| Popis: |
In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here we have identified a long noncoding RNA, PITAR (p53InactivatingTRIM28associatedRNA), as an inhibitor of p53. PITAR is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We found that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels, enhanced p53 ubiquitination, and attenuated DNA damage response. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth and promoted resistance to Temozolomide. DNA damage also activated PITAR, in addition to p53, thus creating an incoherent feedforward loop. Thus, we establish an alternate way of p53 inactivation and propose PITAR, an oncogenic Cancer/testis lncRNA, as a potential therapeutic target. |
