Interaction of Retroviral Tax Oncoproteins With Tristetraprolin and Regulation of Tumor Necrosis Factor-  Expression

Twizere, Jean‐Claude; Kruys, Véronique; Lefèbvre, Laurent; Vanderplasschen, Alain; Collete, Delphine; Debacq, Christophe; Lai, Wi S.; Jauniaux, Jean Claude; Bernstein, Lori R.; Semmes, O. John; Burny, Arsène; Blackshear, Perry J.; Kettmann, Richard; Willems, Lucas

doi:10.1093/jnci/djg118

Cited by 54 publications

(53 citation statements)

References 84 publications

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“…As demonstrated previously, MSX2 protein fused to GFP localizes mainly in the cell nucleus (29). To confirm and extend these observations, the MSX2 protein was tagged with the c-Myc epitope (in plasmid pcDNAMSX2-c-Myc).…”

Section: Tax and Msx2 Interact In Vitro And Coimmunoprecipitate In Cellsupporting

confidence: 66%

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The Homeobox Protein MSX2 Interacts with Tax Oncoproteins and Represses Their Transactivation Activity

Twizere

Lefèbvre

Collete

et al. 2005

Journal of Biological Chemistry

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Bovine leukemia virus (BLV)taxHuman T-cell leukemia virus type 1 (HTLV-1) 1 and bovine leukemia virus (BLV) are members of the Deltaretrovirus genus in the Retroviridae family (1-4). In addition to the structural proteins Gag, Pol, and Env, these viruses also encode a series of regulatory proteins: Tax, Rex, p12/R3, and p13/G4. The Tax protein is a transcriptional activator, which increases the synthesis of viral proteins acting on a triplicate 21-bp element located in the 5Ј long terminal repeat (LTR) (5-7). Tax does not interact directly with DNA but rather acts via cellular factors, such as members of the CREB/ATF family of basic leucine zipper proteins (8 -11). The tax gene is believed to be essential because its presence is absolutely required for infectivity in vivo (12). Besides its role in the regulation of transcription, the Tax protein also exhibits an oncogenic potential (13). Tax behaves as an immortalizing oncogene because it is able to cooperate with the Ha-ras oncoprotein to fully transform primary rat embryo fibroblasts (14, 15). Both transactivation and immortalizing functions of Tax can be dissociated by mutations in specific regions of the protein. For example, mutation of the phosphorylation sites at serines 106 and 293 of BLV Tax abrogates immortalization potential in vitro but maintains transcriptional activity and viral oncogenicity in vivo (16,17). Conversely, the transactivation of the LTR promoter is not required for Tax to transform primary cells in vitro (14). The Tax protein of HTLV-1 (Tax1) is known to activate several cellular genes including IL-2, IL-2R␣, IL-3, TNF-␣, and . Tax1 is also involved in cell cycle regulation by direct activation of cyclin D3 and cyclin kinases cdk4 and cdk6 (21), or by inactivating the cyclin-dependent kinase inhibitor p16 INK4A (22). In fact, protein-protein interactions with cellular factors are crucial for Tax1 to perturb the regulation of many cellular pathways (23). These HTLV-1 Tax binding factors include the human mitotic checkpoint protein HsMAD1 (24), MEKK1 (25), the IB kinase (26), or the PCAF protein (27). In contrast, little is known about the cellular partners of the BLV Tax protein. In this study, we describe a functional interaction between the homeobox protein MSX2 and the BLV Tax oncoprotein. EXPERIMENTAL PROCEDURESPlasmids-Plasmids pSGMSX2 and pEGFPMSX2 were constructed by subcloning the human MSX2-cDNA (kindly offered by Dr. T. Iimura, Tokyo Medical and Dental University, Japan) into pSG5 (Stratagene) and pEGFP-C1 (Clontech), respectively. Plasmids pcDNAMSX2-c-Myc, pcDNAMSX2⌬N-c-Myc, and pcDNAMSX2⌬C-c-Myc, which express respectively, C-terminal c-Myc-tagged full-length, amino acids 80 -267 and amino acids 1-200 of the human MSX-2 protein, were constructed by inserting the human MSX2 cDNA, or PCR-derived MSX2 truncation mutants into pcDNA3.1/myc-HisB (Invitrogen). Plasmid pcDNARAP74-flag was obtained by subcloning the human RAP74 cDNA (kindly offered by Dr. Z. Burton, Michigan State University) into pcDNA3.1Flag (Invitrogen).The pLTRL...

