IGF1 activates cell cycle arrest following irradiation by reducing binding of ΔNp63 to the p21 promoter.
IGF1 activates cell cycle arrest following irradiation by reducing binding of ΔNp63 to the p21 promoter.
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DOI：
10.1038/cddis.2010.28
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发表时间：
2010
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
头颈部肿瘤的放射治疗通常会导致唾液腺功能的持续丧失。唾液功能受损的患者经常过早终止治疗，因为营养不良和其他令人衰弱的副作用导致生活质量下降。此前已有研究表明，在表达组成活性Akt形式(MYR-Akt1)的小鼠中，或在经IGF1预处理的小鼠中，细胞凋亡受到抑制，这与通过刺激唾液流量测量的维持唾液腺功能有关。诱导细胞周期停滞可能对这种保护很重要，因为它允许细胞有时间进行DNA修复。我们观察到接受IGF1预处理的小鼠腮腺在照射后的急性时间点G2/M期细胞积聚增加。由于P53家族的转录靶点p21是维持G2/M期停滞所必需的，我们分析了P53和P63在调节IGF1刺激的p21表达中的作用。照射后ΔNp63与p21启动子的结合减少，与P53结合增加和p21转录持续增强相一致。我们的数据表明，ΔNp63在调节依赖于P53的基因表达以及影响是否启动细胞死亡或细胞周期停滞程序方面发挥了作用。
Radiotherapy for head and neck tumors often results in persistent loss of function in salivary glands. Patients suffering from impaired salivary function frequently terminate treatment prematurely because of reduced quality of life caused by malnutrition and other debilitating side-effects. It has been previously shown in mice expressing a constitutively active form of Akt (myr-Akt1), or in mice pretreated with IGF1, apoptosis is suppressed, which correlates with maintained salivary gland function measured by stimulated salivary flow. Induction of cell cycle arrest may be important for this protection by allowing cells time for DNA repair. We have observed increased accumulation of cells in G2/M at acute time-points after irradiation in parotid glands of mice receiving pretreatment with IGF1. As p21, a transcriptional target of the p53 family, is necessary for maintaining G2/M arrest, we analyzed the roles of p53 and p63 in modulating IGF1-stimulated p21 expression. Pretreatment with IGF1 reduces binding of ΔNp63 to the p21 promoter after irradiation, which coincides with increased p53 binding and sustained p21 transcription. Our data indicate a role for ΔNp63 in modulating p53-dependent gene expression and influencing whether a cell death or cell cycle arrest program is initiated.
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