Abstract
Cyclin D1 is a critical regulator of cell cycle progression and works at the G1 to S-phase transition. Here, we report the isolation and characterization of the novel c-Myc-regulated lncRNA LAST (LncRNA-Assisted Stabilization of Transcripts), which acts as a CCND1 mRNA stabilizer. Mechanistically, LAST was shown to cooperate with CNBP to bind to the 5'UTR of CCND1 mRNA to protect against possible nuclease targeting. In addition, data from CNBP RIP-seq and LAST RNA-seq showed that CCND1 mRNA might not be the only target of LAST and CNBP; three additional mRNAs were shown to be post-transcriptional targets of LAST and CNBP. In a xenograft model, depletion of LAST diminished and ectopic expression of LAST induced tumor formation, which are suggestive of its oncogenic function. We thus report a previously unknown lncRNA involved in the fine-tuned regulation of CCND1 mRNA stability, without which CCND1 exhibits, at most, partial expression.
Highlights
The oncoprotein c-Myc plays a pivotal role in multiple cellular processes, such as cell cycle progression, malignant transformation, differentiation suppression and apoptosis induction, predominantly through its transcription activity (Seth et al, 1993; Drayton et al, 2003; Wei et al, 2003; Demeterco et al, 2002; Prendergast, 1999; Amati et al, 1992; Lee et al, 1996; Hoffman and Liebermann, 2008)
Two of the five Long noncoding RNAs (lncRNAs), namely, lncRNA-51 and lncRNA-52, along with CDK4 were found to be downregulated when c-Myc expression was suppressed by doxycycline treatment (Figure 1A)
As will be shown this lncRNA is able to promote the stability of mRNA transcripts, including CCND1 mRNA; we named it LAST (LncRNA-Assisted Stabilization of Transcripts)
Summary
The oncoprotein c-Myc plays a pivotal role in multiple cellular processes, such as cell cycle progression, malignant transformation, differentiation suppression and apoptosis induction, predominantly through its transcription activity (Seth et al, 1993; Drayton et al, 2003; Wei et al, 2003; Demeterco et al, 2002; Prendergast, 1999; Amati et al, 1992; Lee et al, 1996; Hoffman and Liebermann, 2008). As a master transcriptional factor, c-Myc regulates the expression of approximately 10–15% of genes in the genome, including a variety of protein-coding genes (Lin et al, 2012; Nie et al, 2012; Fernandez et al, 2003), such as CDKN1A, CDKN2B, CCND1, CCND2, CDK4 and E2F2 (Adhikary and Eilers, 2005). Among c-Myc target genes, CCND1 is of particular importance in cell cycle control and is characterized by the dramatic periodicity of the abundance of its protein product cyclin D1 throughout the cell cycle (Sherr, 1995). While early studies showed that the Skp F-box protein is involved in cyclin D1 degradation (Yu et al, 1998), a recent study has identified two additional F-box proteins that play
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
