Targeted intestinal deletion of Rho guanine nucleotide exchange factor 7, βPIX, impairs enterocyte proliferation, villus maturation, and mucosal defenses in mice

Cheng, Kunrong; Larabee, Shannon M.; Tolaymat, Mazen; Hanscom, Marie; Shang, Aaron C.; Schledwitz, Alyssa; Hu, Shien; Drachenberg, Cinthia B.; Zhan, Min; Chahdi, Ahmed; Raufman, Jean‐Pierre

doi:10.1152/ajpgi.00415.2020

Cited by 4 publications

(7 citation statements)

References 77 publications

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“…Supporting the functional importance of MR agonist-induced βPix binding to β-catenin, we found that reducing βPix expression in vitro attenuated M 3 R agonist-induced colon cancer cell proliferation, migration, and invasion. Moreover, in the AOM/DSS murine model of colon cancer, mice with conditional intestinal epithelial cell βPix deficiency 59 had significantly fewer colon tumors, primarily fewer adenocarcinomas, a finding exaggerated in animals treated with a MR agonist.…”

Section: Discussionmentioning

confidence: 99%

“…Targeting the M 3 R/βPix/β-catenin axis has therapeutic potential. Our experience using Arhgef7 CKO mice with intestinal epithelial cell-selective βPix deficiency suggests targeting intestinal βPix would be safe; Arhgef7 CKO mice are healthy and fertile with modest phenotypic changes 59 . Lastly, since other upstream receptors act through PKC-α, our findings may be mechanistically relevant to other receptors and signaling pathways in colon neoplasia and other cancers in which muscarinic receptor signaling plays a prominent role.…”

Section: Discussionmentioning

confidence: 99%

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Muscarinic receptor agonist-induced βPix binding to β-catenin promotes colon neoplasia

Cheng,

Chahdi,

Larabee

et al. 2023

Sci Rep

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M3 muscarinic receptors (M3R) modulate β-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, βPix, binds to β-catenin in colon cancer cells, augmenting β-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M3R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of βPix and β-catenin in stem cells overexpressing M3R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M3R agonist-induced cytoplasmic and nuclear association of βPix with β-catenin. βPix knockdown attenuated M3R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing βPix dose-dependently augmented β-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of βPix. Expression levels of β-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from βPix-deficient conditional knockout mice. Targeting the M3R/βPix/β-catenin axis may have therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Muscarinic receptor agonist-induced βPix binding to β-catenin promotes colon neoplasia

Cheng,

Chahdi,

Larabee

et al. 2023

Sci Rep

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“…4) and can induce membrane ruffling, it is also involved in cell migration, attachment and spreading. In particular, ARGHEF7 function was associated with intestinal cell maturation and proliferation in mice [51]. According to the study, ARHGEF7 is essential for normal small intestinal epithelial cell proliferation, villus development and mucosal resistance to injury.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, ARGHEF7 function was associated with intestinal cell maturation and proliferation in mice [51].…”

