Shelton John G, Steelman Linda S, White Edmond R, McCubrey James A
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA.
Cell Cycle. 2004 Mar;3(3):372-9. Epub 2004 Mar 1.
The insulin like growth factor-1 (IGF-1) receptor (R) induced PI3K/Akt signal transduction cascade has critical roles in prevention of apoptosis and regulation of cell cycle progression. Here, we discuss the effects of IGF-1R-mediated signal transduction on hematopoietic cells which normally require interleukin-3 (IL-3) for growth and prevention of apoptosis. Cytokine-dependent FDC-P1 hematopoietic cells were conditionally transformed to grow in response to overexpression of IGF-1R in the presence of IGF-1. When these cells were deprived of IL-3 or IGF-1 for 24 hrs, they exited the cell cycle, activated caspase 3 and underwent apoptosis. The effects of inhibitors which targeted the PI3K/Akt and Raf/MEK/ERK pathways were determined. When the cells were cultured with IGF-1 and either PI3K or MEK inhibitors, cell cycle progression and DNA synthesis were inhibited and caspase 3 activity and apoptosis were induced. Coinhibition of both pathways synergized to prevent cell cycle progression, inhibit DNA synthesis and induce apoptosis. These inhibitors had more apoptotic inducing effects when the cells were grown in response to IGF-1 than IL-3, indicating that IL-3 can induce additional anti-apoptotic pathways. These results demonstrate that the PI3K/Akt and Raf/MEK/ERK pathways are intimately involved in IGF-1R-mediated cell cycle progression and prevention of apoptosis in hematopoietic cells.
胰岛素样生长因子-1（IGF-1）受体（R）诱导的PI3K/Akt信号转导级联在预防细胞凋亡和调节细胞周期进程中起关键作用。在此，我们讨论IGF-1R介导的信号转导对造血细胞的影响，这些造血细胞通常需要白细胞介素-3（IL-3）来实现生长和预防凋亡。细胞因子依赖性FDC-P1造血细胞在IGF-1存在的情况下，通过IGF-1R的过表达被条件性转化以实现生长。当这些细胞被剥夺IL-3或IGF-1达24小时时，它们退出细胞周期，激活半胱天冬酶3并发生凋亡。我们确定了靶向PI3K/Akt和Raf/MEK/ERK途径的抑制剂的作用。当细胞用IGF-1与PI3K或MEK抑制剂一起培养时，细胞周期进程和DNA合成受到抑制，半胱天冬酶3活性和凋亡被诱导。两条途径的共同抑制协同作用以阻止细胞周期进程、抑制DNA合成并诱导凋亡。当细胞响应IGF-1生长时，这些抑制剂比响应IL-3生长时具有更强的凋亡诱导作用，表明IL-3可以诱导额外的抗凋亡途径。这些结果表明，PI3K/Akt和Raf/MEK/ERK途径密切参与IGF-1R介导的造血细胞的细胞周期进程和凋亡预防。
