanine nucleotide exchange factor for RhoA, but we report here that SmgGDS does not mediate GDP/ GTP exchange on DiRas1. Intriguingly, DiRas1 acts similarly to a dominant-negative small GTPase, binding to SmgGDS and inhibitingSmgGDSbinding to other small GTPases, including K-Ras4B, RhoA, and Rap1A. DiRas1 is expressed in normal breast tissue, but its expression is decreased in most breast cancers, similar to its family member DiRas3 (ARHI). DiRas1 inhibits RhoA- And Smg- GDS-mediated NF-kB transcriptional activity in HEK293T cells. We also report that DiRas1 suppresses basal NF-kB activation in breast cancer and glioblastoma cell lines. Taken together, our data support a model in which DiRas1 expression inhibits malignant features of cancers in part by nonproductively binding to SmgGDS and inhibiting the binding of other small GTPases to SmgGDS. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Pabbidi M.R.,University of Mississippi Medical Center | Juncos J.,University of Mississippi Medical Center | Juncos L.,University of Mississippi Medical Center | Renic M.,Medical College of Wisconsin | And 6 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2013

This study examined the effects of transfer of a 2.4-Mbp region of rat chromosome 1 (RNO1) from Brown Norway (BN) into fawn-hooded hypertensive (FHH) rats on autoregulation (AR) of cerebral blood flow (CBF) and the myogenic response of middle cerebral arteries (MCAs). AR of CBF was poor in FHH and FHH.1BN AR- congenic strains that excluded the critical 2.4-Mbp region. In contrast, AR was restored in FHH.1BN AR+ congenic strains that included this region. The diameter of MCAs of FHH rats increased from 140 ± 14 to 157 ± 18 μm when transmural pressure was increased from 40 to 140 mmHg, but it decreased from 137 ± 5 to 94 ± 7 μm in FHH.1BN AR+ congenic strains. Transient occlusion of MCAs reduced CBF by 80% in all strains. However, the hyperemic response following ischemia was significantly greater in FHH and AR- rats than that seen in AR+ congenic strains (AR-, 173 ± 11% vs. AR+, 124 ± 5%). Infarct size and edema formation were also significantly greater in an AR- strain (38.6 ± 2.6 and 12.1 ± 2%) than in AR- congenic strains (27.6 ± 1.8 and 6.5 ± 0.9%). These results indicate that there is a gene in the 2.4-Mbp region of RNO1 that alters the development of myogenic tone in cerebral arteries. Transfer of this region from BN to FHH rats restores AR of CBF and vascular reactivity and reduces cerebral injury after transient occlusion and reperfusion of the MCA. © 2013 the American Physiological Society. Source

Chen Y.-G.,The Jackson Laboratory | Chen Y.-G.,Max e National Research Center for Juvenile Diabetes | Chen Y.-G.,Human and Molecular Genetics Center | Chen Y.-G.,Medical College of Wisconsin | And 3 more authors.
Genes and Immunity | Year: 2012

Previous studies using gene-targeted mutant mice revealed several molecules important for the development or function of invariant natural killer T (iNKT) cells. However, these gene knockout mice represent cases that are rare in humans. Thus, it remains unclear how naturally occurring allelic variants of these genes or others regulate the numerical and functional diversity of iNKT cells in both mice and humans. Studies in humans are mostly limited to iNKT cells in peripheral blood (PB). It is not known if the relative distribution of iNKT cells between PB and other lymphoid organs is correlated or under common genetic control. To initially address these questions, we analyzed iNKT cells in the spleen, thymus and PB of 38 inbred mouse strains. Percentages of iNKT cells in these three anatomical sites varied significantly in a strain-dependent manner. The correlation between PB and spleen was moderate, and none was observed between PB and thymus. Similarly, proportions of the CD4-expressing subset of iNKT cells differed significantly among inbred strains. The percentages of CD4-positive iNKT cells displayed a strong correlation between PB and spleen, although it remained poor between PB and thymus. Genome-wide association studies across strains identified only partially overlapping loci associated with variability of iNKT cell frequencies within and between differing anatomical sites. © 2012 Macmillan Publishers Limited All rights reserved. Source

