FADD phosphorylation is critical for cell cycle regulation in breast cancer cells.
FADD phosphorylation is critical for cell cycle regulation in breast cancer cells.
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DOI：
10.1038/sj.bjc.6602955
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发表时间：
2006-02-27
影响因子：
8.8
通讯作者：
Konishi, N
中科院分区：
文献类型：
--
作者：
Matsuyoshi, S;Shimada, K;Nakamura, M;Ishida, E;Konishi, N
关键词：
抗雌激素治疗对控制激素受体阳性乳腺癌是有效的，尽管详细的分子机制，包括信号转导，仍不清楚。我们在这里证明，长期他莫昔芬治疗通过c-jun N-末端激酶（JNK）激活引起G2/M细胞周期阻滞，这依赖于雌激素（ER）受体阳性乳腺癌细胞系MCF-7中Fas相关死亡结构域蛋白（FADD）在194丝氨酸的磷酸化。在MCF-7细胞中表达显性失活突变形式的MKK 7（JNK上游的激酶）或突变型FADD（S194 A）可抑制长期他莫昔芬治疗的细胞毒性。令人感兴趣的是，紫杉醇甚至可以在ER阴性细胞系MDA-MB-231中诱发类似的信号传导。此外，使用人乳腺癌标本的免疫组织化学分析显示磷酸化JNK和FADD表达之间存在密切相关性，在具有转移潜力的病例中两者均显著降低。我们的结论是JNK介导的FADD磷酸化在细胞生长和转移的负调控中起着重要作用，独立于乳腺癌的ER状态，因此JNK/FADD信号可能是有希望的癌症治疗靶点。
Anti-oestrogen therapy is effective for control of hormone receptor-positive breast cancers, although the detailed molecular mechanisms, including signal transduction, remain unclear. We demonstrated here that long-term tamoxifen treatment causes G2/M cell cycle arrest through c-jun N-terminal kinase (JNK) activation, which is dependent on phosphorylation of Fas-associated death domain-containing protein (FADD) at 194 serine in an oestrogen (ER) receptor-positive breast cancer cell line, MCF-7. Expression of a dominant negative mutant form of MKK7, a kinase upstream of JNK, or mutant FADD (S194A) in MCF-7 cells suppressed the cytotoxicity of long-term tamoxifen treatment. Of great interest, similar signallings could be evoked by paclitaxel, even in an ER-negative cell line, MDA-MB-231. In addition, immunohistochemical analysis using human breast cancer specimens showed a close correlation between phosphorylated JNK and FADD expression, both being significantly reduced in cases with metastatic potential. We conclude that JNK-mediated phosphorylation of FADD plays an important role in the negative regulation of cell growth and metastasis, independent of the ER status of a breast cancer, so that JNK/FADD signals might be promising targets for cancer therapy.
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影响因子：
5.8
作者：
Cianfrocca, M;Goldstein, LJ
通讯作者：
Goldstein, LJ
DOI：
10.1111/j.1349-7006.2002.tb01219.x
发表时间：
2002-10-01
期刊：
JAPANESE JOURNAL OF CANCER RESEARCH
影响因子：
--
作者：
Shimada, K;Nakamura, M;Konishi, N
通讯作者：
Konishi, N
影响因子：
7.3
作者：
Suo, Z;Risberg, B;Nesland, JM
通讯作者：
Nesland, JM
影响因子：
4.8
作者：
Zhang, Y;Qiu, WJ;Lin, SC
通讯作者：
Lin, SC
影响因子：
45.3
作者：
Henderson, IC;Berry, DA;Norton, L
通讯作者：
Norton, L