ABSTRACT
The intensity and duration of activation of a signal transduction system are important determinants of the specificity of the cellular response to the stimulus. It is unclear how different cells can generate a signal of varying intensity and duration in response to the same cytokine. We investigated the role of the transcriptional activator and Smad1/4 cofactor OAZ in regulating bone morphogenetic protein (BMP) signaling. We demonstrate that upon BMP4 stimulation, an OAZ-Smad1/4 complex binds to and activates the gene encoding Smad6, a specific inhibitor of the BMP pathway. Removal of endogenous OAZ from pluripotent embryonal carcinoma cells prevents the induction of Smad6 by BMP4 and extends the period of detection of phosphorylated Smad1 after BMP stimulation. Conversely, in cells that do not normally express OAZ, such as myoblasts and smooth muscle cells, forced OAZ expression leads to faster and higher Smad6 induction in response to BMP4, decrease of Smad1 phosphorylation, and attenuation of BMP-mediated responses. Our results demonstrate that OAZ can alter the intensity and duration of the BMP stimulus through Smad6 and indicate that the tissue-specific expression of OAZ is a critical determinant of the cellular response to the BMP signal.
Subject(s)
Bone Morphogenetic Proteins/metabolism , DNA-Binding Proteins/metabolism , Gene Expression Regulation , Smad6 Protein/physiology , Acetylcysteine/metabolism , Adenoviridae/metabolism , Alkaline Phosphatase/metabolism , Animals , Apoptosis , Base Sequence , Binding Sites , Bone Morphogenetic Protein 4 , Cell Differentiation , Cell Line , Cell Line, Tumor , Chromatin Immunoprecipitation , Humans , Immunoblotting , Luciferases/metabolism , Mice , Molecular Sequence Data , Myocytes, Smooth Muscle/metabolism , Phosphorylation , Plasmids/metabolism , Promoter Regions, Genetic , Protein Binding , Proteins , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Smad6 Protein/chemistry , Time Factors , Transcriptional ActivationABSTRACT
Signal transduction networks are often described by qualitative models that incorporate experimental findings from different cell types. However, a large body of evidence suggests that cell signaling differs substantially from one cell type to the next. Even in cases in which the topology of signaling networks is conserved, different cell types respond differently under the same experimental conditions. In this work we address the problem of developing quantitative and cell-type specific models of cells signaling that incorporate experimental data obtained from protein arrays and mathematical modeling. As a biological system we examine signaling mediated ErbB receptor family as the current literature is very controversial.
