Latent Protein LANA2 from Kaposi's Sarcoma-Associated Herpesvirus Interacts with 14-3-3 Proteins and Inhibits FOXO3a Transcription Factor

Abstract

The Kaposi's sarcoma-associated herpesvirus latent protein LANA2 has been suggested to have an important role in the transforming activity of the virus based on its capacity to inhibit p53 and PKR-dependent apoptosis as well as the interferon-dependent response. Here, we describe a novel interaction between LANA2 and both the phosphoserine/phosphothreonine-binding 14-3-3 proteins and the transcription factor FOXO3a. In addition, our results indicate that LANA2 inhibits the transcriptional activity of FOXO3a and blocks the G 2 /M arrest induced by 14-3-3 protein overexpression. These results suggest a novel mechanism by which LANA2 may promote tumorigenesis.

Stimulation of c-Myc Transcriptional Activity by vIRF-3 of Kaposi Sarcoma-associated Herpesvirus

“…Inhibition of the IB kinase kinase activity, and down-modulation of the NFB-dependent transcription by vIRF-3 have also been reported (11). Recently, vIRF-3 was shown to interact with 14-3-3 proteins and inhibit FOXO3a transcription factor, which may contribute to cell cycle de-regulation (12).…”

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

“…Akt can phosphorylate FoxO3a and inhibit its activity to sequester FoxO3a in the cytoplasm by association with 14-3-3 proteins (Brunet et al, 2002;Dong et al, 2007;Kino et al, 2005;Munoz-Fontela et al, 2007). In the absence of inhibitory Akt1 phosphorylation, FoxO3a can translocate to the nucleus, and controls a variety of functions that involve cell cycle progression, cell longevity, and apoptosis (Lehtinen et al, 2006;Li et al, 2006a;Maiese et al, 2007a).…”

OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins

“…FoxO3a activation can inhibit cell cycle progression and proliferation of tumor growth in colon carcinoma cell lines [50]. Several studies also suggest that the loss of FoxO3a activity in primary leukemic cells might participate in oncogenic transformation in B-chronic lymphocytic leukemia [75], in the progression of chronic myelogenous leukemia cell lines [51] and in the transformation of cells into Kaposi's sarcoma [76]. Interestingly, loss of functional FoxO3a in human ovarian cancer cell lines can limit the sensitivity of ovarian cancer cells to chemotherapy such as cisplatin [77], which suggests that FoxO proteins might be responsible for altered treatment outcomes in the presence of combined therapeutic approaches.…”

“…These interconnected pathways involve IκB kinase (IKK), IκB, protein 14-3-3, growth-arrest and DNA-damage-response protein 45 (Gadd45), Fas ligand (Fas L), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the BH3-only proteins Noxa and Bim, p53, c-myc, p27, mitochondrial membrane potential (Mito), cytochrome c (Cyto-c) and caspases. Foxo3a depletion leads to oocyte death and infertility [13] Overexpression of Foxo3a leads to oocyte growth retardation, follicular failure and anovulation [14] Mutations in FOXO1a and FOXO3a lead to clinical premature ovarian failure [83] Inflammatory and immune disease Absence of Foxo3a leads to lymphoproliferation, organ inflammation, enhanced helper Tcell activity [15] Increased FOXO3a levels lead to changes in T cell response and activity [88] Foxo3a is necessary for neutrophil activation [16] Rheumatoid arthritis leads to increased post-translational phosphorylation of FOXO1, FOXO3a and FOXO4 in synovial tissue biopsy [84] Progenitor cells in the hematopoietic and nervous systems Erythropoietin leads to the inhibition of Foxo3a activity [19,20,44] Erythropoietin-Foxo3a association promotes erythropoiesis [ Loss of FoxO1 and FoxO3a promotes breast and prostate cancer growth whereas activity of FoxO1 and FoxO3a blocks tumor progression [69][70][71][72] FoxO3a activation leads to inhibition of cell cycle progression and prevents proliferation of human colon cancer cells [50] Loss of FoxO3a activity leads to oncogenic transformation in hematopoietic derived cancers and Kaposi's sarcoma [51,75,76] Changes in FoxO3a activity can alter the sensitivity of tumor cells to chemotherapeutic agents [77] Nomenclature: 'FoxO' pertains to cell culture, tissue or animal studies; 'FOXO' pertains to human studies.…”