Flister M.J.,Human and Molecular Genetics Center | Hoffman M.J.,Human and Molecular Genetics Center | Reddy P.,Human and Molecular Genetics Center | Jacob H.J.,Human and Molecular Genetics Center | And 2 more authors.
Hypertension | Year: 2013

Renin was the first blood pressure (BP) quantitative trait locus mapped by linkage analysis in the rat. Subsequent BP linkage and congenic studies capturing different portions of the renin region have returned conflicting results, suggesting that multiple interdependent BP loci may be residing in the chromosome 13 BP quantitative trait locus that includes Renin. We used SS-13 congenic strains to map 2 BP loci in the Renin region (chr13: 45.2-49.0 Mb). We identified a 1.1-Mb protective Brown Norway region around Renin (chr13: 46.1-47.2 Mb) that significantly decreased BP by 32 mm Hg. The Renin protective BP locus was offset by an adjacent hypertensive locus (chr13: 47.2-49.0 Mb) that significantly increased BP by 29 mm Hg. Sequence analysis of the protective and hypertensive BP loci revealed 1433 and 2063 variants between Dahl salt-sensitive/Mcwi and Brown Norway rats, respectively. To further reduce the list of candidate variants, we regenotyped an overlapping SS-13 congenic strain (S/renrr) with a previously reported BP phenotype. Sequence comparison among Dahl salt-sensitive, Dahl R, and Brown Norway reduced the number of candidate variants in the 2 BP loci by 42% for further study. Combined with previous studies, these data suggest that at least 4 BP loci reside within the 30-cM chromosome 13 BP quantitative trait locus that includes Renin. © 2013 American Heart Association, Inc. Source

Flister M.J.,Human and Molecular Genetics Center | Hoffman M.J.,Human and Molecular Genetics Center | Lemke A.,Human and Molecular Genetics Center | Prisco S.Z.,Human and Molecular Genetics Center | And 9 more authors.
Circulation: Cardiovascular Genetics | Year: 2015

Background-Genome-wide association studies are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes affect disease outcome. Such is the case for SH2B adaptor protein 3 (SH2B3), which is a negative regulator of multiple cytokine signaling pathways and is associated with increased risk of myocardial infarction (MI), but its role in post-MI inflammation and fibrosis is completely unknown. Methods and Results-Using an experimental model of MI (left anterior descending artery occlusion/reperfusion injury) in wild-type and Sh2b3 knockout rats (Sh2b3em2Mcwi), we assessed the role of Sh2b3 in post-MI fibrosis, leukocyte infiltration, angiogenesis, left ventricle contractility, and inflammatory gene expression. Compared with wild-type, Sh2b3em2Mcwi rats had significantly increased fibrosis (2.2-fold; P<0.05) and elevated leukocyte infiltration (>2-fold; P<0.05), which coincided with decreased left ventricle fractional shortening (-Δ11%; P<0.05) at 7 days post left anterior descending artery occlusion/reperfusion injury. Despite an increased angiogenic potential in Sh2b3em2Mcwi rats (1.7-fold; P<0.05), we observed no significant differences in left ventricle capillary density between wild-type and Sh2b3em2Mcwi rats. In total, 12 genes were significantly elevated in the post left anterior descending artery occluded/reperfused hearts of Sh2b3em2Mcwi rats relative to wild-type, of which 3 (NLRP12, CCR2, and IFNγ) were significantly elevated in the left ventricle of heart failure patients carrying the MI-associated rs3184504 [T] SH2B3 risk allele. Conclusions-These data demonstrate for the first time that SH2B3 is a crucial mediator of post-MI inflammation and fibrosis. © 2015 American Heart Association, Inc. Source

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