TRMP,a Novel P53-induced Long Noncoding RNA,regulates G1/S Cell Cycle Progression

The tumor suppressor p53 plays a prominent role in the protection against cancer.The importance of p53 in tumor suppression was demonstrated by the completely penetrant cancer phenotype of p53 knock out mice and more than half of human cancers harboring p53 mutations.Indeed,as a crucial tumor suppressor,activated p53 halts cell proliferation through the induction of cell cycle arrest,apoptosis and senescence in response to a plethora of different cellular stress signals including DNA damage,oxidative stress and oncogene expression.Long noncoding RNAs(lncRNAs)are functionally defined as transcripts longer than 200 nucleotides in length but lacking protein coding potential.In spite of a relatively limited understanding of lncRNAs compared to protein coding gene,increasing studies suggest that lncRNAs regulate gene expression through diverse mechanism and by doing so,they have been implicated in a variety of human diseases including cancer and neurodegenerative diseases.In the context of p53,specific lncRNAs have been identified as p53 targets and some of which have been shown to play an important role in the regulation of p53 network,However,the detail mechanisms remain to be further elucidated.In this study,we screened and identified a p5 3-induced lncRNA,which is able to modulate protein levels of p27 specifically,so we named it TRMP(TP53-regulated modulator of p27).p53 is able to directly activate the transcription of TRMP by binding to the promoter of TRMP.Knockdown of TRMP inhibits cell proliferation and causes G1 cell cycle arrest.Among cell cycle-related genes examined,an only p27 protein levels was affected by TRMP.Mechanistically,TRMP doesn't affect the stability of p27 protein.By RNA pulldown experiment,PTBP1(polypyrimidine tract-binding protein 1)was identified as a TRMP interacting protein.And TRMP suppresses internal ribosomal entry site(IRES)-dependent translation of p27 by competing p27 mRNA for PTBP1 binding.Further,TRMP is able to regulate cell proliferation,G1/S cell cycle progression,and tumor xenograft growth via the inhibition of p27.Taken together,these findings reveal lncRNA as a new player to fine-tune the cell cycle progression and suggest TRMP as a new therapeutic target in cancer.