Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis.

Abstract

We report that K5.Smad7 mice, which express a Smad7 transgene under the control of a keratin 5 promoter, were resistant to radiation-induced oral mucositis, a painful oral ulceration. In addition to nuclear factor κB (NF-κB) activation, which is known to contribute to oral mucositis, we found activated transforming growth factor β (TGF-β) signaling in cells from this condition. Smad7 dampened both pathways to attenuate inflammation, growth inhibition and apoptosis. Additionally, Smad7 promoted oral epithelial migration to close the wound. Further analyses revealed that TGF-β signaling Smads and their co-repressor C-terminal binding protein 1 (CtBP1) transcriptionally repressed Rac1, and that Smad7 abrogated this repression. Knocking down Rac1 expression in mouse keratinocytes abrogated Smad7-induced migration. Topical application of Smad7 protein conjugated with a cell-permeable Tat tag to oral mucosa showed prophylactic and therapeutic effects on radiation-induced oral mucositis in mice. Thus, we have identified new molecular mechanisms involved in oral mucositis pathogenesis, and our data suggest an alternative therapeutic strategy to block multiple pathological processes in this condition.

• Authors: Gangwen Han, Li Bian, Fulun Li, Ana Cotrim, Donna Wang, Jianbo Lu, Yu Deng, Gregory Bird, Anastasia Sowers, James B Mitchell, J Silvio Gutkind, Rui Zhao, David Raben, Peter ten Dijke, Yosef Refaeli, Qinghong Zhang, Xiao-Jing Wang
• Journal: Nature medicine (Nat Med) Vol. 19 Issue 4 Pg. 421-8 (Apr 2013) ISSN: 1546-170X [Electronic] United States
• PMID: 23475202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• NF-kappa B
• Neuropeptides
• Rac1 protein, mouse
• Smad7 Protein
• Smad7 protein, mouse
• Transforming Growth Factor beta
• Alcohol Oxidoreductases
• C-terminal binding protein
• rac GTP-Binding Proteins
• rac1 GTP-Binding Protein

Topics

• Alcohol Oxidoreductases (physiology)
• Animals
• Apoptosis (physiology, radiation effects)
• Cell Movement (physiology)
• DNA-Binding Proteins (physiology)
• Keratinocytes (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (physiology)
• Neuropeptides (physiology)
• Radiation Injuries, Experimental (prevention & control)
• Signal Transduction (physiology)
• Smad7 Protein (genetics, physiology)
• Stomatitis (prevention & control)
• Transforming Growth Factor beta (physiology)
• rac GTP-Binding Proteins (physiology)
• rac1 GTP-Binding Protein