Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cell Cycle. 2012 Mar 15;11(6):1247-59. doi: 10.4161/cc.11.6.19670.
Cisplatin was shown to induce the ataxia telangiectasia mutated (ATM)-dependent phosphorylation of tumor protein p63 isoform, (ΔNp63α), leading to a transcriptional regulation of specific genes implicated in the control of cell death of squamous cell carcinoma (SCC) cells. We previously observed that the cisplatin-induced phosphorylated (p)-ΔNp63α transcriptionally regulates the expression of specific microRNAs (miRNAs) in SCC cells. We found here that cisplatin exposure of SCC cells led to modulation of the members of the autophagic pathway, such as Atg1/Ulk1, Atg3, Atg4A, Atg5, Atg6/Becn1, Atg7, Atg9A and Atg10, by a direct p-ΔNp63α-dependent transcriptional regulation. We further found that specific miRNAs (miR-181a, miR-519a, miR-374a and miR-630), which are critical downstream targets of the p-ΔNp63α, modulated the protein levels of ATG5, ATG6/BECN1, ATG10, ATG12, ATG16L1 and UVRAG, adding another level of expression control for autophagic pathways in SCC cells upon cisplatin exposure. Our data support the notion that the cisplatin-induced p-ΔNp63α could regulate key pathways implicated in response of cancer cells to chemotherapeutics.
顺铂被证明可诱导共济失调毛细血管扩张突变（ATM）依赖性磷酸化肿瘤蛋白 p63 异构体（ΔNp63α），从而导致与鳞状细胞癌（SCC）细胞死亡控制相关的特定基因的转录调控。我们之前观察到，顺铂诱导的磷酸化（p）-ΔNp63α转录调控 SCC 细胞中特定 microRNAs（miRNAs）的表达。我们在这里发现，顺铂暴露于 SCC 细胞导致自噬途径成员的调节，如 Atg1/Ulk1、Atg3、Atg4A、Atg5、Atg6/Becn1、Atg7、Atg9A 和 Atg10，通过直接的 p-ΔNp63α依赖性转录调控。我们进一步发现，特定的 microRNAs（miR-181a、miR-519a、miR-374a 和 miR-630）是 p-ΔNp63α的关键下游靶标，调节 ATG5、ATG6/BECN1、ATG10、ATG12、ATG16L1 和 UVRAG 的蛋白水平，在顺铂暴露于 SCC 细胞时增加了自噬途径表达控制的另一个水平。我们的数据支持这样一种观点，即顺铂诱导的 p-ΔNp63α可以调节与癌细胞对化疗药物反应相关的关键途径。
