Rajah Roopmathy, Lee Kuk-Wha, Cohen Pinchas
Department of Pediatrics, Mattel Children's Hospital at UCLA, 90095, USA.
Cell Growth Differ. 2002 Apr;13(4):163-71.
The insulin-like growth factor (IGF)-independent effects of insulin-like growth factor binding protein-3 (IGFBP-3) to effect cellular apoptosis have now been described in various cellular systems. IGFBP-3 mediates transforming growth factor-beta-induced apoptosis. Other growth-inhibitory and apoptosis-inducing agents such as tumor necrosis factor-alpha (TNF-alpha) and the tumor suppressor gene p53 also induce IGFBP-3. In this report, we demonstrate the role of IGFBP-3 as a mediator of apoptosis induced by TNF-alpha and elucidate the process involved in its signaling mechanism. Treatment of PC-3 cells with TNF-alpha resulted in the induction of IGFBP-3 expression in a dose- and time-dependent fashion and also induced apoptosis. TNF-alpha-induced apoptosis was prevented by cotreatment with IGFBP-3 neutralizing antibodies or IGFBP-3-specific antisense thiolated oligonucleotides. Both IGFBP-3 and TNF-alpha treatment increased the levels of the inactive, serine phosphorylated form of the survival protein Bcl-2. The effect of TNF-alpha on Bcl-2 serine phosphorylation was blocked by IGFBP-3 antisense oligomers. These findings confirm that IGFBP-3 is essential for TNF-alpha-induced apoptosis in PC-3 cells and that this IGFBP-3 effect includes the inactivation of Bcl-2 through serine phosphorylation.
胰岛素样生长因子结合蛋白-3（IGFBP-3）在多种细胞系统中对细胞凋亡产生的不依赖胰岛素样生长因子（IGF）的作用现已得到描述。IGFBP-3介导转化生长因子-β诱导的细胞凋亡。其他生长抑制和凋亡诱导因子，如肿瘤坏死因子-α（TNF-α）和肿瘤抑制基因p53也可诱导IGFBP-3。在本报告中，我们证明了IGFBP-3作为TNF-α诱导凋亡的介质的作用，并阐明了其信号传导机制中涉及的过程。用TNF-α处理PC-3细胞导致IGFBP-3表达呈剂量和时间依赖性诱导，并且也诱导了细胞凋亡。与IGFBP-3中和抗体或IGFBP-3特异性反义硫醇化寡核苷酸共同处理可防止TNF-α诱导的细胞凋亡。IGFBP-3和TNF-α处理均增加了存活蛋白Bcl-2的无活性丝氨酸磷酸化形式的水平。TNF-α对Bcl-2丝氨酸磷酸化的作用被IGFBP-3反义寡聚物阻断。这些发现证实IGFBP-3对于TNF-α诱导的PC-3细胞凋亡至关重要，并且这种IGFBP-3效应包括通过丝氨酸磷酸化使Bcl-2失活。
