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1.
Mol Biol Cell ; 22(10): 1686-98, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21411626

ABSTRACT

Epithelial-mesenchymal transition (EMT) is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. A double-negative feedback loop involving the miR-200 family and ZEB (zinc finger E-box-binding homeobox) transcription factors has been postulated to control the balance between epithelial and mesenchymal states. Here we demonstrate using the epithelial Madin Darby canine kidney cell line model that, although manipulation of the ZEB/miR-200 balance is able to repeatedly switch cells between epithelial and mesenchymal states, the induction and maintenance of a stable mesenchymal phenotype requires the establishment of autocrine transforming growth factor-ß (TGF-ß) signaling to drive sustained ZEB expression. Furthermore, we show that prolonged autocrine TGF-ß signaling induced reversible DNA methylation of the miR-200 loci with corresponding changes in miR-200 levels. Collectively, these findings demonstrate the existence of an autocrine TGF-ß/ZEB/miR-200 signaling network that regulates plasticity between epithelial and mesenchymal states. We find a strong correlation between ZEBs and TGF-ß and negative correlations between miR-200 and TGF-ß and between miR-200 and ZEBs, in invasive ductal carcinomas, consistent with an autocrine TGF-ß/ZEB/miR-200 signaling network being active in breast cancers.


Subject(s)
Autocrine Communication , Epithelial-Mesenchymal Transition/genetics , Homeodomain Proteins/metabolism , MicroRNAs/genetics , Repressor Proteins/metabolism , Transcription Factors/metabolism , Transforming Growth Factor beta/metabolism , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/metabolism , Cell Line , Cofilin 2 , DNA Methylation , Dogs , Feedback, Physiological , Female , Homeodomain Proteins/genetics , Humans , MicroRNAs/metabolism , Repressor Proteins/genetics , Signal Transduction , Transcription Factors/genetics , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/pharmacology , Up-Regulation , Zinc Finger E-box Binding Homeobox 2 , Zinc Finger E-box-Binding Homeobox 1
2.
Cell Cycle ; 7(15): 2290-5, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18677119

ABSTRACT

The TGFbetas are a family of pleiotropic cytokines that mediate diverse effects including the regulation of cell cycle progression, apoptosis, tissue remodelling and epithelial-mesenchymal transition (EMT). These diverse effects allow the TGFbetas to play multiple and even opposing roles in different contexts during embryonal development, tissue homeostasis and cancer progression. We recently reported that the protein tyrosine phosphatase Pez is a novel inducer of TGFbeta signaling, regulating EMT and organogenesis in developing zebrafish embryos, and leading to TGFbeta-mediated EMT when overexpressed in vitro in epithelial MDCK cells. A number of mutations in Pez have been shown to be associated with breast and colorectal cancers, although the effect of these mutations on Pez function and their contribution to cancer progression remains unclear. Our finding that Pez regulates TGFbeta signaling is therefore of interest not only in the context of identifying a novel upstream regulator of TGFbeta signaling, but also in implicating the dysregulation of TGFbeta signaling as a possible link between Pez mutation and cancer progression. Here we discuss the implications of our research, in the context of dysregulation of TGFbeta signaling in cancer and other human pathologies.


Subject(s)
Protein Tyrosine Phosphatases, Non-Receptor/physiology , Signal Transduction/genetics , Transforming Growth Factor beta/physiology , Animals , Disease/etiology , Growth and Development/genetics , Homeostasis/genetics , Humans , Models, Biological , Neoplasms/genetics , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/genetics
3.
J Cell Biol ; 178(7): 1223-35, 2007 Sep 24.
Article in English | MEDLINE | ID: mdl-17893246

ABSTRACT

Epithelial-mesenchymal transition (EMT), crucial during embryogenesis for new tissue and organ formation, is also considered to be a prerequisite to cancer metastasis. We report here that the protein tyrosine phosphatase Pez is expressed transiently in discrete locations in developing brain, heart, pharyngeal arches, and somites in zebrafish embryos. We also find that Pez knock-down results in defects in these organs, indicating a crucial role in organogenesis. Overexpression of Pez in epithelial MDCK cells causes EMT, with a drastic change in cell morphology and function that is accompanied by changes in gene expression typical of EMT. Transfection of Pez induced TGFbeta signaling, critical in developmental EMT with a likely role also in oncogenic EMT. In zebrafish, TGFbeta3 is co- expressed with Pez in a number of tissues and its expression was lost from these tissues when Pez expression was knocked down. Together, our data suggest Pez plays a crucial role in organogenesis by inducing TGFbeta and EMT.


Subject(s)
Epithelial Cells/cytology , Mesoderm/cytology , Organogenesis , Protein Tyrosine Phosphatases/metabolism , Transforming Growth Factor beta/metabolism , Zebrafish Proteins/metabolism , Zebrafish/embryology , Zebrafish/metabolism , Animals , Cell Nucleus/metabolism , Dogs , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/metabolism , Embryonic Development/drug effects , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Gene Expression Regulation, Developmental/drug effects , Humans , Mesoderm/drug effects , Mesoderm/metabolism , Oligonucleotides, Antisense/pharmacology , Organogenesis/drug effects , Phenotype , Protein Transport/drug effects , Protein Tyrosine Phosphatases/genetics , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Protein Tyrosine Phosphatases, Non-Receptor/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/drug effects , Smad4 Protein/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta2/genetics , Transforming Growth Factor beta2/metabolism , Transforming Growth Factor beta3/genetics , Transforming Growth Factor beta3/metabolism , Zebrafish/genetics , Zebrafish Proteins/genetics
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