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Upregulated Vav2 signaling induces a transcriptomic rewiring in epidermal stem cells

ABSTRACT: Signals emanating from Rho GTPases play pivotal roles in epidermal stem cell homeostasis. However, the agents regulating Rho GTPase output within the epidermal stem cell niche are poorly known. Here, we report that the Rho exchange factor Vav2 regulates the epidermal stem cell transcriptome in an age-dependent manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE140152 | GEO | 2023/10/24

REPOSITORIES: GEO

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Upregulated Vav2 signaling promotes regenerative proliferation in squamous cell carcinoma

Project description:Stem cell-like regenerative proliferation and undifferentiation cause poor prognosis in squamous cell carcinoma (SCC). Despite this, the signaling events driving to those traits remain ill-characterized. We report here that VAV2, an enzyme involved in RHO GTPase activation, becomes frequently upregulated in cutaneous and head-and-neck SCC, where it orchestrates a stem cell-like regenerative state.

2020-08-13 | GSE124019 | GEO

Ota2015 - Positive regulation of Rho GTPase activity by RhoGDIs as a result of their direct interaction with GAPs (GDI integrated)

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The Rho guanosine exchange factors Vav2 and Vav3 modulate epidermal stem cell function

Project description:The Rho guanosine exchange factors Vav2 and Vav3 modulate epidermal stem cell function

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The Rho guanosine exchange factors Vav2 and Vav3 modulate epidermal stem cell function

Project description:It is known that Rho GTPases control different aspects of the biology of skin stem cells (SSCs). However, little information is available on the role of its upstream regulators under normal and tumorigenic conditions in this process. To address this issue, we have used here mouse models in which the activity of guanosine nucleotide exchange factors of the Vav subfamily has been manipulated using both gain- and loss-of-function strategies. These experiments indicate that Vav2 and Vav3 regulate the number, functional status, and responsiveness of hair follicle bulge stem cells. This is linked to gene expression programs related to the reinforcement of the SSC identity and the quiescent state. By contrast, Vav proteins promote transcriptomal programs associated with the identity and activation state of SSCs in cancer stem cells.

2022-05-07 | GSE180946 | GEO

An RNAi Screen for Skin Morphogenesis Unravels The Complexities of Rho GTPase Networks

Project description:During embryogenesis, antagonism and synergy between developmental signaling pathways dictate cell fate decisions. How these circuits orchestrate the complex cellular remodeling needed for tissue morphogenesis remains poorly understood. As effectors of cytoskeletal dynamics, Rho GTPases and their regulators are likely to be involved. However, their daunting complexity has hindered progress in dissecting their functions. Here we overcome this hurdle by developing an unbiased, high throughput RNAi-mediated screening approach to identify physiological regulators of morphogenesis. Exploiting in utero lentiviral delivery methods to transduce embryonic mouse skin progenitors, we screened for Rho GTPases and GTPase regulators that differentially function in epidermal versus hair follicle development. Our screen unveiled hitherto unrecognized roles for specific family members in cytoskeletal remodeling events that impact these diverse morphogenetic processes, including epidermal differentiation, follicle downgrowth and planar cell polarity. Our findings underscore the power of our screening strategy for unravel the physiological significance of complex gene families.

2019-10-08 | GSE123047 | GEO

Transcription profiling of human normal and RhoA immortal cells

Project description:Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions including actin cytoskeleton remodeling, cell migration, gene transcription, and cell proliferation. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably utilized immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human mammary epithelial cells (hMECs). We found that ectopic expression of wild-type RhoA as well as a constitutively-active RhoA mutant (G14V) in primary hMEC strains led to their immortalization and preneoplastic transformation. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well known Rho-effectors ,was also capable of immortalizing hMECs.Our results demonstrate that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked cellular transformation and breast cancer. Through microarray analysis, we want to identify genes and pathways linked to RhoA induced hMECs immortalization. Experiment Overall Design: 4 samples, in triplicate analyses per sample.

2008-10-26 | E-GEOD-12917 | biostudies-arrayexpress

Vav proteins maintain epithelial traits in breast cancer cells using miR-200c-dependent and independent mechanisms

Project description:Here, we report that the Rho GTPase activators Vav2 and Vav3 utilize a new, miR-200c-dependent mechanism that maintains the epithelial state by limiting the abundance of the Zeb2 transcriptional repressor in breast cancer cells. In parallel, Vav proteins engage an expression program that maintains epithelial cell traits in 3D culture. Depletion of Vav proteins triggers EMT in epithelioid breast cancer cells and, conversely, expression of constitutively active Vav2 restores both miR-200c expression and epithelial traits in mesenchymal breast cancer cells. In silico analyses suggest that the negative Vav-Zeb2 axis is operative in human luminal breast tumors.

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Both wnt signaling and epidermal stem cell-derived exosomes are involved in epidermal development

Project description:Millions suffer from skin diseases. Functional epidermal stem cells are needed in skin therapy or drug screening in vitro. We obtained functional epidermal stem cells with intact stemness and cell junctions by treating them with wnt3a. Moreover, epidermal stem cell-derived exosomes were useful in epidermal development. Finally, functional epidermal 3D organoids with polarity were cultured using wnt3a and the supernatant derived from epidermal stem cells and fresh medium in a 1:1 ratio. These results provide novel directions for the improvement of skin organoids and their potential in clinical application.

2020-07-14 | PXD020351 | iProX

Transcriptional profiling of the cellular transformation induced by Rho subfamily GTPases

Project description:We have used microarray technology to identify the transcriptional targets of Rho subfamily GTPases. This analysis indicated that murine fibroblasts transformed by these proteins show similar transcriptomal profiles. Functional annotation of the regulated genes indicate that Rho subfamily GTPases target a wide spectrum of biological functions, although loci encoding proteins linked to proliferation and DNA synthesis/transcription are up-regulated preferentially. Rho proteins promote four main networks of interacting proteins nucleated around E2F, c-Jun, c-Myc, and p53. Of those, E2F, c-Jun and c-Myc are essential for the maintenance of cell transformation. Inhibition of Rock, one of the main Rho GTPase targets, leads to small changes in the transcriptome of Rho-transformed cells. Rock inhibition decreases c-myc gene expression without affecting the E2F and c-Jun pathways. Loss-of-function studies demonstrate that c-Myc is important for the blockage of cell-contact inhibition rather than for promoting the proliferation of Rho-transformed cells. However, c-Myc overexpression does not bypass the inhibition of cell transformation induced by Rock blockage, indicating that c-Myc is essential, but not sufficient, for Rock-dependent transformation. These results reveal the complexity of the genetic program orchestrated by the Rho subfamily and pinpoint protein networks that mediate different aspects of the malignant phenotype of Rho-transformed cells Keywords: Rho/Rac GTPases, microarray, oncogenesis, proliferation, gene expression, transcription, Rock, c-Myc

2007-01-03 | GSE5913 | GEO

Quantitative GTPase affinity purification identifies Rho family protein interaction partners

Project description:Although Rho GTPases are essential molecular switches involved in many cellular processes, an unbiased experimental comparison of their interaction partners was not yet performed. Here, we develop quantitative GTPase affinity purification (qGAP) to systematically identify interaction partners of six Rho GTPases (Cdc42, Rac1, RhoA, RhoB, RhoC, RhoD) depending on their nucleotide loading state. We use Stable isotope labeling by Amino acids in cell culture (SILAC) and label free quantification (LFQ). Our interaction network contains many new proteins, reveals highly promiscuous binding of several effectors and mirrors evolutionary relationships of Rho GTPases.

2016-12-23 | PXD004190 | Pride

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