Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors
| Autor: | Gary S. Stein, Amjad Javed, Andre J. Van Wijnen, Mario Galindo, Viktor I. Teplyuk, Jane B. Lian, Daniel W. Young, Nadiya M. Teplyuk, Jitesh Pratap, David S. Lapointe, Janet L. Stein |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
musculoskeletal diseases
Cellular differentiation Core Binding Factor Alpha 1 Subunit SMAD Biochemistry Receptors G-Protein-Coupled RGS4 Mice Molecular Basis of Cell and Developmental Biology stomatognathic system Biological Clocks Animals Molecular Biology Transcription factor RGS2 Cell Line Transformed Oligonucleotide Array Sequence Analysis Regulation of gene expression Mice Knockout Osteoblasts biology Gene Expression Profiling Stem Cells Cell Cycle Cell Differentiation Cell Biology Molecular biology Protein Structure Tertiary RUNX2 Gene Expression Regulation biology.protein Signal transduction Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 283(41) |
| ISSN: | 0021-9258 |
| Popis: | Runt-related transcription factor 2 (Runx2) controls lineage commitment, proliferation, and anabolic functions of osteoblasts as the subnuclear effector of multiple signaling axes (e.g. transforming growth factor-β/BMP-SMAD, SRC/YES-YAP, and GROUCHO/TLE). Runx2 levels oscillate during the osteoblast cell cycle with maximal levels in G1. Here we examined what functions and target genes of Runx2 control osteoblast growth. Forced expression of wild type Runx2 suppresses growth of Runx2-/- osteoprogenitors. Point mutants defective for binding to WW domain or SMAD proteins or the nuclear matrix retain this growth regulatory ability. Hence, key signaling pathways are dispensable for growth control by Runx2. However, mutants defective for DNA binding or C-terminal gene repression/activation functions do not block proliferation. Target gene analysis by Affymetrix expression profiling shows that the C terminus of Runx2 regulates genes involved in G protein-coupled receptor signaling (e.g. Rgs2, Rgs4, Rgs5, Rgs16, Gpr23, Gpr30, Gpr54, Gpr64, and Gna13). We further examined the function of two genes linked to cAMP signaling as follows: Gpr30 that is stimulated and Rgs2 that is down-regulated by Runx2. RNA interference of Gpr30 and forced expression of Rgs2 in each case inhibit osteoblast proliferation. Notwithstanding its growth-suppressive potential, our results surprisingly indicate that Runx2 may sensitize cAMP-related G protein-coupled receptor signaling by activating Gpr30 and repressing Rgs2 gene expression in osteoblasts to increase responsiveness to mitogenic signals. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|