The novel tumor suppressor NOL7 post-transcriptionally regulates thrombospondin-1 expression

Abstract

Thrombospondin-1 (TSP-1) is an endogenous inhibitor of angiogenesis whose expression suppresses tumor growth in vivo. Like many angiogenesis-related genes, TSP-1 expression is tightly controlled by various mechanisms, but there is little data regarding the contribution of post-transcriptional processing to this regulation. NOL7 is a novel tumor suppressor that induces an antiangiogenic phenotype and suppresses tumor growth, in part through upregulation of TSP-1. Here we demonstrate that NOL7 is an mRNA-binding protein that must localize to the nucleoplasm to exert its antiangiogenic and tumor suppressive effects. There, it associates with the RNA-processing machinery and specifically interacts with TSP-1 mRNA through its 3'UTR. Reintroduction of NOL7 into SiHa cells increases luciferase expression through interaction with the TSP-1 3'UTR at both the mRNA and protein levels. NOL7 also increases endogenous TSP-1 mRNA half-life. Further, NOL7 post-transcriptional stabilization is observed in a subset of angiogenesis-related mRNAs, suggesting that the stabilization of TSP-1 may be part of a larger novel mechanism. These data demonstrate that NOL7 significantly alters TSP-1 expression and may be a master regulator that coordinates the post-transcriptional expression of key signaling factors critical for the regulation of the angiogenic phenotype.

Proteome profiling of triple negative breast cancer cells overexpressing NOD1 and NOD2 receptors unveils molecular signatures of malignant cell proliferation

“…Specifically, ERK1/2 can activate STAT6, which was upregulated in HS578T/NOD2. Other targets of ERK1/2 signaling are also upregulated in the NOD2 overexpressing cells, such as nucleolar MK67I ( NFIK ), which regulates mitosis by interacting with the Ki-67 antigen, [108] and the tumor suppressor and cell cycle regulator NOL7 [109].…”

High Level of Staufen1 Expression Confers Longer Recurrence Free Survival to Non-Small Cell Lung Cancer Patients by Promoting THBS1 mRNA Degradation

“…Therefore, the modification of a single RBP such as Stau1 impacts the expression of many downstream targets, but also all the signaling pathways in which these genes are involved. Moreover, other RBPs such as the human antigen R protein (HuR) [ 105 , 106 , 107 ], the nucleolar protein 7 (NOL7) [ 108 ] and the AU-rich element RNA-binding protein 1 (AUF1) [ 109 ] can bind and regulate THBS1 mRNA. Thus, the observed phenotypes subsequent to Stau1 modulation are not due to the defect of regulation of one direct target but rather to the addition of subtle gene modulations acting together in a complex network and leading to establishment of a new balance of pro- and anti-factors involved in migration, angiogenesis and proliferation, thus resulting in the acquisition of a new phenotype.…”

Lysophosphatidic acid induces thrombospondin‐1 production in primary cultured rat cortical astrocytes

“…Cellular synthesis of TSP‐1 is tightly regulated by transcription factors, such as Myc, p53, hypoxia inducible factors (HIFs), and nuclear factor of activated T‐cells (NFAT) that are activated by receptor and intracellular signaling (Zhao et al., 2017). In addition to transcriptional regulation by promoters and repressors, TSP‐1 expression is also post‐transcriptionally regulated by several microRNAs including miR‐18a, or RNA‐binding proteins such as NOL7 through post‐transcriptional mRNA stabilization (Doçi et al., 2013; Zhao et al., 2017). MicroRNAs biogenesis and function appears to be regulated by multiple signaling pathways including p38 MAPK and JNK pathways (Zhou et al., 2011).…”