Insulin-like growth factor binding protein-3 mediates tumor necrosis factor-alpha-induced apoptosis: role of Bcl-2 phosphorylation.
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.
Rajah
Roopmathy
R
Department of Pediatrics, Mattel Children's Hospital at UCLA, 90095, USA.
Lee
Kuk-Wha
KW
Cohen
Pinchas
P
D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020287:In Situ Nick-End Labeling; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000502:physiology*; D008024:Ligands; D008954:Models, Biological; D010766:Phosphorylation; D011233:Precipitin Tests; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018972:Insulin-Like Growth Factor Binding Protein 3; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D012694:Serine; D012313:RNA