Sci. STKE, 11 December 2007
Apoptosis Protecting the Liver from Death
Nancy R. Gough
Science's STKE, AAAS, Washington, DC 20005, USA
The p53 protein plays key roles in regulating cell survival in response to stress, including roles in the nucleus as a transcriptional regulator, as well as transcription-independent roles outside the nucleus. One of these is activation of BAK oligomerization at the mitochondria, thereby promoting mitochondrial permeabilization and apoptosis. When p53 was stabilized by exposure of human HepG2 hepatoma cells to the MDM E3 ligase inhibitor nutlin-3, which does not cause DNA damage, an interaction between BAK and IGFBP1 was detected by affinity purification and coimmunoprecipitation and the two proteins colocalized at the mitochondria. Conditions that elevated p53, but did not inhibit RNA polymerase II (Pol II), also increased the abundance of IGFBP1 mRNA and protein, and protected cells from apoptosis. In HepG2 cells in which p53 was elevated and Pol II was inhibited, the abundance of IGFBP1 did not increase, p53 formed complexes with BAK, and the cells underwent apoptosis. Overexpression of IGFBP1 in osteosarcoma or breast carcinoma cell lines resulted in resistance to apoptosis caused by DNA damage. In isolated mitochondria from nutlin-3-treated HepG2 cells, conditions that promoted the accumulation of IGFBP1 at the mitochondria, the interaction of p53 with BAK and the formation of BAK oligomers was inhibited compared with that of mitochondria from untreated cells. The importance of IGFBP1 in vivo was confirmed with knockout mice, which were highly susceptible to liver damage caused by -amanitin (inhibitor of Pol II) or cisplatin (DNA damage), and, in each case, mitochondrial accumulation of p53 correlated with apoptosis. As the expression of IGFBP1 is limited to liver, endometrium, and kidney, it appears that IGFBP1 may be a tissue-specific inhibitor of the mitochondrial p53 death pathway.
J. I.-J. Leu, D. L. George, Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at the mitochondria. Genes Dev. 21, 3095-3109 (2007). [Abstract] [Full Text]
Citation: N. R. Gough, Protecting the Liver from Death. Sci. STKE 2007, tw447 (2007).
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