The Significance of the CtBP — AdE1A Interaction during Viral Infection and Transformation

Grand, Roger J. A.; Baker, Claire; Barral, Paola M.; Bruton, Rachel; Parkhill, Julian; Szestak, Tadge; Gallimore, Phillip H.

doi:10.1007/978-0-387-39973-7_5

Cited by 5 publications

(4 citation statements)

References 45 publications

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“…The change in epithelialness may provide more suitable cellular environment for HAdv5 replication. Both scenarios may be consistent with a previous observation that siRNA-mediated depletion of CtBP1/2 resulted in enhanced viral replication in human cells (Grand et al, 2007)). Our results suggest that CtBP2 depletion enhances viral replication (Fig.…”

Section: Discussionsupporting

confidence: 93%

Interaction of CtBP with adenovirus E1A suppresses immortalization of primary epithelial cells and enhances virus replication during productive infection

2013

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Adenovirus E1A induces cell proliferation, oncogenic transformation and promotes viral replication through interaction with p300/CBP, TRRAP/p400 multi-protein complex and the retinoblastoma (pRb) family proteins through distinct domains in the E1A N-terminal region. The C-terminal region of E1A suppresses E1A/Ras co-transformation and interacts with FOXK1/K2, DYRK1A/1B/HAN11 and CtBP1/2 (CtBP) protein complexes. To specifically dissect the role of CtBP interaction with E1A, we engineered a mutation (DL→AS) within the CtBP-binding motif, PLDLS, and investigated the effect of the mutation on immortalization and Ras cooperative transformation of primary cells and viral replication. Our results suggest that CtBP-E1A interaction suppresses immortalization and Ras co-operative transformation of primary rodent epithelial cells without significantly influencing the tumorigenic activities of transformed cells in immunodeficient and immunocompetent animals. During productive infection, CtBP-E1A interaction enhances viral replication in human cells. Between the two CtBP family proteins, CtBP2 appears to restrict viral replication more than CtBP1 in human cells.

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Section: Discussionsupporting

confidence: 93%

Interaction of CtBP with adenovirus E1A suppresses immortalization of primary epithelial cells and enhances virus replication during productive infection

2013

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“…This interaction appears to facilitate viral infection (28). In transformation assays, it has been shown that the effect of CtBP's interaction with AdE1A is context dependent, such that loss of CtBP binding increases the frequency of transformation by mutant AdE1A and activated ras whereas frequency of transformation by AdE1A and AdE1B is markedly reduced (6,18,51,52).…”

mentioning

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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“…28 Indeed, CtBP2 has been previously identified as an adenoviral limiting factor. 29,30 Furthermore, KLF8 recruits p300 and PCAF co-activators to promoters. 31 To promote productive virus infection, E1A removes CtBP2 from repressed promoters, sequesters p300 from transcriptional active regions, and redirects it together with Rb to selected host genes, thereby repressing their expression.…”

Section: Discussionmentioning

confidence: 99%

“…31 To promote productive virus infection, E1A removes CtBP2 from repressed promoters, sequesters p300 from transcriptional active regions, and redirects it together with Rb to selected host genes, thereby repressing their expression. 29,32 In those cases, high levels of KLF8 might compete with E1A and lead to reduced adenoviral yields. ELF4 is an ETS transcription factor that becomes activated during the antiviral response and in cells with oncogenic Ras.…”

Section: Discussionmentioning

confidence: 99%

Bioselection Reveals miR-99b and miR-485 as Enhancers of Adenoviral Oncolysis in Pancreatic Cancer

et al. 2019

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Oncolytic viruses are designed for cancer treatment. Cell-virus interactions are key determinants for successful viral replication. Therefore, the extensive reprogramming of gene expression that occurs in tumor cells might create a hurdle for viral propagation. We used a replication-based approach of a microRNA (miRNA) adenoviral library encoding up to 243 human miRNAs as a bioselection strategy to identify miRNAs that facilitate adenoviral oncolytic activity in pancreatic ductal adenocarcinoma. We identify two miRNAs, miR-99b and miR-485, that function as enhancers of adenoviral oncolysis by improving the intra-and extracellular yield of mature virions. An increased adenoviral activity is the consequence of enhanced E1A and late viral protein expression, which is probably mediated by the downregulation of the transcriptional repressors ELF4, MDM2, and KLF8, which we identify as miR-99b or miR-485 target genes. Arming the oncolytic adenovirus ICOVIR15 with miR-99b or miR-485 enhances its fitness and its antitumoral activity. Our results demonstrate the potential of this strategy to improve oncolytic adenovirus potency, and they highlight miR-99b and miR-485 as sensitizers of adenoviral replication.

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The Significance of the CtBP — AdE1A Interaction during Viral Infection and Transformation

Cited by 5 publications

References 45 publications

Interaction of CtBP with adenovirus E1A suppresses immortalization of primary epithelial cells and enhances virus replication during productive infection

Interaction of CtBP with adenovirus E1A suppresses immortalization of primary epithelial cells and enhances virus replication during productive infection

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

Bioselection Reveals miR-99b and miR-485 as Enhancers of Adenoviral Oncolysis in Pancreatic Cancer

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