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The ID proteins contribute to the growth of rodent fibroblasts during LMP1-mediated transformation.

ABSTRACT: LMP1 induces the expression of two members of the family of Id proteins, Id1 and Id3, and affects cell cycle regulation by decreasing the expression of the cyclin dependent kinase inhibitor, p27, and increasing levels and phosphorylation of cdk2 and Rb. In the present study, the contribution of the Id proteins to LMP1-mediated transformation was determined. Although LMP1 effectively inhibited p27 expression, the Id proteins alone did not affect expression of p27, cdk2, and Rb. Neither Id1 nor Id3 was sufficient to transform Rat-1 cells and inhibition of Id1 expression did not affect LMP1-induced morphologic transformation of Rat-1 cells or reduction of p27. However, reduced Id expression resulted in smaller foci and impaired the growth rate of Rat-1 cells. These data indicate that overexpression of the Id proteins is not sufficient for the effects of LMP1 on the cell cycle but that inhibition of Id expression does affect the growth of LMP1-transformed and parental Rat1 cells.

SUBMITTER: Everly DN

PROVIDER: S-EPMC2901101 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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The ID proteins contribute to the growth of rodent fibroblasts during LMP1-mediated transformation.

Everly David N DN Mainou Bernardo A BA Raab-Traub Nancy N

Virology 20080505 2

LMP1 induces the expression of two members of the family of Id proteins, Id1 and Id3, and affects cell cycle regulation by decreasing the expression of the cyclin dependent kinase inhibitor, p27, and increasing levels and phosphorylation of cdk2 and Rb. In the present study, the contribution of the Id proteins to LMP1-mediated transformation was determined. Although LMP1 effectively inhibited p27 expression, the Id proteins alone did not affect expression of p27, cdk2, and Rb. Neither Id1 nor Id ...[more]

PMID: 18456300

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Project description:The Epstein-Barr virus (EBV) encoded oncoprotein Latent Membrane Protein 1 (LMP1) signals through two C-terminal tail domains to drive cell growth, survival and transformation. The LMP1 membrane-proximal TES1/CTAR1 domain recruits TRAFs to activate MAP kinase, non-canonical and canonical NF-kB pathways, and is critical for EBV-mediated B-cell transformation. TRAF1 is amongst the most highly TES1-induced target genes and is abundantly expressed in EBV-associated lymphoproliferative disorders. We found that TRAF1 expression enhanced LMP1 TES1 domain-mediated activation of the p38, JNK, ERK and canonical NF-kB pathways, but not non-canonical NF-kB pathway activity. To gain insights into how TRAF1 amplifies LMP1 TES1 MAP kinase and canonical NF-kB pathways, we performed proteomic analysis of TRAF1 complexes immuno-purified from cells uninduced or induced for LMP1 TES1 signaling. Unexpectedly, we found that LMP1 TES1 domain signaling induced an association between TRAF1 and the linear ubiquitin chain assembly complex (LUBAC), and stimulated linear (M1)-linked polyubiquitin chain attachment to TRAF1 complexes. LMP1 or TRAF1 complexes isolated from EBV-transformed lymphoblastoid B cell lines (LCLs) were highly modified by M1-linked polyubiqutin chains. The M1-ubiquitin binding proteins IKK-gamma/NEMO, A20 and ABIN1 each associate with TRAF1 in cells that express LMP1. TRAF2, but not the cIAP1 or cIAP2 ubiquitin ligases, plays a key role in LUBAC recruitment and M1-chain attachment to TRAF1 complexes, implicating the TRAF1:TRAF2 heterotrimer in LMP1 TES1-dependent LUBAC activation. Depletion of either TRAF1, or the LUBAC ubiquitin E3 ligase subunit HOIP, markedly impaired LCL growth. Likewise, LMP1 or TRAF1 complexes purified from LCLs were decorated by lysine 63 (K63)-linked polyubiqutin chains. LMP1 TES1 signaling induced K63-polyubiquitin chain attachment to TRAF1 complexes, and TRAF2 was identified as K63-Ub chain target. Co-localization of M1- and K63-linked polyubiquitin chains on LMP1 complexes may facilitate downstream canonical NF-kB pathway activation. Our results highlight LUBAC as a novel potential therapeutic target in EBV-associated lymphoproliferative disorders.

Project description:BackgroundEpstein-Barr virus (EBV)-encoded LMP1 protein is commonly expressed in nasopharyngeal carcinoma (NPC). LMP1 is a prime candidate for driving tumourigenesis given its ability to activate multiple signalling pathways and to alter the expression and activity of variety of downstream targets. Resistance to TGFbeta-mediated cytostasis is one of the growth transforming effects of LMP1. Of the downstream targets manipulated by LMP1, the induction of Id1 and inactivation of Foxo3a appear particularly relevant to LMP1-mediated effects. Id1, a HLH protein is implicated in cell transformation and plays a role in cell proliferation, whilst Foxo3a, a transcription factor controls cell integrity and homeostasis by regulating apoptosis. The mechanism(s) by which LMP1 induces these effects have not been fully characterised.ResultsIn this study, we demonstrate that the ability of LMP1 to induce the phosphorylation and inactivation of Foxo3a is linked to the upregulation of Id1. Furthermore, we show that the induction of Id1 is essential for the transforming function of LMP1 as over-expression of Id1 increases cell proliferation, attenuates TGFbeta-SMAD-mediated transcription and renders cells refractory to TGFbeta-mediated cytostasis. Id1 silencing in LMP1-expressing epithelial cells abolishes the inhibitory effect of LMP1 on TGFbeta-mediated cell growth arrest and reduces the ability of LMP1 to attenuate SMAD transcriptional activity. In response to TGFbeta stimulation, LMP1 does not abolish SMAD phosphorylation but inhibits p21 protein expression. In addition, we found the induction of Id1 in LMP1-expressing cells upon stimulation by TGFbeta. We provide evidence that LMP1 suppresses the transcriptional repressor ATF3, possibly leading to the TGFbeta-induced Id1 upregulation.ConclusionThe current data provide novel information regarding the mechanisms by which LMP1 suppresses TGFbeta-induced cytostasis, highlighting the importance of Id1 in LMP1 mediated cell transformation.

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The ID proteins contribute to the growth of rodent fibroblasts during LMP1-mediated transformation.

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The ID proteins contribute to the growth of rodent fibroblasts during LMP1-mediated transformation.

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