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Analysis of Rho GTPase expression in T-ALL identifies RhoU as a target for Notch involved in T-ALL cell migration.

ABSTRACT: NOTCH1 is frequently mutated in T-cell acute lymphoblastic leukaemia (T-ALL), and can stimulate T-ALL cell survival and proliferation. Here we explore the hypothesis that Notch1 also alters T-ALL cell migration. Rho GTPases are well known to regulate cell adhesion and migration. We have analysed the expression levels of Rho GTPases in primary T-ALL samples compared with normal T cells by quantitative PCR. We found that 5 of the 20 human Rho genes are highly and consistently upregulated in T-ALL, and 3 further Rho genes are expressed in T-ALL but not detectable in normal T cells. Of these, RHOU expression is highly correlated with the expression of the Notch1 target DELTEX-1. Inhibition of Notch1 signalling with a ?-secretase inhibitor (GSI) or Notch1 RNA interference reduced RhoU expression in T-ALL cells, whereas constitutively active Notch1 increased RhoU expression. In addition, Notch1 or RhoU depletion, or GSI treatment, inhibits T-ALL cell adhesion, migration and chemotaxis. These results indicate that NOTCH1 mutation stimulates T-ALL cell migration through RhoU upregulation that could contribute to the leukaemia cell dissemination.

SUBMITTER: Bhavsar PJ

PROVIDER: S-EPMC3378627 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Analysis of Rho GTPase expression in T-ALL identifies RhoU as a target for Notch involved in T-ALL cell migration.

Bhavsar P J PJ Infante E E Khwaja A A Ridley A J AJ

Oncogene 20120220 2

NOTCH1 is frequently mutated in T-cell acute lymphoblastic leukaemia (T-ALL), and can stimulate T-ALL cell survival and proliferation. Here we explore the hypothesis that Notch1 also alters T-ALL cell migration. Rho GTPases are well known to regulate cell adhesion and migration. We have analysed the expression levels of Rho GTPases in primary T-ALL samples compared with normal T cells by quantitative PCR. We found that 5 of the 20 human Rho genes are highly and consistently upregulated in T-ALL, ...[more]

PMID: 22349824

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Project description:The vertebrate heart undergoes early complex morphologic events in order to develop key cardiac structures that regulate its overall function (Fahed et al., 2013). Although many genetic factors that participate in patterning the heart have been elucidated (Tu and Chi, 2012), the cellular events that drive cardiac morphogenesis have been less clear. From a chemical genetic screen to identify cellular pathways that control cardiac morphogenesis in zebrafish, we observed that inhibition of the Rho signaling pathways resulted in failure to form the atrioventricular canal and loop the linear heart tube. To identify specific Rho proteins that may regulate this process, we analyzed cardiac expression profiling data and discovered that RhoU was expressed at the atrioventricular canal during the time when it forms. Loss of RhoU function recapitulated the atrioventricular canal and cardiac looping defects observed in the ROCK inhibitor treated zebrafish. Similar to its family member RhoV/Chp (Tay et al., 2010), we discovered that RhoU regulates the cell junctions between cardiomyocytes through the Arhgef7b/Pak kinase pathway in order to guide atrioventricular canal development and cardiac looping. Inhibition of this pathway resulted in similar underlying cardiac defects and conversely, overexpression of a PAK kinase was able to rescue the loss of RhoU cardiac defect. Finally, we found that Wnt signaling, which has been implicated in atrioventricular canal development (Verhoeven et al., 2011), may regulate the expression of RhoU at the atrioventricular canal. Overall, these findings reveal a cardiac developmental pathway involving RhoU/Arhgef7b/Pak signaling, which helps coordinate cell junction formation between atrioventricular cardiomyocytes to promote cell adhesiveness and cell shapes during cardiac morphogenesis. Failure to properly form these cell adhesions during cardiac development may lead to structural heart defects and mechanistically account for the cellular events that occur in certain human congenital heart diseases.

Dataset Information

Analysis of Rho GTPase expression in T-ALL identifies RhoU as a target for Notch involved in T-ALL cell migration.

Publications

Analysis of Rho GTPase expression in T-ALL identifies RhoU as a target for Notch involved in T-ALL cell migration.

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