Adenovirus Small E1A Employs the Lysine Acetylases p300/CBP and Tumor Suppressor Rb to Repress Select Host Genes and Promote Productive Virus Infection

Ferrari, Roberto; Gou, Dawei; Jawdekar, Gauri W.; Johnson, Sarah A.; Nava, Miguel; Su, Trent; Yousef, Ahmed F.; Zemke, Nathan R.; Pellegrini, Matteo; Kurdistani, Siavash K.; Berk, Arnold

doi:10.1016/j.chom.2014.10.004

Cited by 95 publications

(155 citation statements)

References 55 publications

(84 reference statements)

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“…Currently, there is surprisingly little information about precisely which genomic loci are controlled directly and specifically by pRB. The genomic distribution of pRB varies between cycling, quiescent, and senescent cells (Wells et al 2003;Chicas et al 2010;Ferrari et al 2014;Kareta et al 2015). It is uncertain what proportion of pRB is bound directly at E2F-regulated promoters or whether this is the most functionally relevant population of the protein, and it is unclear which or how many E2F-regulated promoters are truly rate-limiting for pRB-mediated control of cell proliferation.…”

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confidence: 99%

RB1: a prototype tumor suppressor and an enigma

2016

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The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?

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RB1: a prototype tumor suppressor and an enigma

2016

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“…The N-terminal 80-amino-acid region of E1A, which includes a conserved domain (CR1), interacts with p300/CBP lysine acetyl transferases (5). In cells infected with human adenovirus 5 (hAd5), E1A expression resulted in quantitative sequestration of these acetyl transferases by E1A, resulting in massive deacetylation of histone H3 Lys18 (H3K18Ac) (6), and also targeted the E1A-pRB repressive complex to a battery of cellular genes that normally inhibit viral replication (7). However, the precise role of E1A-p300/CBP interaction in cell transformation still remains unclear.…”

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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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“…Therefore, Rb does not appear to be a suppressor of adenovirus. In fact, during adenoviral infection, Rb-E2F1 complexes selectively remain intact (25), and recently E1A-Rb complexes were demonstrated to suppress the transcription of genes with antiviral functions in adenovirus-infected cells (26). Thus, Rb might contribute to adenovirus infection in a positive way, although this remains to be determined through knockdown or knockout studies.…”

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The Retinoblastoma Tumor Suppressor Promotes Efficient Human Cytomegalovirus Lytic Replication

VanDeusen

Kalejta

2015

J Virol

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The retinoblastoma (Rb) tumor suppressor controls cell cycle, DNA damage, apoptotic, and metabolic pathways. DNA tumor virus oncoproteins reduce Rb function by either inducing Rb degradation or physically disrupting complexes between Rb and its myriad binding proteins. Human cytomegalovirus (HCMV), a betaherpesvirus being investigated for potential roles in human cancers, encodes multiple lytic-phase proteins that inactivate Rb in distinct ways, leading to the hypothesis that reduced Rb levels and/or activity would benefit HCMV lytic infection. Paradoxically, we found that Rb knockdown prior to infection, whether transient or constitutive, impaired HCMV lytic infection at multiple stages, notably viral DNA replication, late protein expression, and infectious virion production. The existence of differentially modified forms of Rb, the temporally and functionally distinct means by which HCMV proteins interact with Rb, and the necessity of Rb for efficient HCMV lytic replication combine to highlight the complex relationship between the virus and this critical tumor suppressor. T he retinoblastoma (Rb) protein is a tumor suppressor (1, 2). Loss of both Rb alleles predisposes patients to the development of cancer (3). Rb, through its association with more than 200 other cellular proteins (4), controls pathways that regulate cell cycle progression, DNA repair, apoptosis, and energy metabolism, all of which are intimately involved in oncogenic transformation and tumor cell survival (5-7). Most, if not all, human tumors have defects (mutations) in one or more components of the pathways controlled by Rb (8).The unphosphorylated or hypophosphorylated form of Rb is generally considered the active form of the protein (9). Hypophosphorylated Rb interacts with many cellular proteins, including a critical association with the E2F family of transcription factors (10). E2F transcription factors control the expression of many genes required for cell cycle progression, and Rb binding inhibits E2F-dependent transcription (11). Rb binding to E2F protects cells from untimely progression through the cell cycle and prevents E2F-mediated oncogenic transformation (12, 13). During normal cell cycle progression, a series of cellular cyclin-dependent kinases (Cdks) phosphorylate Rb, converting it into a fully phosphorylated form, termed hyperphosphorylated Rb. This form is considered inactive (14), although it may retain some unrecognized function (15). Hyperphosphorylated Rb no longer binds E2F and thus permits E2F-dependent transcription and cell cycle progression (10). Recently, Cdk-dependent monophosphorylation of Rb has been reported (16), but the physiological relevance of this is unknown. Rb can also be acetylated, methylated, SUMOylated, ubiquitinated, and phosphorylated on non-Cdkmediated sites in response to stimuli that may activate non-cellcycle-associated functions of Rb (17).In addition to being a tumor suppressor, Rb might also be a "virus suppressor," at least for the DNA tumor virus human papillomavirus (HPV). The H...

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Adenovirus Small E1A Employs the Lysine Acetylases p300/CBP and Tumor Suppressor Rb to Repress Select Host Genes and Promote Productive Virus Infection

Cited by 95 publications

References 55 publications

RB1: a prototype tumor suppressor and an enigma

RB1: a prototype tumor suppressor and an enigma

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

The Retinoblastoma Tumor Suppressor Promotes Efficient Human Cytomegalovirus Lytic Replication

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