Authors' Affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
Authors' Affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
Cancer Res. 2014 Jul 15;74(14):3923-34. doi: 10.1158/0008-5472.CAN-13-1866. Epub 2014 May 19.
Inactivation of p53, the master regulator of cellular stress and damage signals, often allows cells that should die or senesce to live. Loss of Dicer, an RNase III-like enzyme critical in microRNA biogenesis, causes embryonic lethality and activation of the p53 pathway. Several nonhematopoietic cell types that contain inactivated p53 have been shown to survive Dicer deletion, suggesting that p53 loss may protect cells from the negative consequences of Dicer deletion. However, here, we report that loss of p53 did not provide a survival advantage to B cells, as they underwent rapid apoptosis upon Dicer deletion. Moreover, a deficiency in p53 neither rescued the Dicer deletion-induced delay in Myc-driven B-cell lymphomagenesis, nor allowed a single B-cell lymphoma to develop with biallelic deletion of Dicer. A p53 deficiency did, however, restore the pre-B/B-cell phenotype and CD19 surface expression of the lymphomas that emerged in conditional Dicer knockout Eμ-myc transgenic mice. Moreover, p53 loss in transformed B cells did not confer protection from apoptosis, as Dicer deletion in established p53-null B-cell lymphomas induced apoptosis, and all of the 1,260 B-cell lymphoma clones analyzed that survived Cre-mediated Dicer deletion retained at least one allele of Dicer. Moreover, Dicer deletion in lymphomas in vivo reduced tumor burden and prolonged survival. Therefore, inactivation of p53 is insufficient to allow untransformed B cells and B-cell lymphomas to survive without Dicer, presenting a potential therapeutic opportunity for the treatment of B-cell lymphomas.
p53 是细胞应激和损伤信号的主要调节因子，其失活常常导致本应死亡或衰老的细胞存活。Dicer（一种在 microRNA 生物发生中起关键作用的 RNase III 样酶）的缺失会导致胚胎致死和 p53 通路的激活。已经有研究表明，几种含有失活 p53 的非造血细胞类型在 Dicer 缺失后能够存活，这表明 p53 的缺失可能会保护细胞免受 Dicer 缺失的负面影响。然而，在这里，我们报告称，p53 的缺失并没有为 B 细胞提供生存优势，因为它们在 Dicer 缺失后迅速凋亡。此外，p53 的缺失既不能挽救 Dicer 缺失诱导的 Myc 驱动的 B 细胞淋巴瘤发生延迟，也不能使双等位基因缺失 Dicer 的情况下发生单一 B 细胞淋巴瘤。然而，p53 的缺失确实恢复了条件性 Dicer 敲除 Eμ-myc 转基因小鼠中出现的淋巴瘤的前 B/B 细胞表型和 CD19 表面表达。此外，转化的 B 细胞中 p53 的缺失并没有赋予抗凋亡的保护作用，因为在已建立的 p53 缺失的 B 细胞淋巴瘤中，Dicer 的缺失诱导了细胞凋亡，而且在分析的 1260 个 B 细胞淋巴瘤克隆中，存活的 Cre 介导的 Dicer 缺失均保留了至少一个 Dicer 等位基因。此外，体内 Dicer 的缺失可减少肿瘤负担并延长生存期。因此，p53 的失活不足以使未转化的 B 细胞和 B 细胞淋巴瘤在没有 Dicer 的情况下存活，这为治疗 B 细胞淋巴瘤提供了潜在的治疗机会。
