LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression

Abstract

RNA-binding proteins (RBPs) bind to and post-transcriptionally regulate the stability of mRNAs. La-related protein 1 (LARP1) is a conserved RBP that interacts with poly-A-binding protein and is known to regulate 5′-terminal oligopyrimidine tract (TOP) mRNA translation. Here, we show that LARP1 is complexed to 3000 mRNAs enriched for cancer pathways. A prominent member of the LARP1 interactome is mTOR whose mRNA transcript is stabilized by LARP1. At a functional level, we show that LARP1 promotes cell migration, invasion, anchorage-independent growth and in vivo tumorigenesis. Furthermore, we show that LARP1 expression is elevated in epithelial cancers such as cervical and non-small cell lung cancers, where its expression correlates with disease progression and adverse prognosis, respectively. We therefore conclude that, through the post-transcriptional regulation of genes such as mTOR within cancer pathways, LARP1 contributes to cancer progression.

LARP4B is an AU-rich sequence associated factor that promotes mRNA accumulation and translation

“…5B). These results confirm the previously reported stimulatory effect of these LARPs on gene expression (Burrows et al 2010;Schäffler et al 2010;Yang et al 2011;Aoki et al 2013;Mura et al 2014;Tcherkezian et al 2014). The simultaneous knockdown of LARP4 and LARP4B led to a decrease in the luciferase activity by 55%.…”

“…Similar biochemical and functional properties were reported for LARP4B, LARP4, and LARP1. They are cytoplasmic proteins that translocate into stress granules under cellular stress conditions, interact with PABPC1, associate with actively translating ribosomes and exert stabilizing effects on target mRNAs (Burrows et al 2010;Schäffler et al 2010;Yang et al 2011;Aoki et al 2013;Mura et al 2014;Tcherkezian et al 2014). This suggests that they might fulfill overlapping or redundant functions in mRNA metabolism.…”

“…Accordingly, members of the LARP3 and LARP7 families associate predominantly with RNA polymerase III (RNAPIII) transcripts in vivo and influence their stability and/or maturation pathways (Sobel and Wolin 1999;Intine et al 2000;Aigner et al 2003;Chakshusmathi et al 2003;Aigner and Cech 2004;Prathapam et al 2005;Stone et al 2007;Copela et al 2008;Krueger et al 2008;Markert et al 2008). While other LARP family members also contain La modules, recent evidence suggested that LARP1, LARP4, and LARP6 are associated with mRNAs rather than RNAPIII transcripts (Nykamp et al 2008;Blagden et al 2009;Wang et al 2009;Weng et al 2009;Burrows et al 2010;Cai et al 2010a;Schäffler et al 2010;Zanin et al 2010;Yang et al 2011;Aoki et al 2013;Mura et al 2014;Tcherkezian et al 2014). LARP6 has been shown to interact with a hairpin structure located in the 5 ′ untranslated region (UTR) of the mRNA encoding collagen.…”

“…Whereas LARP6 likely targets only a small number of mRNAs carrying a specific secondary sequence motif in cis, LARP1 and LARP4 appear to influence translation in a broader sense. LARP1 has been shown to associate with many cytoplasmic mRNPs, primarily via interactions with translation factors including the poly(A)-binding protein PABPC1 but also via RNA sequences (Blagden et al 2009;Burrows et al 2010;Aoki et al 2013;Mura et al 2014;Tcherkezian et al 2014). LARP1 has recently attracted major attention as it acts in the mTORC1 pathway to control the translation and stability of mRNAs containing the 5 ′ terminal oligopyrimidine tract (TOP) motif (Aoki et al 2013;Tcherkezian et al 2014).…”

Protective effect of glycyrrhizin on myocardial ischemia/reperfusion injury-induced oxidative stress, inducible nitric oxide synthase and inflammatory reactions through high-mobility group box 1 and mitogen-activated protein kinase expression

“…To reduce the effects of myocardial infiltration, neutrophils may predominantly reduce the discharge of oxygen radicals. This effect may relieve stunned myocardium after ischemia and shorten the duration of stunned myocardium, which would relieve the degrees of myocardial I/R injury and shorten the duration required to protect myocardial I/R injury (22). The present study demonstrated that pretreatment with 2-10 mg/kg glycyrrhizin significantly elevated plasma GSH and GSH-PX levels in rats with myocardial I/R injury.…”