Phosphorylation at the carboxy terminus of the 55-kilodalton adenovirus type 5 E1B protein regulates transforming activity

Teodoro, Jose G.; Halliday, T; Whalen, Steve G.; Takayesu, D; Graham, Frank L.; Branton, Philip E.

doi:10.1128/jvi.68.2.776-786.1994

Cited by 55 publications

(54 citation statements)

References 74 publications

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“…1B to be defective in the 289R-dependent block in accumulation of p53. Clearly, both mutant 55-kDa proteins were able to form complexes with E4orf6 at normal levels, in agreement with the finding that they induce host cell shutoff normally (59). These results also indicated that complex formation between E4orf6 and p53 is not sufficient to induce a reduction in p53 levels and that inhibition of p53 transactivation activity may be necessary.…”

Section: Fig 5 Analysis Of P53 Accumulation and E4orf6 Expression Isupporting

confidence: 87%

“…However, three observations argued strongly that generalized shutoff of host protein synthesis induced by complexes of E4orf6 and 55-kDa protein plays little or no role in the block in p53 accumulation. The first was that mutants pm490/1A and pm490/1/5A, which encode 55-kDa proteins lacking two or all three of the carboxy-terminal phosphorylation sites, fail to prevent the rise in p53 levels even though these mutant E1B products induce host cell shutoff effectively (59). Second, generalized host cell shutoff in infected 293 cells started over 7 h after the beginning of the decline in p53 levels.…”

Section: Discussionmentioning

confidence: 99%

“…Mutant E1B/55K Ϫ (originally pm2019/2250) fails to express the E1B 55-kDa protein, and mutant E1B/19K Ϫ (originally pm1716/2072) does not express the E1B 19-kDa polypeptide (36). Additional E1B 55-kDa protein mutants included pm490/1A and pm490/1/5A, which contain alanine residues in place of the Ser-490, Ser-491, and Thr-495 phosphorylation sites, thus reducing transforming and transcriptional repression activities and the ability to inhibit p53 activity but not affecting complex formation with p53 (58,59), and mutants A262 and R309, which contain insertions next to residues 262 and 309 which block interactions with p53 (28,65). E1A and E1B mutant viruses were propagated on 293 cells.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…Studies were also conducted with mutants pm490/1A and pm490/1/5A, which contain Ala residues in place of the Ser-490, Ser-491, and Thr-495 phosphorylation sites of the E1B 55-kDa species. These alterations have been found to diminish cell transformation dependent on the 55-kDa protein, reduce its ability to inhibit p53 activation activity, and eliminate its transcriptional repression activity without affecting the efficiency of binding to p53 or the induction of host cell shutoff (58,59). The precise role of phosphorylation in the regulation of these functions has still not been established.…”

Section: Expression Of the 243r But Not The 289r E1a Protein Induces mentioning

confidence: 99%

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Regulation of p53 levels by the E1B 55-kilodalton protein and E4orf6 in adenovirus-infected cells

Querido

Marcellus

Lai

et al. 1997

J Virol

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216

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The adenovirus type 5 243R E1A protein induces p53-dependent apoptosis in the absence of the 19-and 55-kDa E1B polypeptides. This effect appears to result from an accumulation of p53 protein and is unrelated to expression of E1B products. We now report that in the presence of the E1B 55-kDa polypeptide, the 289R E1A protein does not induce such p53 accumulation and, in fact, is able to block that induced by E1A 243R. This inhibition also requires the 289R-dependent transactivation of E4orf6 expression. E4orf6 is known to form complexes with the E1B 55-kDa protein and to function both in the transport and stabilization of viral mRNA and in shutoff of host cell protein synthesis. We demonstrated that the block in p53 accumulation is not due to the generalized shutoff of host cell metabolism. Rather, it appears to result from a mechanism targeted specifically to p53, most likely involving a decrease in the stability of p53 protein. The E1B 55-kDa protein is known to interact with both E4orf6 and p53, and as demonstrated recently by others, we showed that E4orf6 also binds directly to p53. Thus, multiple interactions between all three proteins may regulate p53 stability, resulting in the maintenance of low levels of p53 following virus infection.

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Section: Fig 5 Analysis Of P53 Accumulation and E4orf6 Expression Isupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Cells and Virusesmentioning

confidence: 99%

Section: Expression Of the 243r But Not The 289r E1a Protein Induces mentioning

confidence: 99%

See 2 more Smart Citations

Regulation of p53 levels by the E1B 55-kilodalton protein and E4orf6 in adenovirus-infected cells

Querido

Marcellus

Lai

et al. 1997

J Virol

Self Cite

216

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“…E1B from HAdV5 undergoes SUMOylation at lysine 104 and phosphorylation at the C‐terminal serine 490, serine 491, and threonine 495 (Fig A). Covalent addition of SUMO modulates protein–protein interactions, protein stability, and localization, and regulates many cellular processes, including DNA repair, antiviral responses, and tumor suppression .…”

