Transforming Growth Factor-β Stimulates Parathyroid Hormone-related Protein and Osteolytic Metastases via Smad and Mitogen-activated Protein Kinase Signaling Pathways
| Autor: | Juan Juan Yin, Barry Grubbs, Sanna M. Kakonen, Theresa A. Guise, Mark Dallas, Suzanne Burns, John M. Chirgwin, Wayne Rankin, Katri Selander, Yong Cui |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
TGF alpha
MAP Kinase Signaling System Bone Neoplasms Breast Neoplasms Smad Proteins SMAD Biochemistry MAP2K7 Transforming Growth Factor beta Tumor Cells Cultured Humans Protease Inhibitors c-Raf Neoplasm Metastasis Molecular Biology Parathyroid hormone-related protein biology Akt/PKB signaling pathway Chemistry Cyclin-dependent kinase 2 Parathyroid Hormone-Related Protein Proteins Cell Biology DNA-Binding Proteins Trans-Activators Cancer research biology.protein Female Mitogen-Activated Protein Kinases Signal transduction Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 277:24571-24578 |
| ISSN: | 0021-9258 |
| Popis: | Transforming growth factor (TGF)-beta promotes breast cancer metastasis to bone. To determine whether the osteolytic factor parathyroid hormone-related protein (PTHrP) is the primary mediator of the tumor response to TGF-beta, mice were inoculated with MDA-MB-231 breast cancer cells expressing a constitutively active TGF-beta type I receptor. Treatment of the mice with a PTHrP-neutralizing antibody greatly decreased osteolytic bone metastases. There were fewer osteoclasts and significantly decreased tumor area in the antibody-treated mice. TGF-beta can signal through both Smad and mitogen-activated protein (MAP) kinase pathways. Stable transfection of wild-type Smad2, Smad3, or Smad4 increased TGF-beta-stimulated PTHrP secretion, whereas dominant-negative Smad2, Smad3, or Smad4 only partially reduced TGF-beta-stimulated PTHrP secretion. When the cells were treated with a variety of protein kinases inhibitors, only specific inhibitors of the p38 MAP kinase pathway significantly reduced both basal and TGF-beta-stimulated PTHrP production. The combination of Smad dominant-negative blockade and p38 MAP kinase inhibition resulted in complete inhibition of TGF-beta-stimulated PTHrP production. Furthermore, TGF-beta treatment of MDA-MB-231 cells resulted in a rapid phosphorylation of p38 MAP kinase. Thus, the p38 MAP kinase pathway appears to be a major component of Smad-independent signaling by TGF-beta and may provide a new molecular target for anti-osteolytic therapy. |
| Databáze: | OpenAIRE |
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