Transcriptional control by adenovirus E1A conserved region 3 via p300/CBP

Pelka, Peter; Ablack, Jailal; Torchia, Joseph; Turnell, Andrew; Grand, Roger J. A.; Mymryk, Joe S.

doi:10.1093/nar/gkn1057

Cited by 47 publications

(84 citation statements)

References 49 publications

(52 reference statements)

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“…E1A utilizes its N-terminal region (residues 1-25) and residues within the CR1 region to bind CBP/p300 (13,(27)(28)(29)(30), although an additional weak interaction through CR3 has been reported (31). The regions of CR1 that bind CBP/p300 and pRb appear to be distinct and nonoverlapping (28).…”

mentioning

confidence: 99%

Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein

Ferreon

Martinez-Yamout²,

Dyson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

119

186

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The adenovirus early region 1A (E1A) oncoprotein mediates cell transformation by deregulating host cellular processes and activating viral gene expression by recruitment of cellular proteins that include cyclic-AMP response element binding (CREB) binding protein (CBP)/p300 and the retinoblastoma protein (pRb). While E1A is capable of independent interaction with CBP/p300 or pRb, simultaneous binding of both proteins is required for maximal biological activity. To obtain insights into the mechanism by which E1A hijacks the cellular transcription machinery by competing with essential transcription factors for binding to CBP/p300, we have determined the structure of the complex between the transcriptional adaptor zinc finger-2 (TAZ2) domain of CBP and the conserved region-1 (CR1) domain of E1A. The E1A CR1 domain is unstructured in the free state and upon binding folds into a local helical structure mediated by an extensive network of intermolecular hydrophobic contacts. By NMR titrations, we show that E1A efficiently competes with the N-terminal transactivation domain of p53 for binding to TAZ2 and that pRb interacts with E1A at 2 independent sites located in CR1 and CR2. We show that pRb and the CBP TAZ2 domain can bind simultaneously to the CR1 site of E1A to form a ternary complex and propose a structural model for the pRb:E1A:CBP complex on the basis of published x-ray data for homologous binary complexes. These observations reveal the molecular basis by which E1A inhibits p53-mediated transcriptional activation and provide a rationale for the efficiency of cellular transformation by the adenoviral E1A oncoprotein.CBP/p300 ͉ NMR ͉ protein structure ͉ transcriptional coactivator ͉ retinoblastoma protein T he adenovirus early region 1A (E1A) protein plays a central function in viral infection by activating genes required for viral replication and by deregulating the host cell cycle to force entry into S phase and repress differentiation (1-3). E1A deregulates the cell cycle through interactions with key cellular proteins, including the general transcriptional coactivators cyclic-AMP response element binding (CREB) binding protein (CBP) and p300 (4, 5) and the retinoblastoma protein (pRb) (6), which lead to epigenetic modifications and reprogramming of host cell transcriptional processes (7). Binding of E1A to pRb displaces the E2F transcription factors, thereby relieving E2F repression and resulting in premature S-phase entry and transcriptional activation of E2F-regulated genes (8-10). Association of E1A with CBP/p300 results in global hypoacetylation of K18 of histone H3 and may be linked to the ability of E1A to induce oncogenic transformation (11). E1A is a multifunctional protein (12) composed of 4 conserved regions (CR1-CR4, Fig. 1A). E1A uses both CR1 and CR2 for interaction with pRb (13,14). CR2 contains a characteristic pRb recognition motif, LX-CXE, which binds with high affinity to the B cyclin fold domain of the pRb pocket region (15, 16). The CR1 region of E1A binds at the interface of the A and B ...

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mentioning

confidence: 99%

Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein

Ferreon

Martinez-Yamout²,

Dyson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

119

186

View full text Add to dashboard Cite

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“…Expression vectors for human TBP (pcDNA4HA-hTBP) and hSug1 (pcDNA4HA-hSug1) were described previously (28). The p300 expression vector was described previously (27).…”

Section: Methodsmentioning

confidence: 99%

“…siRNA knockdown. Custom small interfering RNA (siRNA) against p300 was used as described previously (27). Silencer select siRNAs against TBP (s13826 siRNA) and hSug1 (s11381 siRNA) were purchased from Ambion.…”

Section: Methodsmentioning

confidence: 99%

“…E1A is a potent activator of transcription, and Ad5 E1A CR3 (residues 139 to 204) is sufficient to activate transcription when it is fused to a heterologous DBD in mammalian and yeast cells (26)(27)(28)(29)(30)34). We tested whether the corresponding E1A CR3 portions of Ad type 3, 4, 9, 12, and 40 E1A proteins, which represent E1A proteins from the other five Ad subgroups, were capable of activating transcription as Gal4-DBD fusions in the A549 human alveolar basal epithelial cell line (Fig.…”

