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Role of DeltaNp63gamma in epithelial to mesenchymal transition.

ABSTRACT: Although members of the p63 family of transcription factors are known for their role in the development and differentiation of epithelial surfaces, their function in cancer is less clear. Here, we show that depletion of the ?Np63? and ? isoforms, leaving only ?Np63?, results in epithelial to mesenchymal transition (EMT) in the normal breast cell line MCF10A. EMT can be rescued by the expression of the ?Np63? isoform. We also show that ?Np63? expressed in a background where all the other ?Np63 are knocked down causes EMT with an increase in TGF?-1, -2, and -3 and downstream effectors Smads2/3/4. In addition, a p63 binding site in intron 1 of TGF? was identified. Inhibition of the TGF? response with a specific inhibitor results in reversion of EMT in ?Np63?- and ?-depleted cells. In summary, we show that p63 is involved in inhibiting EMT and reduction of certain p63 isoforms may be important in the development of epithelial cancers.

SUBMITTER: Lindsay J

PROVIDER: S-EPMC3030392 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Role of DeltaNp63gamma in epithelial to mesenchymal transition.

Lindsay Jaime J McDade Simon S SS Pickard Adam A McCloskey Karen D KD McCance Dennis J DJ

The Journal of biological chemistry 20101202 5

Although members of the p63 family of transcription factors are known for their role in the development and differentiation of epithelial surfaces, their function in cancer is less clear. Here, we show that depletion of the ΔNp63α and β isoforms, leaving only ΔNp63γ, results in epithelial to mesenchymal transition (EMT) in the normal breast cell line MCF10A. EMT can be rescued by the expression of the ΔNp63α isoform. We also show that ΔNp63γ expressed in a background where all the other ΔNp63 ar ...[more]

PMID: 21127042

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Project description:Epithelial-to-mesenchymal transition (EMT) is a key biological process involved in a multitude of developmental and pathological events. It is characterized by the progressive loss of cell-to-cell contacts and actin cytoskeletal rearrangements, leading to filopodia formation and the progressive up-regulation of a mesenchymal gene expression pattern enabling cell migration. Epithelial-to-mesenchymal transition is already observed in early embryonic stages such as gastrulation, when the epiblast undergoes an EMT process and therefore leads to the formation of the third embryonic layer, the mesoderm. Epithelial-to-mesenchymal transition is pivotal in multiple embryonic processes, such as for example during cardiovascular system development, as valve primordia are formed and the cardiac jelly is progressively invaded by endocardium-derived mesenchyme or as the external cardiac cell layer is established, i.e., the epicardium and cells detached migrate into the embryonic myocardial to form the cardiac fibrous skeleton and the coronary vasculature. Strikingly, the most important biological event in which EMT is pivotal is cancer development and metastasis. Over the last years, understanding of the transcriptional regulatory networks involved in EMT has greatly advanced. Several transcriptional factors such as Snail, Slug, Twist, Zeb1 and Zeb2 have been reported to play fundamental roles in EMT, leading in most cases to transcriptional repression of cell?cell interacting proteins such as ZO-1 and cadherins and activation of cytoskeletal markers such as vimentin. In recent years, a fundamental role for non-coding RNAs, particularly microRNAs and more recently long non-coding RNAs, has been identified in normal tissue development and homeostasis as well as in several oncogenic processes. In this study, we will provide a state-of-the-art review of the functional roles of non-coding RNAs, particularly microRNAs, in epithelial-to-mesenchymal transition in both developmental and pathological EMT.

Dataset Information

Role of DeltaNp63gamma in epithelial to mesenchymal transition.

Publications

Role of DeltaNp63gamma in epithelial to mesenchymal transition.

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