Insulin-like growth factor I induces MDM2-dependent degradation of p53 via the p38 MAPK pathway in response to DNA damage
Insulin-like growth factor I induces MDM2-dependent degradation of p53 via the p38 MAPK pathway in response to DNA damage
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DOI：
10.1074/jbc.m111142200
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发表时间：
2002-05-03
影响因子：
4.8
通讯作者：
LeRoith, D
中科院分区：
文献类型：
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作者：
Héron-Milhavet, L;LeRoith, D
在许多组织中，已知胰岛素样生长因子I （IGF-I）受体（IGF-IR）具有抗细胞凋亡的功能。最近，我们证明了IGF-IR通过激活DNA修复途径在修复DNA受损成纤维细胞中的直接作用(Heron-Milhavet， L., Karas， M., Goldsmith， C. M., Baum， B. J.和LeRoith， D. (2001) J. Biol。化学276,18185-18192)。p53是一种核转录因子，可以阻断细胞周期进程，调节DNA修复，引发细胞凋亡。在这项工作中，我们测试了igf - 1对p53信号级联的调节作用。将dna损伤剂4-硝基喹啉1-氧化物应用于过表达正常IGF-IRs的NIH-3T3细胞（NWTb3细胞）。我们发现，在4-硝基喹啉1-氧化物诱导的DNA损伤后，IGF-I诱导p53蛋白从细胞核中排除，并导致其在细胞质中降解，而p53 mRNA不受影响。p53蛋白的降解与MDM2的增加有关，MDM2是p53蛋白半衰期和活性的上游调节剂。P53的降解也与p21的下调有关。我们进一步发现IGF-I对mdm2转录和mdm2 /p19 ARF关联的影响是通过p38 MAPK途径介导的。总之，我们描述了igf - 1在DNA损伤过程中调控MDM2/p53/p21信号通路中的新作用。
In many tissues, the insulin-like growth factor I (IGF-I) receptor (IGF-IR) is known to functionally oppose apoptosis. Recently, we demonstrated a direct role for the IGF-IR in the rescue of DNA-damaged fibroblasts by activating a DNA repair pathway (Heron-Milhavet, L., Karas, M., Goldsmith, C. M., Baum, B. J., and LeRoith, D. (2001) J. Biol. Chem. 276, 18185-18192). p53 is a nuclear transcription factor that can block progression of the cell cycle, modulate DNA repair, and trigger apoptosis. In this work, we tested the effect of IGF-I on the regulation of the p53 signaling cascade. The DNA-damaging agent 4-nitroquinoline 1-oxide was applied to NIH-3T3 cells overexpressing normal IGF-IRs (NWTb3 cells). We showed that after 4-nitroquinoline 1-oxide-induced DNA damage, IGF-I induced exclusion of the p53 protein from the nucleus and led to its degradation in the cytoplasm, whereas p53 mRNA was unaffected. Degradation of the p53 protein was associated with an increase in MDM2, an upstream modulator of the half-life and activity of the p53 protein. p53 degradation was also associated with down-regulation of p21. We further showed that the effects of IGF-I on mdm2 transcription and on MDM2/p19 ARF association were mediated by the p38 MAPK pathway. In conclusion, we describe a novel role for IGF-I in the regulation of the MDM2/p53/p21 signaling pathway during DNA damage.