Section: Structural and Functional Features Of E1b 55kmentioning

confidence: 99%

The biology of the adenovirus E1B 55K protein

Hidalgo

Dobner

et al. 2019

FEBS Letters

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The adenovirus E1B 55K (E1B) protein plays major roles in productive adenoviral infection and cellular transformation. Interest in E1B increased because of the potential of adenoviruses as therapeutic vectors, and the E1B gene is commonly deleted from adenovirus vectors for anticancer therapy. E1B activities are spatiotemporally regulated through SUMOylation and phosphorylation, and through interactions with multiple partners that occur presumably at different intracellular sites and times postinfection. E1B is implicated in the formation of viral replication compartments and regulates viral genome replication and transcription, transcriptional repression, degradation of cellular proteins, and several intranuclear steps of viral late mRNA biogenesis. Here, we review advances in our understanding of E1B during productive adenovirus replication and discuss fundamental aspects that remain unresolved.The adenovirus E1B 55K protein (called E1B throughout this review) plays key roles during productive viral replication and contributes to oncogenic transformation. The E1B gene is usually deleted or modified in oncolytic adenoviruses because such viruses preferentially replicate in and kill cancer cells (reviewed in [1,2]). Although structural data for the 496 amino acid (aa) polypeptide are scarce, some structural or functional motifs are known or have been proposed, and the E1B protein may contain intrinsically disordered regions (IDR). E1B activities are regulated by posttranslational modifications (PTMs) that impact on both intracellular localization and the interactions that E1B establishes with viral and cellular proteins. E1B acts as a small ubiquitin-like modifier (SUMO)-1 ligase for p53 and participates in the polyubiquitylation-induced degradation of cellular targets that would otherwise interfere with viral replication. E1B also promotes viral replication through repression of interferon (IFN)-stimulated genes (ISG) and p53 regulation. Of note, efficient viral DNA replication depends on the formation of adenoviral replication compartments (RCs), another process in which E1B is involved. Furthermore, E1B interacts with viral RNA and this interaction optimizes production and splicing of viral late mRNAs. Yet, many aspects of the biology of E1B remain to be elucidated, including the protein's threedimensional structure and the molecular mechanisms whereby E1B regulates viral genome replication and gene expression. Most of the knowledge of E1B comes from the study of the human serotypes 2 and 5 from species C; however, sequences and functional features from other adenovirus species have also been described. A very complete review of the E1B protein Abbreviations CRM1, chromosome region maintenance 1 protein homolog; CDK, cyclin-dependent kinase; E1B-AP5, E1B-associated protein 5; eIF4E, eukaryotic translation initiation factor 4E; hnRNP, heteronuclear ribonucleoprotein; LH3, hexon-interlacing protein LH3; I-TASSER, iterative threading ASSEmbly refinement; Mre11, meiotic recombination 11; Nxf1/Tap, nuclear RNA expo...

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transE1 Component Requirements for Maximal Replication of E1-Defective Recombinant Adenovirus

et al. 1998

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Strategies that enable E1-defective recombinant adenoviruses to selectively undergo replication in neoplastic tissue may be useful for future investigations or therapies of malignancies. A growing body of evidence suggests that some molecular alterations commonly associated with malignancies, such as p53 mutations, can modify the specific E1 requirements for replication of human serotype adenoviruses. In the studies reported here, a panel of human non-small cell lung cancer cell lines with previously defined p53 status were characterized for basal interleukin-6 (IL-6) and bcl-2 content because previous studies have indicated both proteins can functionally substitute for the replication requirements provided by native E1 viral proteins. Cell lines were infected with E1-defective adenovirus 5 and simultaneously transfected with different combinations of E1 plasmids, or a bcl-2 expression plasmid, and adenovirus present in the cells was quantified 6 days later. These assays demonstrated that E1A with both 19- and 55-kDa E1B-encoding plasmids were required for maximal adenoviral replication, independent of the varying p53/IL-6/basal bcl-2 phenotypes of the host cell lines. E1A was required for maximal replication enablement, independent of the basal IL-6 content of these cell lines, and exogenous IL-6 also did not obviate the E1A requirement. Interestingly, the bcl-2 expression plasmid did not consistently substitute for the 19-kDa expression plasmid in the context of this replication complementation assay. These results suggest that (1) basal levels of IL-6 greater than that present in these cell lines are necessary for functional replacement of the E1A replication function and (2) bcl-2 does not predictably substitute for the 19-kDa E1B replication function in the context of trans complementation.

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Phosphorylation at the carboxy terminus of the 55-kilodalton adenovirus type 5 E1B protein regulates transforming activity

Cited by 55 publications

References 74 publications

Regulation of p53 levels by the E1B 55-kilodalton protein and E4orf6 in adenovirus-infected cells

Regulation of p53 levels by the E1B 55-kilodalton protein and E4orf6 in adenovirus-infected cells

The biology of the adenovirus E1B 55K protein

transE1 Component Requirements for Maximal Replication of E1-Defective Recombinant Adenovirus

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