The role of transforming growth factor-β on the regulation of FoxO group members and p27ᴷᴵᴾ¹ in fibroblast cells

Abstract

Transforming Growth Factor-β (TGF-β) regulates a variety of biological effects, including cellular proliferation, dependent on the cellular context. There is growing evidence that TGF-β regulates numerous pathways independent of Smad, including the PI3K/Akt pathway. Therefore, since FoxO is downstream of PI3K/Akt, we examined the role of TGF-β on the post-translational regulation of FoxO family members. It was found that TGF-β increased the phosphorylation of FoxO1, 3a, and 4, as well as the cytoplasmic localization of FoxO1 in fibroblasts via the PI3K/Akt pathway. In addition, since Akt and FoxO members can induce phosphorylation and transcription of p27ᵏⁱᵖ¹ (a cyclin dependent kinase inhibitor), respectively, we examined both the post-translational and transcriptional regulation of p27ᵏⁱᵖ¹ by TGF-β in fibroblasts. p27ᵏⁱᵖ¹ phosphorylation increased following TGF-β addition, resulting in cytoplasmic localization in fibroblasts over time. p27ᵏⁱᵖ¹ mRNA expression decreased following TGF-β treatment in fibroblasts, however, we were unable to show the decrease was dependent on PI3K or FoxO4. Therefore, the results demonstrated that TGF-β regulates the FoxO group posttranslationally via the PI3K/Akt pathway, and FoxO group functionality through transcription and post-translational modifications of p27ᵏⁱᵖ¹ in fibroblasts.