Smurf1 regulation of DAB2IP controls cell proliferation and migration.
Ontology highlight
ABSTRACT:
SUBMITTER: Li X
PROVIDER: S-EPMC5041964 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Here, we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seq analyses of both oestrogen receptor receptor-positive and receptor-negative breast cancer cells overexpressing miR-515-5p reveal down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2B and MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3' UTR interaction and that MARK4 knock-down mimics the effect of miR-515-5p on breast and lung cancer cell migration. MARK4 overexpression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation. Furthermore, miR-515-5p expression is reduced in metastases compared to primary tumours derived from both in vivo xenografts and samples from patients with breast cancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination in a mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expression correlate with increased breast and lung cancer patients' survival, respectively. Taken together, these data demonstrate the importance of miR-515-5p/MARK4 regulation in cell migration and metastasis across two common cancers.
| S-EPMC4818771 | biostudies-literature
Project description:The scaffold protein syntenin abounds during fetal life where it is important for developmental movements. In human adulthood, syntenin gain-of-function is increasingly associated with various cancers and poor prognosis. Depending on the cancer model analyzed, syntenin affects various signaling pathways. We previously have shown that syntenin allows syndecan heparan sulfate proteoglycans to escape degradation. This indicates that syntenin has the potential to support sustained signaling of a plethora of growth factors and adhesion molecules. Here, we aim to clarify the impact of syntenin loss-of-function on cancer cell migration, growth, and proliferation, using cells from various cancer types and syntenin shRNA and siRNA silencing approaches. We observed decreased migration, growth, and proliferation of the mouse melanoma cell line B16F10, the human colon cancer cell line HT29 and the human breast cancer cell line MCF7. We further documented that syntenin controls the presence of active ?1 integrin at the cell membrane and G1/S cell cycle transition as well as the expression levels of CDK4, Cyclin D2, and Retinoblastoma proteins. These data confirm that syntenin supports the migration and growth of tumor cells, independently of their origin, and further highlight the attractiveness of syntenin as potential therapeutic target.
| S-EPMC4612656 | biostudies-literature
Project description:Hypopharyngeal carcinoma (HPC) is an aggressive malignancy with the worst prognosis among all head and neck cancers. MicroRNAs (miRNAs) are involved in the development of many human cancers, and may function as oncogenes or tumor suppressors. The present study aimed to evaluate the effects of miRNA (miR)?194?5p on the proliferation and invasion of HPC cells and to identify the potential regulatory mechanism. First, miR?194?5p and Smad ubiquitin regulatory factor 1 (SMURF1) expression levels were examined in HPC tissues. Subsequently, to explore the effects of miR?194?5p on SMURF1, a dual?luciferase reporter gene assay was performed to verify the target relationship. To define the role of miR?194?5p in HPC progression, miR?194?5p upregulation and depletion were used to evaluate its effects on cell viability, invasion and migration. SMURF1 silencing and rapamycin [an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway] treatment were also used to analyze the regulatory mechanism in HPC. Finally, tumor growth was assessed in xenografted tumors in nude mice. SMURF1 was demonstrated to be highly expressed, whereas miR?194?5p was poorly expressed in HPC tissues; SMURF1 was identified as a target gene of miR?194?5p. FaDu hypopharyngeal squamous cell carcinoma cells treated with miR?194?5p mimics exhibited decreased viability, invasion and migration. The results indicated that miR?194?5p may inactivate the mTOR signaling pathway by targeting SMURF1. In addition, the in vivo experiments further verified these regulatory effects. These data suggested that miR?194?5p?targeted SMURF1 inhibition may be involved in the disruption of HPC progression through the repression of the mTOR signaling pathway.
| S-EPMC6411369 | biostudies-literature
Project description:Rho GTPase-activating protein 26 (ARHGAP26) is a negative regulator of the Rho family that converts the small GTP-binding protein RhoA (GTP-RhoA) to its inactive GDP-bound form and is a putative tumor suppressor gene associated with cell growth and migration. Here, the involvement of ARHGAP26 in ovarian cancer cell proliferation and migration was investigated. In this study, low ARHGAP26 expression was observed in ovarian cancer tissues and was associated with a poor overall survival and higher β-catenin expression in patients with ovarian cancer. A2780 and HEY cells with ARHGAP26 upregulation showed decreased cell proliferation, migration, and invasion, along with decreased GTP-RhoA, β-catenin, VEGF, MMP2, and MMP7 expression. ARHGAP26 upregulation in A2780 cells also inhibited lung metastasis in vivo. SKOV3 cells with ARHGAP26 downregulation demonstrated an inverse effect, which was inhibited by ARHGAP26 overexpression or DKK1, an antagonist of the β-catenin pathway. SMURF1, an E3 ubiquitin ligase, interacted with and induced ubiquitination of ARHGAP26. ARHGAP26 upregulation in SKOV3 cells significantly inhibited SMURF1 upregulation-induced cell migration and invasion. Overall, SMURF1-mediated ubiquitination of ARHGAP26 may promote invasion and migration of ovarian cancer cells via the β-catenin pathway.
| S-EPMC6474862 | biostudies-literature
Project description:Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.
