p53 Activates the Long Noncoding RNA Pvt1b to Inhibit Myc and Suppress Tumorigenesis

Identification and characterization of functional long noncoding RNAs in cancer

“…146 In contrast, our group identified a stressinduced, p53-dependent isoform of Pvt1, Pvt1b, which is both necessary and sufficient to repress Myc transcription. 103 These findings were recapitulated in vitro using a genetic loss-of-function approach to mutate the p53-binding site required for Pvt1b expression. 103 Importantly, mutagenesis of the Pvt1-associated p53-binding site at the time of tumor initiation in an autochthonous mouse model of lung cancer led to larger tumors and indicated a key role for Pvt1b in restraining tumor growth downstream of p53.…”

“…These included lincRNA-p21; 88 PANDAR (Promoter Of CDKN1A Antisense DNA Damage-Activated RNA, also known as PANDA); 89 p53BERs (p53-Bound Enhancer Regions); 90 102 and an isoform of Pvt1, Pvt1b. 103 Functional characterizations have suggested that many of these lncRNAs contribute to p53 tumor suppressor activities.…”

“…The increased tumor growth observed in a Myc/Pvt1 co-amplification GEMM (Myc/Pvt1 AMP ) compared to Myc amplification alone (Myc AMP ) when crossed to the MMTV-Neu BC (breast cancer) GEMM suggests an oncogenic function for Pvt1 (red box, 145 ). However, the increased tumor growth in Pvt1-associated p53RE mutagenized lung tumors following Cre-mediated tumor initiation in a Kras-driven lung adenocarcinoma (LUAD) GEMM suggests a tumor suppressor function (green box, 103 ) decreased MYC protein levels. 145 However, later studies found evidence for MYC enhancers within the region of deletion, raising questions about the role of the PVT1 locus and its associated RNA in MYC regulation.…”

“…103 Importantly, mutagenesis of the Pvt1-associated p53-binding site at the time of tumor initiation in an autochthonous mouse model of lung cancer led to larger tumors and indicated a key role for Pvt1b in restraining tumor growth downstream of p53. 103 In the future, it would be interesting to deconvolve the oncogenic and tumor suppressive elements in the PVT1 locus and to differentiate between DNA elements and RNA isoforms with potentially distinct functions.…”

From Cancer to Rejuvenation: Incomplete Regeneration as the Missing Link (Part II: Rejuvenation circle)

“…Pvt1a or circular Pvt1 isoforms operate like the so-called oncogenes [ 102 , 103 , 106 , 109 ], which include through its interacting with FOXM1 [ 110 ]. However, the authors of a recently published paper [ 111 ] report that p53-dependent isoform Pvt1b ‘is necessary and sufficient to suppress Myc transcription in cis without altering the chromatin organization of the locus’. This is consistent with data on tumor-suppressive elements in the Pvt1 locus [ 109 , 112 , 113 ].…”