A Role for the Rho-GTPase Pathway in Pediatric Obese Asthma.
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ABSTRACT:
SUBMITTER: Sharma S
PROVIDER: S-EPMC7365369 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
Publications
A Role for the Rho-GTPase Pathway in Pediatric Obese Asthma.
American journal of respiratory and critical care medicine 20200701 2
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Project description:Rationale: Obesity-related asthma disproportionately affects minority children and is associated with nonatopic T-helper type 1 (Th1) cell polarized inflammation that correlates with pulmonary function deficits. Its underlying mechanisms are poorly understood.Objectives: To use functional genomics to identify cellular mechanisms associated with nonatopic inflammation in obese minority children with asthma.Methods: CD4+ (cluster of differentiation 4-positive) Th cells from 59 obese Hispanic and African American children with asthma and 61 normal-weight Hispanic and African American children with asthma underwent quantification of the transcriptome and DNA methylome and genotyping. Expression and methylation quantitative trait loci revealed the contribution of genetic variation to transcription and DNA methylation. Adjusting for Th-cell subtype proportions discriminated loci where transcription or methylation differences were driven by differences in subtype proportions from loci that were independently associated with obesity-related asthma.Measurements and Main Results: Obese children with asthma had more memory and fewer naive Th cells than normal-weight children with asthma. Differentially expressed and methylated genes and methylation quantitative trait loci in obese children with asthma, independent of Th-cell subtype proportions, were enriched in Rho-GTPase pathways. Inhibition of CDC42 (cell division cycle 42), one of the Rho-GTPases associated with Th-cell differentiation, was associated with downregulation of the IFNγ, but not the IL-4, gene. Differential expression of the RPS27L (40S ribosomal protein S27-like) gene, part of the p53/mammalian target of rapamycin pathway, was due to nonrandom distribution of expression quantitative trait loci variants between groups. Differentially expressed and/or methylated genes, including RPS27L, were associated with pulmonary function deficits in obese children with asthma.Conclusions: We found enrichment of Rho-GTPase pathways in obese asthmatic Th cells, identifying them as a novel therapeutic target for obesity-related asthma, a disease that is suboptimally responsive to current therapies.
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Project description:The basal-like breast cancer (BLBC) subtype accounts for a disproportionately high percentage of overall breast cancer mortality. The current therapeutic options for BLBC need improvement; hence, elucidating signaling pathways that drive BLBC growth may identify novel targets for the development of effective therapies. Rho GTPases have previously been implicated in promoting tumor cell proliferation and metastasis. These proteins are inactivated by Rho-selective GTPase-activating proteins (RhoGAP), which have generally been presumed to act as tumor suppressors. Surprisingly, RNA-Seq analysis of the Rho GTPase signaling transcriptome revealed high expression of several RhoGAP genes in BLBC tumors, raising the possibility that these genes may be oncogenic. To evaluate this, we examined the roles of two of these RhoGAPs, ArhGAP11A (also known as MP-GAP) and RacGAP1 (also known as MgcRacGAP), in promoting BLBC. Both proteins were highly expressed in human BLBC cell lines, and knockdown of either gene resulted in significant defects in the proliferation of these cells. Knockdown of ArhGAP11A caused CDKN1B/p27-mediated arrest in the G1 phase of the cell cycle, whereas depletion of RacGAP1 inhibited growth through the combined effects of cytokinesis failure, CDKN1A/p21-mediated RB1 inhibition, and the onset of senescence. Random migration was suppressed or enhanced by the knockdown of ArhGAP11A or RacGAP1, respectively. Cell spreading and levels of GTP-bound RhoA were increased upon depletion of either RhoGAP. We have established that, via the suppression of RhoA, ArhGAP11A and RacGAP1 are both critical drivers of BLBC growth, and propose that RhoGAPs can act as oncogenes in cancer. Cancer Res; 76(13); 3826-37. ©2016 AACR.
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