| S-EPMC2714540 | biostudies-literature
Project description:Epidermal growth factor (EGF) is a well-known growth factor that induces cancer cell migration and invasion. Previous studies have shown that SMAD ubiquitination regulatory factor 1 (SMURF1), an E3 ubiquitin ligase, regulates cell motility by inducing RhoA degradation. Therefore, we examined the role of SMURF1 in EGF-induced cell migration and invasion using MDA-MB-231 cells, a human breast cancer cell line. EGF increased SMURF1 expression at both the mRNA and protein levels. All ErbB family members were expressed in MDA-MB-231 cells and receptor tyrosine kinase inhibitors specific for the EGF receptor (EGFR) or ErbB2 blocked the EGF-mediated induction of SMURF1 expression. Within the signaling pathways examined, ERK1/2 and protein kinase C activity were required for EGF-induced SMURF1 expression. The overexpression of constitutively active MEK1 increased the SMURF1 to levels similar to those induced by EGF. SMURF1 induction by EGF treatment or by the overexpression of MEK1 or SMURF1 resulted in enhanced cell migration and invasion, whereas SMURF1 knockdown suppressed EGF- or MEK1-induced cell migration and invasion. EGF treatment or SMURF1 overexpression decreased the endogenous RhoA protein levels. The overexpression of constitutively active RhoA prevented EGF- or SMURF1-induced cell migration and invasion. These results suggest that EGFinduced SMURF1 plays a role in breast cancer cell migration and invasion through the downregulation of RhoA.
| S-EPMC3887964 | biostudies-literature
Project description:Interneurons navigate along multiple tangential paths to settle into appropriate cortical layer. They undergo saltatory migration, which is paced by intermittent nuclear jumps whose regulation relies on interplay between extracellular cues and genetic-encoded information. However, it remains unclear how cycles of pause and movement are coordinated at the molecular level. Post-translational modification of proteins contributes to cell migration regulation. The present study uncovers that carboxypeptidase 1, which promotes deglutamylation, is a pivotal regulator of pausing of cortical interneurons. Moreover, we show that pausing during migration controls the flow of interneurons invading the cortex by generating heterogeinity in movement at the population level. Interfering with the regulation of pausing not only affects the size of the cortical interneuron cohort but also secondarily impairs the generation of age-matched upper layer projection neurons.
2018-02-14 | PXD006397 | Pride
Project description:Ubiquitin ligase Smurf1-deficient mice develop an increased-bone-mass phenotype in an age-dependent manner. It was reported that such a bone-mass increase is related to enhanced activities of differentiated osteoblasts. Although osteoblasts are of mesenchymal stem cell (MSC) origin and MSC proliferation and differentiation can have significant impacts on bone formation, it remains largely unknown whether regulation of MSCs plays a role in the bone-mass increase of Smurf1-deficient mice. In this study we found that bone marrow mesenchymal progenitor cells from Smurf1(-/-) mice form significantly increased alkaline phosphatase-positive colonies, indicating roles of MSC proliferation and differentiation in bone-mass accrual of Smurf1(-/-) mice. Interestingly, Smurf1(-/-) cells have an elevated protein level of AP-1 transcription factor JunB. Biochemical experiments demonstrate that Smurf1 interacts with JunB through the PY motif and targets JunB protein for ubiquitination and proteasomal degradation. Indeed, Smurf1-deficient MSCs have higher proliferation rates, consistent with the facts that cyclin D1 mRNA and protein both are increased in Smurf1(-/-) cells and JunB can induce cyclinD1 promoter. Moreover, JunB overexpression induces osteoblast differentiation, shown by higher expression of osteoblast markers, and JunB knock-down not only decreases osteoblast differentiation but also restores the osteogenic potential to wild-type level in Smurf1(-/-) cells. In conclusion, our results suggest that Smurf1 negatively regulates MSC proliferation and differentiation by controlling JunB turnover through an ubiquitin-proteasome pathway.
| S-EPMC3153132 | biostudies-literature
Project description:Accumulating evidence has suggests that women with advanced endometriosis exhibit alterations in the expression of genes in the endometrium compared to healthy controls. Furthermore, replication stress is a characteristic feature of cancer cells, which results from sustained proliferative signaling induced by either the activation of oncogenes or the loss of tumor suppressors. In the present study, we propose that DNA replication ATP-dependent helicase/nuclease 2 (DNA2) might be upregulated in endometriosis. Immunohistochemical staining results confirmed the hypothesis that DNA2 is overexpressed in the eutopic/ectopic endometrium compared to that in a control endometrium from a healthy donor. Subsequently, ectopic endometrium-derived endometrial mesenchymal stem cells (EMSCs) showed the highest level of DNA2 and checkpoint kinase 1 (CHK1), as well as the strongest proliferation and migration capabilities, followed by eutopic endometrium-derived EMSCs, and then control EMSCs. To further analyze the function of DNA2, we knocked-down DNA2 expression in KLE cells. As expected, proliferation and migration declined when cells were transfected with DNA2 small interfering RNA. Taken together, our study demonstrated the overexpression of DNA2 in human endometriosis, which might be responsible for the upregulated cell proliferation and migration. This study provides insights into the mechanisms underlying human endometriosis.
| S-EPMC8324585 | biostudies-literature
Project description:The selective autophagy substrate p62 serves as a molecular link between autophagy and cancer. Suppression of autophagy causes p62 accumulation and thereby contributes to tumorigenesis. Here we demonstrate that autophagy deficiency promotes cell proliferation and migration through p62-dependent stabilization of the oncogenic transcription factor Twist1. p62 binds to Twist1 and inhibits degradation of Twist1. In mice, p62 up-regulation promotes tumor cell growth and metastasis in a Twist1-dependent manner. Our findings demonstrate that Twist1 is a key downstream effector of p62 in regulation of cell proliferation and migration and suggest that targeting p62-mediated Twist1 stabilization is a promising therapeutic strategy for prevention and treatment of cancer.
| S-EPMC4078859 | biostudies-literature