Zang Yunjin, Shi Ying, Liu Kai, Qiao Luxin, Guo Xianghua, Chen Dexi
Capital Medical University affiliated Beijing You An Hospital, Beijing 100069, China.
Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Shandong Province, 266003, China.
Oncotarget. 2017 Feb 21;8(8):12754-12763. doi: 10.18632/oncotarget.14460.
Δ40p53 is an isoform of wild-type p53 (wtp53). Here, we assessed whether Δ40p53 has the same functions as wild-type p53 in the regulation of cell death and autophagy. First, we used HCT116 (p53+/+) and H1299 (p53-free) cells to produce two cell lines (HCT116-Δ40p53 and H1299-Δ40p53) that express exogenous Δ40p53 but not wtp53. By using these cell lines, we determined that Δ40p53 inhibited starvation-induced autophagy, as does wtp53. This inhibition arises from both Δ40p53 and wtp53 having 3'-5' exonuclease activity, which reduces the levels of double-stranded RNA (dsRNA) and then inhibits PKR/eIF2α-induced autophagy in cells exposed to starvation. Like wtp53, the translocation of Δ40p53 to the nucleus increased in cells in response to Methyl methane sulfonate (MMS) treatment-induced DNA damage. Previous studies have shown that nuclear wtp53 can induce DRAM expression and DRAM-induced autophagy in cells in response to DNA damage, thereby contributing to apoptotic cell death as DRAM-induced autophagy is a pro-apoptotic factor. Here, nuclear Δ40p53 did not individually induce DRAM-induced autophagy and cell death in response to DNA damage. However, nuclear Δ40p53 inhibited wtp53-induced DRAM expression and cell death. Thus, Δ40p53 and wtp53 have 3'-5' exonuclease activity and inhibit starvation-induced autophagy in the cytoplasm; however, nuclear Δ40p53 inhibits wtp53-induced cell death by impairing the transactivation activity of wtp53. Because wtp53 inhibits tumor and viral infection by inhibiting autophagy and promoting degradation of viral dsRNA, it is reasonable to believe that Δ40p53 has the similar functions. A deeper study of these functions of Δ40p53 is needed in the future.
Δ40p53是野生型p53（wtp53）的一种异构体。在此，我们评估了Δ40p53在细胞死亡和自噬调节方面是否具有与野生型p53相同的功能。首先，我们使用HCT116（p53+/+）和H1299（无p53）细胞构建了两个表达外源性Δ40p53但不表达wtp53的细胞系（HCT116-Δ40p53和H1299-Δ40p53）。通过使用这些细胞系，我们确定Δ40p53与wtp53一样，抑制饥饿诱导的自噬。这种抑制源于Δ40p53和wtp53都具有3'-5'核酸外切酶活性，该活性降低双链RNA（dsRNA）水平，进而抑制暴露于饥饿状态下细胞中PKR/eIF2α诱导的自噬。与wtp53一样，响应甲基磺酸甲酯（MMS）处理诱导的DNA损伤时，细胞中Δ40p53向细胞核的转位增加。先前的研究表明，细胞核中的wtp53可在细胞中响应DNA损伤诱导DRAM表达和DRAM诱导的自噬，从而促进凋亡性细胞死亡，因为DRAM诱导的自噬是一种促凋亡因子。在此，细胞核中的Δ40p53不会单独响应DNA损伤诱导DRAM诱导的自噬和细胞死亡。然而，细胞核中的Δ40p53抑制wtp53诱导的DRAM表达和细胞死亡。因此，Δ40p53和wtp53具有3'-5'核酸外切酶活性，并在细胞质中抑制饥饿诱导的自噬；然而，细胞核中的Δ40p53通过损害wtp53的反式激活活性来抑制wtp53诱导的细胞死亡。由于wtp53通过抑制自噬和促进病毒dsRNA降解来抑制肿瘤和病毒感染，因此有理由认为Δ40p53具有类似功能。未来需要对Δ40p53的这些功能进行更深入的研究。
