C-terminal-binding protein interacting protein binds directly to adenovirus early region 1A through its N-terminal region and conserved region 3

Bruton, Rachel; Rasti, Mozhgan; Mapp, Katie; Young, Neville; Carter, R Z; I, Abramowicz; Sedgwick, Garry G.; Onion, David; Shuen, Michael; Mymryk, Joe S.; Turnell, Andrew; Grand, Roger J. A.

doi:10.1038/sj.onc.1210551

Cited by 12 publications

(9 citation statements)

References 46 publications

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“…None of these substitutions are predicted to disrupt the a-helical structure of the N-terminal region (Rasti et al, 2005); therefore, inhibition is probably because of the loss of specific side-chain recognition motifs required for optimal binding. In earlier analyses, similar effects were observed (Rasti et al, 2005;Bruton et al, 2007). For example, mutation of I11 and T12 caused a marked decrease in binding to p300/CBP associated factor (PCAF), hGCN5, S4, S8 and TBP (Rasti et al, 2005), as it does for IRS-4.…”

Section: Discussionsupporting

confidence: 63%

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

et al. 2008

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Using mass spectrometric analysis insulin receptor substrate 4 (IRS-4) has been identified as a novel adenovirus 5 early region 1A (Ad5E1A)-binding protein. IRS-4 interacts with both the transcriptional activation domain (conserved region 3) and the N-terminal region of Ad5E1A13S. Prolonged expression of Ad5E1A13S is required for the observed dramatic increase in the levels of IRS-4 mRNA and protein in Ad5E1-transformed human cell lines. Once expressed, as well as binding to E1A and the insulin receptor, IRS-4 remains tyrosine phosphorylated and constitutively associates with the regulatory p85 subunit of phosphoinositide 3 kinase, resulting in the phosphorylation of Akt (causing activation) and GSK-3b (causing inhibition). Reducing IRS-4 expression using small interfering RNA (siRNA) in established Ad5E1A-expressing cell lines decreases the activation of Akt and cellular proliferation. During Ad5 infection, IRS-4 is not expressed. However, Ad5E1A associates with IRS-1, increasing Akt and GSK-3b phosphorylation and tyrosine phosphorylation of IRS-1 itself. We conclude that the association and altered regulation of IRS proteins by Ad5E1A contribute to the adenovirus-transformed phenotype and modulates viral infection in an Akt-dependent manner.

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Section: Discussionsupporting

confidence: 63%

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

et al. 2008

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“…For example, knockdown of Mre11 to similar levels sensitized human adenocarcinoma cells to ionizing radiation (45). Additionally, knockdown of CtIP to similar levels reduced the ability of its interacting protein AdE1A to transactivate a luciferase reporter (46). In light of these reports, it seems less likely that residual protein levels are masking any expansion phenotype in our system.…”

Section: Resultsmentioning

confidence: 99%

MutSβ and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells

Gannon

Frizzell

Healy

et al. 2012

Nucleic Acids Research

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Trinucleotide repeat (TNR) expansions cause at least 17 heritable neurological diseases, including Huntington’s disease. Expansions are thought to arise from abnormal processing of TNR DNA by specific trans-acting proteins. For example, the DNA repair complex MutSβ (MSH2–MSH3 heterodimer) is required in mice for on-going expansions of long, disease-causing alleles. A distinctive feature of TNR expansions is a threshold effect, a narrow range of repeat units (∼30–40 in humans) at which mutation frequency rises dramatically and disease can initiate. The goal of this study was to identify factors that promote expansion of threshold-length CTG•CAG repeats in a human astrocytic cell line. siRNA knockdown of the MutSβ subunits MSH2 or MSH3 impeded expansions of threshold-length repeats, while knockdown of the MutSα subunit MSH6 had no effect. Chromatin immunoprecipitation experiments indicated that MutSβ, but not MutSα, was enriched at the TNR. These findings imply a direct role for MutSβ in promoting expansion of threshold-length CTG•CAG tracts. We identified the class II deacetylase HDAC5 as a novel promoting factor for expansions, joining the class I deacetylase HDAC3 that was previously identified. Double knockdowns were consistent with the possibility that MutSβ, HDAC3 and HDAC5 act through a common pathway to promote expansions of threshold-length TNRs.

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“…It has previously been shown that when CR3 is tethered to a promoter by fusion to the DNA binding domain (DBD) of GAL4, it can strongly activate transcription. Following CtBP1 and -2 knockdown using appropriate siRNAs (as previously described [8]), A549 cells were transfected with GAL4-DBD or GAL4-CR3 in the presence of a GAL4-responsive luciferase gene. After 24 h, luciferase activity was measured.…”

Section: Resultsmentioning

confidence: 99%

“…A549 cells were transfected using Lipofectamine 2000 (Invitrogen) for the small intefering RNA (siRNA) experiment. The primers used for reduction of CtBP expression were as previously described (8). Cells were transfected with the siRNAs using Lipofectamine and left for 3 days.…”

Section: Methodsmentioning

confidence: 99%

Identification of a Second CtBP Binding Site in Adenovirus Type 5 E1A Conserved Region 3

Bruton

Pelka

Mapp

et al. 2008

J Virol

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C-terminal binding protein (CtBP) binds to adenovirus early region 1A (AdE1A) through a highly conserved PXDLS motif close to the C terminus. We now have demonstrated that CtBP1 also interacts directly with the transcriptional activation domain (conserved region 3 [CR3]) of adenovirus type 5 E1A (Ad5E1A) and requires the integrity of the entire CR3 region for optimal binding. The interaction appears to be at least partially mediated through a sequence ( 161 RRNTGDP 167 ) very similar to a recently characterized novel CtBP binding motif in ZNF217 as well as other regions of CR3. Using reporter assays, we further demonstrated that CtBP1 represses Ad5E1A CR3-dependent transcriptional activation. Ad5E1A also appears to be recruited to the E-cadherin promoter through its interaction with CtBP. Significantly, Ad5E1A, CtBP1, and ZNF217 form a stable complex which requires CR3 and the PLDLS motif. It has been shown that Ad513SE1A, containing the CR3 region, is able to overcome the transcriptional repressor activity of a ZNF217 polypeptide fragment in a GAL4 reporter assay through recruitment of CtBP1. These results suggest a hitherto-unsuspected complexity in the association of Ad5E1A with CtBP, with the interaction resulting in transcriptional activation by recruitment of CR3-bound factors to CtBP1-containing complexes.

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C-terminal-binding protein interacting protein binds directly to adenovirus early region 1A through its N-terminal region and conserved region 3

Cited by 12 publications

References 46 publications

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

MutSβ and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells

Identification of a Second CtBP Binding Site in Adenovirus Type 5 E1A Conserved Region 3

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