Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity
Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity
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DOI：
10.1073/pnas.0400195101
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发表时间：
2004-03-23
影响因子：
11.1
通讯作者：
Ronai, Z
中科院分区：
文献类型：
--
作者：
Bhoumik, A;Jones, N;Ronai, Z
黑色素瘤细胞对药物治疗的臭名昭著的抗性可以通过表达衍生自活化转录因子2（ATF 2（50-100））的50-aa肽来克服。在这里，我们证明，ATF 2（50-100）诱导凋亡的隔离ATF 2的细胞质，从而抑制其转录活性。此外，ATF 2（50-100）结合c-Jun N-末端激酶（JNK）并增加其活性。ATF 2（50-100）内损害与JNK的结合的突变和通过RNA干扰（RNAi）抑制JNK或c-Jun表达降低了ATF 2（50-100）诱导的细胞凋亡的程度。相比之下，TAM 67（Jun家族转录因子的显性阴性）或JunD RNAi减弱表达ATF 2（50-100）的黑素瘤细胞在用茴香霉素（其用作模型药物）处理后对细胞凋亡的敏化。ATF 2的JNK结合区内的突变（50-100）或TAM 67或JunD RNAi的表达减弱了ATF 2对黑素瘤致瘤性的抑制（50-100）。我们得出结论，ATF 2的抑制与JNK/Jun和JunD活性的增加是黑色素瘤细胞凋亡和抑制其致瘤性的敏感性的中心。
The notorious resistance of melanoma cells to drug treatment can be overcome by expression of a 50-aa peptide derived from activating transcription factor 2 (ATF2(50-100)). Here we demonstrate that ATF2(50-100) induced apoptosis by sequestering ATF2 to the cytoplasm, thereby inhibiting its transcriptional activities. Furthermore, ATF2(50-100) binds to c-Jun N-terminal kinase (JNK) and increases its activity. Mutation within ATF2(50-100) that impairs association with JNK and the inhibition of JNK or c-Jun expression by RNA interference (RNAi) reduces the degree of ATF2(50-100)-induced apoptosis. In contrast, TAM67, a dominant negative of the Jun family of transcription factors, or JunD RNAi attenuates sensitization of melanoma cells expressing ATF2(50-100) to apoptosis after treatment with anisomycin, which is used as a model drug. Mutations within the JNK binding region of ATF2(50-100) or expression of TAM67 or JunD RNAi attenuates inhibition of melanoma's tumorigenicity by ATF2(50-100). We conclude that inhibition of ATF2 in concert with increased JNK/Jun and JunD activities is central for the sensitization of melanoma cells to apoptosis and inhibition of their tumorigenicity.