Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India.
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
Elife. 2024 Sep 20;12:RP88256. doi: 10.7554/eLife.88256.
In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, (53 nactivating RIM28 ssociated NA), as an inhibitor of p53. is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of interaction with RNA stabilized mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated , in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a -dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by , which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose as a potential GBM therapeutic target.
在 WT p53 肿瘤中，报道了 p53 失活的其他机制。在这里，我们鉴定了一种长非编码 RNA，（53 nactivating RIM28 ssociated NA），作为 p53 的抑制剂。是一种致癌的癌症/睾丸 lncRNA，在胶质母细胞瘤（GBM）和神经胶质瘤干细胞（GSC）中高度表达。我们确定编码 p53 特异性 E3 泛素连接酶的 mRNA 是 的直接靶标，与 RNA 的相互作用稳定了 mRNA，导致 TRIM28 蛋白水平升高和 p53 稳态水平降低，这是由于增强了 p53 的泛素化。DNA 损伤以 p53 非依赖性方式激活，除了 p53 之外，还激活了 ，从而创建了一个不连贯的前馈环，通过 p53 抑制 DNA 损伤反应。虽然沉默抑制了体外含有 WT p53 的 GSCs 的生长，并减少了体内神经胶质瘤肿瘤的生长，但它的过表达以依赖的方式增强了肿瘤的生长，并促进了对替莫唑胺的耐药性。因此，我们建立了一种通过 来失活 p53 的替代方法，它在正常细胞中维持低水平的 p53，并减弱 p53 的 DNA 损伤反应。最后，我们提出 作为一种潜在的 GBM 治疗靶点。
