Abstract
The desmosome is a cell‐cell adhesion complex which facilitates the mechanical stability of tissues and cell‐cell communication. Desmosome function depends upon a tripartite organizational structure wherein transmembrane cadherins (Desmoglein and Desmocollin) link adjacent cells in the extracellular space, armadillo proteins (Plakophilin and Plakoglobin) stabilizethe intracellular plaque, and the cytolinker Desmoplakin (DP) connects the plaque to the intermediate filament network. In addition to their central role in maintaining cell‐cell junction integrity, desmosomal cadherins also coordinate biological processes such as proliferation, apoptosis, differentiation and cell migration. Many studies have reported diverse mechanisms by which cancer progression alters DSM gene expression, but the signaling pathways that govern the expression and localization of DSM constituent proteins remain elusive. Recent work has identified the transcription factor serum response factor (SRF) as a regulator of mRNA levels and localization of DSM proteins such as the cadherin Desmoglein‐1. In our study, we treated several cancer cell lines with siRNA to SRF and its cofactor, MAL, to broadly investigate the role of these transcription factors in regulating DSM gene expression and protein localization. Our results demonstrate that abrogation of MAL/SRF signaling through RNAi results in a decrease in localization of DP to cell‐cell borders, along with perturbation of other desmosomal and adherens junction markers. Importantly, we also demonstrate that MAL/SRF abrogation causes a reduction in mRNA levels (by quantitative PCR) and protein levels (by western blot) of DP, indicating the importance of these transcription factors for controlling the expression of DP. Our data therefore highlight a novel link between MAL/SRF signaling and DP expression, and contribute to a growing understanding of the variety of signaling pathways involved in mediating DSM gene expression.Support or Funding InformationNIH INBRE Developmental Research Grant
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