LincRNA-p21 acts as a mediator of ING1b-induced apoptosis

Abstract

ING1b is a tumor suppressor that affects transcription, cell cycle control and apoptosis. ING1b is deregulated in disease, and its activity is closely linked to that of p53. In addition to regulating protein-coding genes, we found that ING1b also influences the expression of large intergenic non-coding RNAs (lincRNAs). In particular, lincRNA-p21 was significantly induced after DNA-damage stress or by ING1b overexpression. Furthermore, lincRNA-p21 expression in response to DNA damage was significantly attenuated in cells lacking ING1b. LincRNA-p21 is also a target of p53 and can trigger apoptosis in mouse cell models. We found that this function of lincRNA-p21 is conserved in human cell models. Moreover, ING1b and p53 could function independently to influence lincRNA-p21 expression. However, their effects become more additive under conditions of stress. In particular, ING1b regulates lincRNA-p21 levels by binding to its promoter and is required for induction of lincRNA-p21 by p53. The ability of ING1b to cause apoptosis is also impaired in the absence of lincRNA-p21. Surprisingly, deletion of the ING1b plant homeodomain, which allows it to bind histones and regulate chromatin structure, did not alter regulation of lincRNA-p21. Our findings suggest that ING1b induces lincRNA-p21 expression independently of histone 3 lysine 4 trimethylation mark recognition and that lincRNA-p21 functions downstream of ING1b. Thus, regulation at the level of lincRNA-p21 may represent the point at which ING1b and p53 pathways converge to induce apoptosis under specific stress conditions.

lincRNA‐p21 inhibits hepatic stellate cell activation and liver fibrogenesis via p21

“…Recently, Tran et al reported that lincRNA-p21 induces apoptosis in mouse cell models [31]. Enforced expression of lincRNA-p21 has been shown to enhance the sensitivity of human colorectal cancer to radiotherapy [22].…”

Expanding the p53 regulatory network: LncRNAs take up the challenge

“…Besides this initial finding in mouse cells, other studies supported the importance of lincRNA-p21 in regulating p53-mediated response in mouse and human models [38,39]. Notably, it has been reported that lincRNA-p21 maintains its role as mediator of p53 activity also in somatic reprograming of murine cells [40].…”

In Vivo Characterization of Linc-p21 Reveals Functional cis -Regulatory DNA Elements

“…Since its discovery in 2010, Linc-p21 has been the subject of intense study due to its reported roles in important biological processes (Huarte et al, 2010, Dimitrova et al, 2014, Yang et al, 2014, Hall et al, 2015, Bao et al, 2015, Yoon et al, 2012, Wu et al, 2014, Wang et al, 2014, Tran et al, 2015, Tang et al, 2015). However, despite extensive investigation, the nature of transcription at the Linc-p21 locus and the mechanism by which the gene functions have not been tested outside of cell-based assays.…”