Posttranscriptional regulation of thrombospondin-1 by the novel tumor suppressor NOL7.

摘要

Tumor angiogenesis is a pathological process required for cancer progression. While characterization of the basic mechanisms that regulate this process has expanded, their contribution to disease is still poorly understood. Specifically, our understanding of RNA processing and surveillance and its contribution to angiogenesis and disease is still unclear.;NOL7 is a novel tumor suppressor that significantly suppresses in vivo tumor growth. NOL7 is rapidly and efficiently targeted to the nucleus and nucleolus. The localization dynamics of NOL7 suggest that it shuttles between these compartments and is incorporated into a large, stable nucleolar complex. NOL7 nucleolar targeting is dependent upon ongoing rRNA biogenesis, as depletion of RNA and rRNA abolished its nucleolar localization early in rRNA transcriptional inhibition. NOL7 was found to comigrate with a large, RNA-dependent RNP complex, which was subsequently identified as the nuclear RNA processing machinery. NOL7 interacts with RNAPII processing proteins, particularly those involved in mRNA maturation. In support, NOL7 was found to interact specifically with mRNA.;The interaction of NOL7 with mRNA and RNA maturation factors suggested that NOL7 may upregulate TSP-1 through posttranscriptional mechanisms. It was demonstrated NOL7 binds TSP-1 mRNA through a specific interaction with its 3'UTR, and this interaction is sufficient to posttranscriptionally upregulate gene expression at the mRNA and protein levels. Reintroduction of NOL7 expression significantly increased TSP-1 mRNA half-life. Finally, this posttranscriptional regulation was demonstrated to be specific to a subset of angiogenesis-related mRNAs.;Taken together, this demonstrates that NOL7 is a novel RBP that posttranscriptionally upregulates TSP-1 through an increase in mRNA stability. Further characterization of the mechanism underlying this function and the phenotypic consequences will illustrate the potential role of NOL7 as a master regulator of the angiogenic phenotype through subcellular localization and posttranscriptional modulation of gene expression.