An amidation a day keeps apoptosis away

杨柳

Weintraub/Elsevier8 _2 Q: i* O, y$ W" \5 C& |

' y7 I# e* Z) @Rapidly dividing cells such as tumor cells are susceptible to DNA damage that then induces apoptosis. As a result, DNA-damaging chemicals such as cisplatin are used as anticancer treatments. How the majority of nontumor cells survive chemotherapy has been mysterious. The trivial explanation is that the cells are growth-arrested and thus less susceptible to DNA-damaging agents. But a more precise explanation is put forth in a new article by Benjamin Deverman, Steven Weintraub (Washington University, St. Louis, MO), and colleagues, who have identified an antiapoptotic activity necessary to keep damaged but nondividing cells alive./ K* j5 a: E4 Q1 Q+ H! f

# Z) G& ?7 H" T; a# `" C6 T9 c  BThe proapoptotic activity that allows tumor cells to die is an unusual modification of the antiapoptotic protein Bcl-xL caused by DNA-damaging agents. This modification, deamidation of two asparagine residues, inactivated Bcl-xL, thereby allowing cell death to proceed. Growth-arrested cells escaped apoptosis by blocking deamidation. To prevent deamidation, cells needed Rb, a tumor suppressor protein that inhibits cell cycle progression. Because tumor cells lack Rb, and cycling cells down-regulate Rb, they are more sensitive to DNA-damaging agents. "Deamidation is like a checkpoint," says Weintraub. "If you undergo DNA damage in the absence of Rb, then cells are susceptible to death."# q- I8 V3 L$ G

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3 ]' |' R2 t3 M" ^, I) |0 sDeverman, B., et al. 2002. Cell. 111:51–62.(Bcl-xL modification by cisplatin is bloc)