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Gene Expression Profiles in erythroblasts and progenitor cells of mDia2 conditional KO mice

ABSTRACT: The goal of this study is to investigate the transcriptional network regulated by DIAPH3 gene (mDia2) using the conditional hematopoietic specific knockout mouse model, especially in the cell proliferation, cell survive (including oxidative stress), cell adhesion & migration, cell cycle and hematopoiesis pathway-related genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE68422 | GEO | 2015/04/30

SECONDARY ACCESSION(S): PRJNA282690

REPOSITORIES: GEO

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Project description:Diaphanous-related formin-3 (DIAPH3), a cytoskeletal regulator of the formin family, is lost at high frequency in metastatic breast and prostate cancers and has characteristics of a non-canonical metastasis suppressor. We previously demonstrated that DIAPH3 silencing evokes transition to an “amoeboid” phenotype, characterized by rapid motility, RhoA/ROCK and MEK/ERK pathway activation, dynamic membrane blebbing, and increased shedding of microvesicles. Here we report that low DIAPH3 mRNA expression correlates with reduced survival in multiple cancer patient cohorts. In line with induction of amoeboid behavior, traction force microscopy (TFM) revealed that polarized force generation, contractility, and response to substrate stiffness are reduced by DIAPH3 loss. Proteomic analyses revealed that DIAPH3 precipitates with tubulins, and reciprocal co-immunoprecipitation analyses revealed greater binding of DIAPH3 to MT polymers than soluble tubulin. DIAPH3 also bound to acetylated-tubulin (Ac-tubulin), suggesting association with a stable MT population. DIAPH3 silencing reduced Ac-tubulin and increased the cellular content of dynamic MT, as indicated by TFM and live cell imaging. DIAPH3 silencing also increased responsiveness to MT-disrupting agents. Treatment with the taxanes paclitaxel and docetaxel, and the non-taxane epothilone B, induced a greater change in Ac-tubulin when cells lacked DIAPH3. Intracellular accumulation of Oregon Green 488-paclitaxel was also increased by DIAPH3 loss, and accordingly, DIAPH3 silencing enhanced cytotoxicity by paclitaxel, docetaxel, or epothilone B. Gene expression profiles of breast cancer patients treated with chemotherapeutic regimens containing taxanes revealed an association of low DIAPH3 expression with improved relapse-free survival. Collectively, these results suggest that regulation of MT stability/dynamics by DIAPH3 enhances amoeboid tumor cell susceptibility to microtubule poisons. These findings have potential therapeutic implications.

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Gene Expression Profiles in erythroblasts and progenitor cells of mDia2 conditional KO mice

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