TY - JOUR
T1 - A signal transduction pathway from TGF-β1 to SKP2 via Akt1 and c-Myc and its correlation with progression in human melanoma
AU - Qu, Xuan
AU - Shen, Liangliang
AU - Zheng, Yan
AU - Cui, Yang
AU - Feng, Zhihui
AU - Liu, Feng
AU - Liu, Jiankang
PY - 2014/1
Y1 - 2014/1
N2 - Both SKP2 (S-phase kinase-associated protein 2) and transforming growth factor-β1 (TGF-β1) play important roles in cancer metastasis through different mechanisms: TGF-β1 via induction of epithelial-mesenchymal transition (EMT) and SKP2 via downregulating p27kip1. Recent studies indicated that c-Myc and Akt1 were active players in metastasis. In this study we demonstrated a crosstalk between these pathways. Specifically, we found that TGF-β1 treatment increased SKP2 expression accompanied with increased phosphorylation of Akt1 and c-Myc protein accumulation during EMT. We demonstrated that Akt1 was required for TGF-β1-mediated SKP2 upregulation and that c-Myc transcription factor specifically bound to the promoter of SKP2 for its enhanced transcription. Analysis of 25 samples of normal human skin, nevi, and melanomas revealed a positive correlation between c-Myc and SKP2 accumulation. Furthermore, accumulation of SKP2 and c-Myc proteins was significantly higher in metastatic melanoma samples as compared with that in primary melanomas, which again was higher than that in normal skin or nevi. In summary, our results integrated TGF-β1 signals to SKP2 via Akt1 and c-Myc during EMT, and provided, to our knowledge, a previously unreported mechanistic molecular event for TGF-β1-induced metastasis in human melanoma.
AB - Both SKP2 (S-phase kinase-associated protein 2) and transforming growth factor-β1 (TGF-β1) play important roles in cancer metastasis through different mechanisms: TGF-β1 via induction of epithelial-mesenchymal transition (EMT) and SKP2 via downregulating p27kip1. Recent studies indicated that c-Myc and Akt1 were active players in metastasis. In this study we demonstrated a crosstalk between these pathways. Specifically, we found that TGF-β1 treatment increased SKP2 expression accompanied with increased phosphorylation of Akt1 and c-Myc protein accumulation during EMT. We demonstrated that Akt1 was required for TGF-β1-mediated SKP2 upregulation and that c-Myc transcription factor specifically bound to the promoter of SKP2 for its enhanced transcription. Analysis of 25 samples of normal human skin, nevi, and melanomas revealed a positive correlation between c-Myc and SKP2 accumulation. Furthermore, accumulation of SKP2 and c-Myc proteins was significantly higher in metastatic melanoma samples as compared with that in primary melanomas, which again was higher than that in normal skin or nevi. In summary, our results integrated TGF-β1 signals to SKP2 via Akt1 and c-Myc during EMT, and provided, to our knowledge, a previously unreported mechanistic molecular event for TGF-β1-induced metastasis in human melanoma.
UR - https://www.scopus.com/pages/publications/84891041882
U2 - 10.1038/jid.2013.281
DO - 10.1038/jid.2013.281
M3 - 文章
C2 - 23792459
AN - SCOPUS:84891041882
SN - 0022-202X
VL - 134
SP - 159
EP - 167
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 1
ER -