Section: E1a Cr3-mediated Transactivation Differs Greatly Betweenmentioning

confidence: 99%

“…A second interaction site for the cellular repressor C-terminal binding protein (CtBP) was also mapped to the CR3 region of Ad5 E1A, and CtBP appears to repress E1A CR3 transactivation (7). The p300/ CREB binding protein (CBP) acetyltransferase is critical for Ad5 E1A CR3 transactivation and binds directly to E1A CR3 independently of other interaction motifs in E1A (27). Most recently, the histone acetyltransferase p300/CBP-associated factor (pCAF) was identified to interact with the E1A CR3 region and enhance transactivation (26).…”

mentioning

confidence: 99%

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Comparison of E1A CR3-Dependent Transcriptional Activation across Six Different Human Adenovirus Subgroups

Ablack

Pelka

Yousef

et al. 2010

J Virol

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The largest E1A isoform of human adenovirus (Ad) includes a C-4 zinc finger domain within conserved region 3 (CR3) that is largely responsible for activating transcription of the early viral genes. CR3 interacts with multiple cellular factors, but its mechanism of action is modeled primarily on the basis of the mechanism for the prototype E1A protein of human Ad type 5. We expanded this model to include a representative member from each of the six human Ad subgroups. All CR3 domains tested were capable of transactivation. However, there were dramatic differences in their levels of transcriptional activation. Despite these functional variations, the interactions of these representative CR3s with known cellular transcriptional regulators revealed only modest differences. Four common cellular targets of all representative CR3s were identified: the proteasome component human Sug1 (hSug1)/S8, the acetyltransferases p300/CREB binding protein (CBP), the mediator component mediator complex subunit 23 (MED23) protein, and TATA binding protein (TBP). The first three factors appear to be critical for CR3 function. RNA interference against human TBP showed no significant reduction in transactivation by any CR3 tested. These results indicate that the cellular factors previously shown to be important for transactivation by Ad5 CR3 are similarly bound by the E1A proteins of other types. This was confirmed experimentally using a transcriptional squelching assay, which demonstrated that the CR3 regions of each Ad type could compete with Ad5 CR3 for limiting factors. Interestingly, a mutant of Ad5 CR3 (V147L) was capable of squelching wild-type Ad5 CR3, despite its failure to bind TBP, MED23, p300/CBPassociated factor (pCAF), or p300/CBP, suggestive of the possibility that an additional as yet unidentified cellular factor is required for transactivation by E1A CR3.The adenovirus (Ad) E1A oncoprotein is the first gene expressed upon infection and performs two essential roles in order to initiate the viral replication cycle. E1A uncouples the cell cycle control program of the host cell, driving it into S phase to provide an optimal cellular environment for viral replication. This function can be carried out by the smaller major E1A isoform (243 residues in Ad type 5 [Ad5] E1A) (11,25). The other function of E1A is to activate transcription of the early viral promoters and is predominantly mediated by the largest E1A isoform (4,18,23,24). The largest E1A isoform, coding for 289 residues in Ad5 E1A, differs from the smaller isoform only by a unique 46-amino-acid C-4 zinc finger domain within conserved region 3 (CR3), which is essential for viral transactivation (4, 18). Single point mutations in CR3 were originally isolated as Ad mutants with a host range limited to HEK 293 cells, which supply wild-type (wt) E1A in trans. These "host range" mutations render E1A unable to transactivate viral promoters, thus preventing virus growth in cells at a low multiplicity of infection (MOI), unless wt E1A is supplied in trans (13,16).Transactiva...

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Adenovirus in the omics era – a multipronged strategy

2020

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Human adenoviruses (HAdVs) are common pathogens associated with a wide variety of respiratory, ocular, and gastrointestinal diseases. To achieve its effective lytic mode of replication, HAdVs have to reprogram host-cell gene expression and fine-tune viral gene expression in a temporal manner. In two decades, omics revolution has advanced our knowledge about the HAdV and host-cell interplay at the RNA and protein levels. This review summarizes the current knowledge from large-scale datasets on how HAdV infections adjust coding and noncoding RNA expression, as well as how they reprogram host-cell proteome during the lytic course of infection.

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Transcriptional control by adenovirus E1A conserved region 3 via p300/CBP

Cited by 47 publications

References 49 publications

Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein

Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein

Comparison of E1A CR3-Dependent Transcriptional Activation across Six Different Human Adenovirus Subgroups

Adenovirus in the omics era – a multipronged strategy

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