A signal transduction pathway from TGF-β1 to SKP2 via Akt1 and c-Myc and its correlation with progression in human melanoma.

Abstract

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 p27(kip1). 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.

• Authors: Xuan Qu, Liangliang Shen, Yan Zheng, Yang Cui, Zhihui Feng, Feng Liu, Jiankang Liu
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 134 Issue 1 Pg. 159-167 (Jan 2014) ISSN: 1523-1747 [Electronic] United States
• PMID: 23792459 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MYC protein, human
• Proto-Oncogene Proteins c-myc
• S-Phase Kinase-Associated Proteins
• Transforming Growth Factor beta1
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Cell Line, Tumor
• Disease Progression
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Humans
• Melanoma (metabolism, secondary)
• Promoter Regions, Genetic (physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• S-Phase Kinase-Associated Proteins (genetics, metabolism)
• Signal Transduction (physiology)
• Skin Neoplasms (metabolism, pathology)
• Transcription, Genetic (physiology)
• Transforming Growth Factor beta1 (metabolism)