Adenovirus Type 5 E1A and E6 Proteins of Low-Risk Cutaneous Beta-Human Papillomaviruses Suppress Cell Transformation through Interaction with FOXK1/K2 Transcription Factors

Komorek, Jessica; Kuppuswamy, Mohan; Subramanian, T.; Vijayalingam, S.; Lomonosova, Elena; Zhao, Lingjun; Mymryk, Joe S.; Schmitt, Kimberly; Chinnadurai, G.

doi:10.1128/jvi.02119-09

Cited by 42 publications

(98 citation statements)

References 61 publications

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“…Furthermore, these sequences have a similarity to the FoxK1/ K2-interacting domain of adenovirus E1A (Fig. 2E), another protein known to interact with FoxK1 and FoxK2 in a phosphorylation-dependent manner (37). In addition, Thr-493 in human BAP1 is highly conserved among BAP1 homologs (Fig.…”

Section: Identification Of the Foxk1/k2-interacting Region Of Bap1-mentioning

confidence: 90%

BRCA1-associated Protein 1 (BAP1) Deubiquitinase Antagonizes the Ubiquitin-mediated Activation of FoxK2 Target Genes

Okino¹,

Machida²,

Frankland-Searby

et al. 2015

Journal of Biological Chemistry

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Background:The mechanism of gene regulation by the H2A deubiquitinase BAP1 is unclear. Results: BAP1 loss increases FoxK2 target gene expression but not in the absence of the H2A ubiquitin ligase complex Ring1B-Bmi1. Conclusion: BAP1 counteracts Ring1B-Bmi1-dependent activation of FoxK2 target genes. Significance: BAP1 deficiency in cancer cells might cause up-regulation of target genes in a Ring1B-Bmi1-dependent manner.

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Section: Identification Of the Foxk1/k2-interacting Region Of Bap1-mentioning

confidence: 90%

BRCA1-associated Protein 1 (BAP1) Deubiquitinase Antagonizes the Ubiquitin-mediated Activation of FoxK2 Target Genes

Okino¹,

Machida²,

Frankland-Searby

et al. 2015

Journal of Biological Chemistry

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“…A number of previous immunoprecipitation studies using the well-defined hAd5 E1A mutant dl1102 (18) have identified the interaction of TRRAP (8, 10) and p400 (11) with the E1A domain encompassing residues 26 to 35. During our unbiased proteomic analyses of cellular proteins associated with L-E1A and S-E1A (20,22), we detected associations of several proteins (in addition to TRRAP, p400, and GCN5) that we reasoned might be constituents of the TRRAP/p400 and TRRAP-GCN5 complexes. These proteins included Tip49, Tip50, BAF53, c-MYC, MYCBP, and ENY2.…”

Section: Defining the Transforming Activity Of E1a N-terminal Domainsmentioning

confidence: 99%

“…The E1A-associated cellular protein complexes were prepared from KB cells infected with hAd5 mutants that express epitope-tagged (Flag and HA) S-E1A (FH-12S) or L-E1A (FH-13S). The protein complexes were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) as described previously (20).…”

Section: Methodsmentioning

confidence: 99%

The Cellular Protein Complex Associated with a Transforming Region of E1A Contains c-MYC

Vijayalingam

Subramanian

Zhao

et al. 2016

J Virol

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The cell-transforming activity of human adenovirus 5 (hAd5) E1A is mediated by the N-terminal half of E1A, which interacts with three different major cellular protein complexes, p300/CBP, TRRAP/p400, and pRb family members. Among these protein interactions, the interaction of pRb family proteins with conserved region 2 (CR2) of E1A is known to promote cell proliferation by deregulating the activities of E2F family transcription factors. The functional consequences of interaction with the other two protein complexes in regulating the transforming activity of E1A are not well defined. Here, we report that the E1A N-terminal region also interacted with the cellular proto-oncoprotein c-MYC and the homolog of enhancer of yellow 2 (ENY2). Our results suggested that these proteins interacted with an essential E1A transforming domain spanning amino acid residues 26 to 35 which also interacted with TRRAP and p400. Small interfering RNA (siRNA)-mediated depletion of TRRAP reduced c-MYC interaction with E1A, while p400 depletion did not. In contrast, depletion of TRRAP enhanced ENY2 interaction with E1A, suggesting that ENY2 and TRRAP may interact with E1A in a competitive manner. The same E1A region additionally interacted with the constituents of a deubiquitinase complex consisting of USP22, ATXN7, and ATXN7L3 via TRRAP. Acute short hairpin RNA (shRNA)-mediated depletion of c-MYC reduced the E1A transforming activity, while depletion of ENY2 and MAX did not. These results suggested that the association of c-MYC with E1A may, at least partially, play a role in the E1A transformation activity, independently of MAX. IMPORTANCEThe transforming region of adenovirus E1A consists of three short modules which complex with different cellular protein complexes. The mechanism by which one of the transforming modules, CR2, promotes cell proliferation, through inactivating the activities of the pRb family proteins, is better understood than the activities of the other domains. Our analysis of the E1A proteome revealed the presence of the proto-oncoprotein c-MYC and of ENY2. We mapped these interactions to a critical transforming module of E1A that was previously known to interact with the scaffolding molecule TRRAP and the E1A-binding protein p400. We showed that c-MYC interacted with E1A through TRRAP, while ENY2 interacted with it independently. The data reported here indicated that depletion of c-MYC in normal human cells reduced the transforming activity of E1A. Our result raises a novel paradigm in oncogenic transformation by a DNA viral oncogene, the E1A gene, that may exploit the activity of a cellular oncogene, the c-MYC gene, in addition to inactivation of the tumor suppressors, such as pRb.

