Identification of a set of KSRP target transcripts upregulated by PI3K-AKT signaling

Istituto Nazionale per la Ricerca sul Cancro (IST), 16132 Genova, Italy. <>
BMC Molecular Biology (Impact Factor: 2.06). 02/2007; 8:28. DOI: 10.1186/1471-2199-8-28
Source: PubMed

ABSTRACT KSRP is a AU-rich element (ARE) binding protein that causes decay of select sets of transcripts in different cell types. We have recently described that phosphatidylinositol 3-kinase/AKT (PI3K-AKT) activation induces stabilization and accumulation of the labile beta-catenin mRNA through an impairment of KSRP function.
Aim of this study was to identify additional KSRP targets whose stability and steady-state levels are enhanced by PI3K-AKT activation. First, through microarray analyses of the AU-rich transcriptome in pituitary alphaT3-1 cells, we identified 34 ARE-containing transcripts upregulated in cells expressing a constitutively active form of AKT1. In parallel, by an affinity chromatography-based technique followed by microarray analyses, 12 mRNAs target of KSRP, additional to beta-catenin, were identified. Among them, seven mRNAs were upregulated in cells expressing activated AKT1. Both steady-state levels and stability of these new KSRP targets were consistently increased by either KSRP knock-down or PI3K-AKT activation.
Our study identified a set of transcripts that are targets of KSRP and whose expression is increased by PI3K-AKT activation. These mRNAs encode RNA binding proteins, signaling molecules and a replication-independent histone. The increased expression of these gene products upon PI3K-AKT activation could play a role in the cellular events initiated by this signaling pathway.

  • Source
    • "HuR, an RNA binding protein, is the only known factor able to stabilize b-catenin mRNA and to enhance b-catenin protein production, and it contributes to b-catenin accumulation in colon cancer (Lopez de Silanes et al, 2003). On the other hand, factors that destabilize b-catenin mRNA or reduce b-catenin protein production have also been identified, including KSRP, eIF6 and Quaking (Bikkavilli & Malbon, 2010; Gherzi et al, 2006; Ji et al, 2008; Ruggiero et al, 2007; Yang et al, 2010). Compared with our understanding of b-catenin degradation, the regulation of b-catenin protein production is far less clear and therefore requires further investigation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Wnt/β-catenin signalling is widely implicated in embryogenesis, tissue homeostasis and tumorigenesis. The key event in Wnt signalling activation is β-catenin accumulation, which is controlled by both its production and degradation. However, much more emphasis has been placed on the understanding of its degradation. Here, we show that the synthesis of β-catenin protein, which requires a group of serine/arginine-rich splicing factors (SRSF), also contributes to its tumorigenic activity. Overexpression of SRSF1 and SRSF9 promote β-catenin accumulation via the recruitment of β-catenin mRNA and by enhancing its translation in an mTOR-dependent manner. We further demonstrate that, like SRSF1, SRSF9 is also an oncogene, and is frequently overexpressed in multiple types of human tumours. Finally, our results suggest that promoting degradation and blocking production of β-catenin synergistically reduce β-catenin levels under pathological conditions and that a combinational therapy could be a promising approach for the treatment of cancer patients.
    EMBO Molecular Medicine 05/2013; 5(5). DOI:10.1002/emmm.201202218 · 8.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A new method of phase error estimation that utilizes the weighted least square (WLS) algorithm is presented for SAR autofocus applications. The method has the capability to estimate all kinds of phase errors, no matter they are of low-order, high-order or random. The WLS estimation is optimal in the sense that it has the minimum variance of the estimation error. Excellent results have been obtained in autofocusing experiments
    Geoscience and Remote Sensing Symposium Proceedings, 1998. IGARSS '98. 1998 IEEE International; 08/1998
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: mRNA stability is a major determinant of inflammatory gene expression. Rapid degradation of interleukin-8 (IL-8) mRNA is imposed by a bipartite AU-rich element (ARE) in the 3' untranslated region (R. Winzen et al., Mol. Cell. Biol. 24:4835-4847, 2004). Small interfering RNA-mediated knockdown of the ARE-binding protein KSRP resulted in stabilization of IL-8 mRNA or of a beta-globin reporter mRNA containing the IL-8 ARE. Rapid deadenylation was impaired, indicating a crucial role for KSRP in this step of mRNA degradation. The two IL-8 ARE domains both contribute to interaction with KSRP, corresponding to the importance of both domains for rapid degradation. Exposure to the inflammatory cytokine IL-1 has been shown to stabilize IL-8 mRNA through p38 mitogen-activated protein (MAP) kinase and MK2. IL-1 treatment impaired the interaction of KSRP with the IL-8 ARE in a manner dependent on p38 MAP kinase but apparently independent of MK2. Instead, evidence that TTP, a target of MK2, can also destabilize the IL-8 ARE reporter mRNA is presented. In a comprehensive approach to identify mRNAs controlled by KSRP, two criteria were evaluated by microarray analysis of (i) association of mRNAs with KSRP in pulldown assays and (ii) increased amounts in KSRP knockdown cells. According to both criteria, a group of 100 mRNAs is controlled by KSRP, many of which are unstable and encode proteins involved in inflammation. These results indicate that KSRP functions as a limiting factor in inflammatory gene expression.
    Molecular and Cellular Biology 01/2008; 27(23):8388-400. DOI:10.1128/MCB.01493-07 · 5.04 Impact Factor
Show more