Section: Arhgef7mentioning

confidence: 98%

Body weight changes and bipolar disorder: a molecular pathway analysis

Calabrò

Briuglia

Crisafulli

et al. 2022

Pharmacogenetics and Genomics

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Background There is evidence suggesting a link between weight-related disorders and bipolar disorder (BD). The pathophysiology of the association includes psychological, social and psychotropic treatment-related variables, together with psychiatric comorbidity. Weight changes during BD may influence compliance to the treatment, quality of life and prognosis, and can modulate risk of death associated with, for example, diabetes or cardiovascular disorders. MethodsThe STEP-BD sample is analyzed through a hypothesis-free molecular pathway analysis in order to detect the molecular pathways that distinguish individuals who experience weight change during BD treatment from those who do not. A total of 618 individuals were available for the analysis, mean age = 41.19 ± 12.58, females = 351 (56.8%). Socioeconomic variables and treatment-related variables were included as clinical covariates. A cluster analysis in the genetic dataset provided the genetic covariate input to the study to avoid stratification factors.Result After applying the quality analysis that is typical for this kind of investigation, no Genome Wide Association Study significant finding was retrieved. Six molecular pathways were found to be significantly associated with weight change during the first 3 months of treatment after correction for multiple testing. Of those, CDC42 (R-HSA-9013148) participates in insulin synthesis and secretion and contributes to the pathogenesis of insulin resistance and Rac Family Small GTPase 1 (R-HSA-9013149) is involved in metabolic regulation of pancreatic islet β-cells and in diabetes pathophysiology.Discussion Pathways that are central in energy homeostasis may play a role to separate individuals with BD that will experience weight changes during treatment from those who will not. If confirmed, such finding can be instrumental in the identification of the correct preventive strategies and most correct treatment to increase compliance and efficacy in the treatment of BD.

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“…Herein, evolutionary forces acting on cytoskeletal organization-related genes (ARHGEF7 and CADM2) provided additional evidence reflective of thermal selection in O. oratoria. ARHGEF7 can regulate Rho GTPase activity and plays a role in regulating cytoskeletal and cell adhesion dynamics (Cheng et al, 2021), while CADM2 is a cell adhesion molecule that functions in cell recognition, adhesion, migration and differentiation (Edelman, 1983). Selection on genes involved in cytoskeletal organization has also been implicated in the warm-adapted marine mussel Mytilus galloprovincialis compared with its cold-adapted congeners (Popovic and Riginos, 2020).…”

Section: Environmental Heterogeneity Driving Adaptive Divergence In O...mentioning

confidence: 99%

Insights into adaptive divergence of Japanese mantis shrimp Oratosquilla oratoria inferred from comparative analysis of full-length transcriptomes

et al. 2022

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The heterogeneous seascapes in the northwestern Pacific (NWP) can be important selective forces driving adaptive divergence of marine coastal species distributed along the gradients. Here, we tested this hypothesis in Japanese mantis shrimp (Oratosquilla oratoria) with a wide distribution in the NWP and a significant north-south population structure. To this end, the full-length (FL) transcriptomes of northern and southern O. oratoria were firstly sequenced using PacBio single molecule real-time sequencing technology. Based on the FL transcriptome data, we captured large-scale FL transcripts of O. oratoria and predicted the FL transcriptome structure, including coding region, transcription factor and long noncoding RNA. To reveal the divergence between northern and southern O. oratoria, we identified 2,182 pairs of orthologous genes and inferred their sequence divergences. The average differences in coding, 5’ untranslated and 3’ untranslated region were 1.44%, 2.79% and 1.46%, respectively, providing additional support to previous proposition that northern and southern O. oratoria are two species. We provided further evolutionary context to our analysis by identifying positive selected genes (PSGs) between northern and southern O. oratoria. In total, 98 orthologs were found evolving under positive selection and involved several environmentally responsive genes associated with stress response, immunity and cytoskeletal organization, etc. Furthermore, we found PSGs also diverged in gene expression response of northern and southern O. oratoria to heat stress. These findings not only highlight the importance of genetic variation in these genes in adapting to environmental changes in O. oratoria, but also suggest that natural selection may act on the plasticity of gene expression to facilitate O. oratoria adaptation to environmental gradients. Overall, our work contributes to understanding how marine coastal species has evolved to adapt to heterogeneous seascapes in the NWP.

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Targeted intestinal deletion of Rho guanine nucleotide exchange factor 7, βPIX, impairs enterocyte proliferation, villus maturation, and mucosal defenses in mice

Cited by 4 publications

References 77 publications

Muscarinic receptor agonist-induced βPix binding to β-catenin promotes colon neoplasia

Muscarinic receptor agonist-induced βPix binding to β-catenin promotes colon neoplasia

Body weight changes and bipolar disorder: a molecular pathway analysis

Insights into adaptive divergence of Japanese mantis shrimp Oratosquilla oratoria inferred from comparative analysis of full-length transcriptomes

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