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“…Knockdown TAP and MS. To isolate cellular protein complexes associated with S-E1A and L-E1A, a suspension culture of KB cells was mock infected or infected with HF-12S or HF-13S. Tandem affinity purification (TAP) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses were carried out as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

Adenovirus L-E1A Activates Transcription through Mediator Complex-Dependent Recruitment of the Super Elongation Complex

Vijayalingam

Chinnadurai

2013

J Virol

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The adenovirus large E1A (L-E1A) protein is a prototypical transcriptional activator, and it functions through the action of a conserved transcriptional activation domain, CR3. CR3 interacts with a mediator subunit, MED23, that has been linked to the transcriptional activity of CR3. Our unbiased proteomic analysis revealed that human adenovirus 5 (HAdv5) L-E1A was associated with many mediator subunits. In MED23-depleted cells and in Med23 knockout (KO) cells, L-E1A was deficient in association with other mediator subunits, suggesting that MED23 links CR3 with the mediator complex. Short interfering RNA (siRNA)-mediated depletion of several mediator subunits suggested differential effects of various subunits on transcriptional activation of HAdv5 early genes. In addition to MED23, mediator subunits such as MED14 and MED26 were also essential for the transcription of HAdv5 early genes. The L-E1A proteome contained MED26-associated super elongation complex. The catalytic component of the elongation complex, CDK9, was important for the transcriptional activity of L-E1A and HAdv5 replication. Our results suggest that L-E1A-mediated transcriptional activation involves a transcriptional elongation step, like HIV Tat, and constitutes a therapeutic target for inhibition of HAdv replication. Adenovirus E1A is the immediate-early viral gene that plays an essential role in viral replication by driving quiescent host cells into the cell cycle and by transcriptional activation of other viral early genes (reviewed in references 1 and 2). The E1A gene codes for two major protein isoforms, designated small E1A (S-E1A) and large E1A (L-E1A). The two protein isoforms differ only by the presence of a 46-amino-acid unique region (designated conserved region 3, or CR3) that is conserved among different adenovirus serotypes. While both E1A proteins can promote proliferation of quiescent target cells by activation of S phase genes, L-E1A is required for transcriptional activation of other viral early genes (3, 4). The role of CR3 in the transcriptional activation of viral early genes was established on the basis of results that showed a substantial decrease in expression of viral early genes in cells infected with different human adenovirus 5 (HAdv5) mutants with lesions in CR3 (3, 4). Further, protein microinjection and transcriptional tethering studies also demonstrated that a synthetic CR3 peptide (5, 6) or a CR3-Gal4 DNA binding domain (DBD) chimeric gene (7,8) can activate viral early promoters. Although E1A CR3 constitutes a powerful trans-activation domain of a viral transcriptional activator and has been intensely investigated as a model trans-activation domain, the mechanism by which it mediates transcriptional activation of other viral early genes remains incompletely understood. The N-terminal 40-aminoacid region of CR3 which forms the C-4 zinc finger (9) has been postulated to function as the trans-activation subdomain, as it is sufficient for transcriptional activation as a Gal4 DNA binding domain fusion protein. The N-te...

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Adenovirus Type 5 E1A and E6 Proteins of Low-Risk Cutaneous Beta-Human Papillomaviruses Suppress Cell Transformation through Interaction with FOXK1/K2 Transcription Factors

Cited by 42 publications

References 61 publications

BRCA1-associated Protein 1 (BAP1) Deubiquitinase Antagonizes the Ubiquitin-mediated Activation of FoxK2 Target Genes

BRCA1-associated Protein 1 (BAP1) Deubiquitinase Antagonizes the Ubiquitin-mediated Activation of FoxK2 Target Genes

The Cellular Protein Complex Associated with a Transforming Region of E1A Contains c-MYC

Adenovirus L-E1A Activates Transcription through Mediator Complex-Dependent Recruitment of the Super Elongation Complex

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