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Section: Tax and Msx2 Interact In Vitro And Coimmunoprecipitate In Cellsupporting

confidence: 66%

“…Plasmids pADMSX2 and pSV40 code for the Gal4-activating domain (AD) fused to the human MSX2 protein or the amino acids 84 -708 of the SV40 large T-antigen, respectively. Vector pGexTax codes for a fusion protein between Tax and the glutathione S-transferase (GST) (29).…”

Section: Methodsmentioning

confidence: 99%

The Homeobox Protein MSX2 Interacts with Tax Oncoproteins and Represses Their Transactivation Activity

Twizere

Lefèbvre

Collete

et al. 2005

Journal of Biological Chemistry

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“…Phosphorylation of TTP may also affect its association with exosome [65], stress granule [36], nucleoporin CAN/Nup214 [66], and retroviral Tax oncoproteins [67]. Phosphorylation may play a role in TTP-mediated delivery of ARE-mRNAs to processing bodies for translational silencing and mRNA decay since ARE-mRNA localization in processing bodies is mediated by the phosphorylation site-rich N-and C-termini of TTP [68].…”

Section: Expert Commentary and Five-year Viewmentioning

confidence: 99%

“…The amino acid sequences used in the alignment include human (NP_003398) [77], mouse (NP_035886) [27], rat (P47973) [78], bovine (P53781) [79], sheep (AY462109) [67], pig (AJ943797, CB288050, CB286240, DY416794 and DY419026) [80], horse (CD536573 and CD536523), chimpanzee (CR555169 andXM_001136016) and dog (AAEX01054372.1 and AAEX01054371.1) [81]. The sequences were aligned with the PILEUP program from GCG.…”

Section: Key Issuesmentioning

confidence: 99%

Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin

Cao¹,

Deterding²,

Blackshear³

2007

Expert Review of Proteomics

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Tristetraprolin (TTP) is a member of the CCCH zinc finger proteins and is an anti-inflammatory protein. Mice deficient in TTP develop a profound inflammatory syndrome with erosive arthritis, autoimmunity and myeloid hyperplasia. TTP binds to mRNA AU-rich elements with high affinity for UUAUUUAUU nucleotides and causes destabilization of those mRNA molecules. TTP is phosphorylated extensively in vivo and is a substrate for multiple protein kinases in vitro. A number of approaches have been used to identify its phosphorylation sites. This article highlights the recent progress and different approaches utilized for the identification of phosphorylation sites in mammalian TTP. Important but limited results are obtained using traditional methods including in vivo labeling, site-directed mutagenesis, phosphopeptide mapping and protein sequencing. Mass spectrometry including MALDI/MS, MALDI/MS/MS, LC/MS/MS, IMAC/MALDI/MS/MS and multidimensional protein identification technology (MudPIT) has led the way in identifying TTP phosphorylation sites. The combination of these approaches has identified multiple phosphorylation sites in mammalian TTP, some of which are predicted by motif scanning to be phosphorylated by several protein kinases. This information should provide the molecular basis for future investigation of TTP's regulatory functions in controlling pro-inflammatory cytokines.

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“…The exact mechanism whereby Tax is recruited to SGs remains to be elucidated. We have previously reported that Tax interacts with TTP, an ARE-binding protein involved in the turnover of specific cellular transcripts (Twizere et al, 2003). The region of Tax that mediates the interaction with TTP lies in the C-terminal portion of the protein and is thus still present in the D2-22 Tax mutant.…”

Section: Discussionmentioning

confidence: 99%

The HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6

Legros

Boxus

Gatot³

et al. 2011

Oncogene

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Interaction of Retroviral Tax Oncoproteins With Tristetraprolin and Regulation of Tumor Necrosis Factor- Expression

Abstract: Tax, through its interactions with the TTP repressor, indirectly increases TNF-alpha expression. This observation is of importance for the cell transformation process induced by leukemogenic retroviruses, because TNF-alpha overexpression plays a central role in pathogenesis.

Cited by 54 publications

References 84 publications

The Homeobox Protein MSX2 Interacts with Tax Oncoproteins and Represses Their Transactivation Activity

The Homeobox Protein MSX2 Interacts with Tax Oncoproteins and Represses Their Transactivation Activity

Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin

The HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6

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