Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells

Sauer, Lysann; Gitenay, Delphine; Vo, Cassandra; Baron, Véronique

doi:10.1038/onc.2010.24

Cited by 74 publications

(53 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Egr-1 upregulates the expression of multiple genes, including PTEN and several tumor suppressor genes. Transcription of Egr1 was previously shown to be induced by MAPK pathways, especially by ERK signaling through phosphorylation and activation of Elk1 using MEK inhibitors or the natural anticancer compound curcumin, in various types of tumors (25)(26)(27)(28). In addition to the transcriptional regulation of Egr1 by ERK, we show here that KRT19 plays a role in regulating the nuclear localization of Egr1 by modulating its association with Imp7.…”

Section: Discussionsupporting

confidence: 54%

Regulation of Cell Proliferation and Migration by Keratin19-Induced Nuclear Import of Early Growth Response-1 in Breast Cancer Cells

Yang

Lee

et al. 2013

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Keratin19 (KRT19) is the smallest known type I intermediate filament and is used as a marker for reverse transcriptase PCR-mediated detection of disseminated tumors. In this study, we investigated the functional analysis of KRT19 in human breast cancer.Experimental Design: Using a short hairpin RNA system, we silenced KRT19 in breast cancer cells. KRT19 silencing was verified by Western blot analysis and immunocytochemistry. We further examined the effect of KRT19 silencing on breast cancer cells by cell proliferation, migration, invasion, colony formation assay, cell-cycle analysis, immunocytochemistry, immunohistochemistry, and mouse xenograft assay.Results: Silencing of KRT19 resulted in increased cell proliferation, migration, invasion, and survival. These effects were mediated by upregulation of Akt signaling as a result of reduced PTEN mRNA expression. Silencing of KRT19 decreased the nuclear import of early growth response-1 (Egr1), a transcriptional factor for PTEN transcription, through reduced association between Egr1 and importin-7. We also confirmed that silencing of KRT19 increased tumor formation in a xenograft model.Conclusions: KRT19 is a potential tumor suppressor that negatively regulates Akt signaling through modulation of Egr1 nuclear localization.

show abstract

Section: Discussionsupporting

confidence: 54%

Regulation of Cell Proliferation and Migration by Keratin19-Induced Nuclear Import of Early Growth Response-1 in Breast Cancer Cells

Yang

Lee

et al. 2013

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Mutant p53 expression correlates with elevated MAPK/ERK pathway activity (ref. 43 and Supplemental Figure 7D) and increased levels of EGR1 transcription factor (44), which modifies expression of several genes involved in cytoskeletal regulation and filopodia formation (45). We observed that inhibition of the MAPK/ERK pathway efficiently reduced EGR1 and Myo10 in p53 mutant MDA-MB-231 cells but not p53 WT MCF10A cells ( Figure 7A).…”

Section: Myo10 Regulates Dissemination Of Breast Cancer Cells In Vivomentioning

confidence: 99%

Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis

et al. 2014

View full text Add to dashboard Cite

Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53-driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport β 1 integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53-driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.

show abstract

“…Its involvement has been reported in cancer metastasis [12], inﬂammation [13], atherosclerosis [14], and ischemic injury [15]. Moreover, recent studies revealed that abnormal expression and function of Egr-1 are linked to animal models of fibrosis, as well as human fibrotic disorders, including idiopathic pulmonary fibrosis and scleroderma [16,17,18].…”

Section: Introductionmentioning

confidence: 99%

Egr-1 Mediates Chronic Hypoxia-Induced Renal Interstitial Fibrosis via the PKC/ERK Pathway

et al. 2014

View full text Add to dashboard Cite

Background: Chronic hypoxia-induced epithelial-to-mesenchymal transition (EMT) is a crucial process in renal fibrogenesis. Egr-1, as a transcription factor, has been proven to be important in promoting EMT. However, whether it functions in hypoxia-induced renal tubular EMT has not been fully elucidated. Methods: Egr-1 were detected at mRNA and protein levels by qPCR and Western blot analysis respectively after renal epithelial cells were subjected to hypoxia treatment. Meanwhile, EMT phenotype was also observed through identification of relevant EMT-specific markers. siRNA was used to knock down Egr-1 expression and subsequent changes were observed. Specific PKC and MAPK/ERK inhibitors were employed to determine the molecular signaling pathway involved in Egr-1-mediated EMT phenotype. In vivo assays using rat remnant kidney model were used to validate the in vitro results. Furthermore, Egr-1 expression was examined in the samples of CKD patients with the clinical relevance revealed. Results: Hypoxia treatment enhanced the mRNA and protein levels of Egr-1 in HK-2 cells, which was accompanied by a reduced expression of the epithelial marker E-cadherin and an enhanced expression of the mesenchymal marker Fsp-1. Downregulation of Egr-1 with siRNA reversed hypoxia-induced EMT. Using the specific inhibitors to protein kinase C (calphostin C) or MAPK/ERK (PD98059), we identified that hypoxia induced Egr-1 expression through the PKC/ERK pathway. In addition, the upregulation of Egr-1 raised endogenous Snail levels, and the downregulation of Snail inhibited Egr-1-mediated EMT in HK-2 cells. Through in vivo assays using rat remnant kidney and CKD patients' kidney tissues, we found that Egr-1 and Snail were overexpressed in tubular epithelial cells with EMT. Conclusion: Egr-1 may be an important regulator of the development of renal tubular EMT induced by hypoxia through the PKC/ERK pathway and the activation of Snail. Targeting Egr-1 expression or activity might be a novel therapeutic strategy to control renal fibrosis.

show abstract

Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells

Cited by 74 publications

References 32 publications

Regulation of Cell Proliferation and Migration by Keratin19-Induced Nuclear Import of Early Growth Response-1 in Breast Cancer Cells

Regulation of Cell Proliferation and Migration by Keratin19-Induced Nuclear Import of Early Growth Response-1 in Breast Cancer Cells

Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis

Egr-1 Mediates Chronic Hypoxia-Induced Renal Interstitial Fibrosis via the PKC/ERK Pathway

Contact Info

Product

Resources

About