Regulation of myeloma cell growth through Akt/Gsk3/forkhead signaling pathway

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• 作者：G-Amlak ; Maaza ; Uddin ; Shahab ; Mahmud ; Dolores ; Damacela ; Ingrid ; Lavelle ; Donald ; Ahmed ; Maqbool ; et. al.
• 关键词：Myeloma ; Interleukin-6 ; Glycogen synthase kinase 3 ; Forkhead transcription factors ; Apoptosis
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2002
• 出版时间：October 4, 2002
• 年：2002
• 卷：297
• 期：4
• 页码：760-764
• 全文大小：186 K

文摘

The interleukin-6 (IL-6) signaling pathway contributes to myeloma cell growth and viability through activation of the PI3/Akt kinase pathway. To understand the downstream signaling elements in the PI3/Akt kinase pathway that are involved in the regulation of myeloma cell growth, we determined the role played by glycogen synthase kinase 3 (Gsk3) and forkhead transcription factors (FH) in the RPMI-8226 myeloma cell line. We demonstrate that both Gsk3 and FH transcription factors FKHRL1 (FOX3a), FKHR (FOXO1a), and AFX (FOXO4) are phosphorylated (inactivated) by IL-6. Further, we show that inhibitors of Gsk3 induce dephosphorylation of FKHRL1 and FKHR at their threonine sites and upregulate the cyclin-dependent kinase inhibitor p27^kip1. Finally, we show that inhibition of Gsk3 activity is sufficient to suppress cell growth and induce apoptosis thus overriding the effects of IL-6 in myeloma cells.