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- Title
Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling.
- Authors
Jeong-Han Kang; Mi-Yeon Jung; Xueqian Yin; Andrianifahanana, Mahefatiana; Hernandez, Danielle M.; Leof, Edward B.; Kang, Jeong-Han; Jung, Mi-Yeon; Yin, Xueqian
- Abstract
TGF-β is considered a master switch in the pathogenesis of organ fibrosis. The primary mediators of this activity are the SMAD proteins, particularly SMAD3. In the current study, we have developed a cell-penetrating peptide (CPP) conjugate of the HIV TAT protein that is fused to an aminoterminal sequence of sorting nexin 9 (SNX9), which was previously shown to bind phosphorylated SMAD3 (pSMAD3). We determined that specifically preventing the nuclear import of pSMAD3 using the TAT-SNX9 peptide inhibited profibrotic TGF-β activity in murine cells and human lung fibroblasts as well as in vivo with no demonstrable toxicity. TGF-β signaling mediated by pSMAD2, bone morphogenetic protein 4 (BMP4), EGF, or PDGF was unaffected by the TAT-SNX9 peptide. Furthermore, while the TAT-SNX9 peptide prevented TGF-β's profibrotic activity in vitro as well as in 2 murine treatment models of pulmonary fibrosis, a 3-amino acid point mutant that was unable to bind pSMAD3 proved ineffective. These findings indicate that specifically targeting pSMAD3 can ameliorate both the direct and indirect fibroproliferative actions of TGF-β.
- Subjects
TRANSFORMING growth factors-beta; FIBROSIS; PROTEINS; NUCLEOTIDE sequence; PHOSPHORYLATION; ANIMAL experimentation; BIOLOGICAL models; CARRIER proteins; CELL lines; CELLULAR signal transduction; GROWTH factors; MICE; PEPTIDES; PULMONARY fibrosis
- Publication
Journal of Clinical Investigation, 2017, Vol 127, Issue 7, p2541
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI88696