Harkin D P, Bean J M, Miklos D, Song Y H, Truong V B, Englert C, Christians F C, Ellisen L W, Maheswaran S, Oliner J D, Haber D A
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown 02129, USA.
Cell. 1999 May 28;97(5):575-86. doi: 10.1016/s0092-8674(00)80769-2.
The breast cancer susceptibility gene BRCA1 encodes a protein implicated in the cellular response to DNA damage, with postulated roles in homologous recombination as well as transcriptional regulation. To identify downstream target genes, we established cell lines with tightly regulated inducible expression of BRCA1. High-density oligonucleotide arrays were used to analyze gene expression profiles at various times following BRCA1 induction. A major BRCA1 target is the DNA damage-responsive gene GADD45. Induction of BRCA1 triggers apoptosis through activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), a signaling pathway potentially linked to GADD45 gene family members. The p53-independent induction of GADD45 by BRCA1 and its activation of JNK/SAPK suggest a pathway for BRCA1-induced apoptosis.
乳腺癌易感基因BRCA1编码一种与细胞对DNA损伤的反应有关的蛋白质，推测其在同源重组以及转录调控中发挥作用。为了鉴定下游靶基因，我们建立了BRCA1表达受严格调控的诱导性细胞系。利用高密度寡核苷酸阵列分析BRCA1诱导后不同时间点的基因表达谱。一个主要的BRCA1靶基因是DNA损伤反应基因GADD45。BRCA1的诱导通过激活c-Jun氨基末端激酶/应激激活蛋白激酶（JNK/SAPK）触发细胞凋亡，这是一条可能与GADD45基因家族成员相关的信号通路。BRCA1对GADD45的p53非依赖性诱导及其对JNK/SAPK的激活提示了一条BRCA1诱导细胞凋亡的途径。
