adenovirus e4 proteins


Summary: Proteins transcribed from the E4 region of ADENOVIRUSES. The E4 19K protein transactivates transcription of the adenovirus E2F protein and complexes with it.

Top Publications

  1. Shepard R, Ornelles D. Diverse roles for E4orf3 at late times of infection revealed in an E1B 55-kilodalton protein mutant background. J Virol. 2004;78:9924-35 pubmed
    ..Finally, within the context of an E1B-55K mutant virus, the E4orf3 protein acts to suppress host cell translation and preserve the viability of cells at moderately late times of infection. ..
  2. Schreiner S, Bürck C, Glass M, Groitl P, Wimmer P, Kinkley S, et al. Control of human adenovirus type 5 gene expression by cellular Daxx/ATRX chromatin-associated complexes. Nucleic Acids Res. 2013;41:3532-50 pubmed publisher
    ..We show for the first time that cellular Daxx/ATRX chromatin remodelling complexes play essential roles in Ad gene expression and illustrate the importance of early viral proteins to counteract cellular chromatin remodelling. ..
  3. Cheng C, Gilson T, Dallaire F, Ketner G, Branton P, Blanchette P. The E4orf6/E1B55K E3 ubiquitin ligase complexes of human adenoviruses exhibit heterogeneity in composition and substrate specificity. J Virol. 2011;85:765-75 pubmed publisher
  4. Weitzman M. Functions of the adenovirus E4 proteins and their impact on viral vectors. Front Biosci. 2005;10:1106-17 pubmed
    ..This review will summarize our knowledge of E4 functions and the implications of recent findings on the development of rAd vectors. ..
  5. Seandel M, Butler J, Kobayashi H, Hooper A, White I, Zhang F, et al. Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene. Proc Natl Acad Sci U S A. 2008;105:19288-93 pubmed publisher
  6. Havenga M, Vogels R, Zuijdgeest D, Radosevic K, Mueller S, Sieuwerts M, et al. Novel replication-incompetent adenoviral B-group vectors: high vector stability and yield in PER.C6 cells. J Gen Virol. 2006;87:2135-43 pubmed
    ..It is concluded that the described improvements to the rAd35 vector contribute significantly to the further development of rAd35 carriers for mass-vaccination programmes for diseases such as tuberculosis, AIDS and malaria. ..
  7. Querido E, Morrison M, Chu Pham Dang H, Thirlwell S, Boivin D, Branton P, et al. Identification of three functions of the adenovirus e4orf6 protein that mediate p53 degradation by the E4orf6-E1B55K complex. J Virol. 2001;75:699-709 pubmed
    ..Thus, this study implies that the E4orf6-E1B55K complex may direct p53 for degradation by a novel mechanism. ..
  8. Tauber B, Dobner T. Adenovirus early E4 genes in viral oncogenesis. Oncogene. 2001;20:7847-54 pubmed
    ..Here, we summarize the recent data and discuss how E4 gene product interactions may contribute to viral oncogenesis. ..
  9. Rathod M, Vangipuram S, Krishnan B, Heydari A, Holland T, Dhurandhar N. Viral mRNA expression but not DNA replication is required for lipogenic effect of human adenovirus Ad-36 in preadipocytes. Int J Obes (Lond). 2007;31:78-86 pubmed
    ..The objective of this study was to determine the adipogenic roles of viral mRNA and DNA, which may explain the differential effects of Ad-36 and Ad-2 on preadipocyte differentiation...

More Information


  1. Maoz T, Koren R, Ben Ari I, Kleinberger T. YND1 interacts with CDC55 and is a novel mediator of E4orf4-induced toxicity. J Biol Chem. 2005;280:41270-7 pubmed
    ..NTPDase-4/Lalp70/UDPase, the closest mammalian homologue of Ynd1p, associated with E4orf4 in mammalian cells, suggesting that the results in yeast are relevant to the mammalian system. ..
  2. Ullman A, Hearing P. Cellular proteins PML and Daxx mediate an innate antiviral defense antagonized by the adenovirus E4 ORF3 protein. J Virol. 2008;82:7325-35 pubmed publisher
    ..We propose that, in addition to its ability to repress gene expression, the PML-NB participates in additional innate immune activities...
  3. Cherubini G, Petouchoff T, Grossi M, Piersanti S, Cundari E, Saggio I. E1B55K-deleted adenovirus (ONYX-015) overrides G1/S and G2/M checkpoints and causes mitotic catastrophe and endoreduplication in p53-proficient normal cells. Cell Cycle. 2006;5:2244-52 pubmed
  4. Querido E, Blanchette P, Yan Q, Kamura T, Morrison M, Boivin D, et al. Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex. Genes Dev. 2001;15:3104-17 pubmed
    ..E4orf6/E1B55K failed to induce the degradation of p53 at the nonpermissive temperature. Thus, our results identify a novel role for the Cullin-based machinery in regulation of p53. ..
  5. Dhurandhar E, Dubuisson O, Mashtalir N, Krishnapuram R, Hegde V, Dhurandhar N. E4orf1: a novel ligand that improves glucose disposal in cell culture. PLoS ONE. 2011;6:e23394 pubmed publisher
    ..Thus, the highly attractive anti-hyperglycemic effect of Ad36 is mirrored by E4orf1 protein, which may offer a novel ligand to develop anti-hyperglycemic drugs. ..
  6. Mohammadi E, Ketner E, Johns D, Ketner G. Expression of the adenovirus E4 34k oncoprotein inhibits repair of double strand breaks in the cellular genome of a 293-based inducible cell line. Nucleic Acids Res. 2004;32:2652-9 pubmed
    ..Consistent with this, induction of expression of E4 34k in the inducible cell line also reduces the steady state level of Mre11 protein. ..
  7. Araujo F, Stracker T, Carson C, Lee D, Weitzman M. Adenovirus type 5 E4orf3 protein targets the Mre11 complex to cytoplasmic aggresomes. J Virol. 2005;79:11382-91 pubmed
    ..These data suggest that E4orf3 can target the Mre11 complex to an aggresome and may explain how the cellular repair complex is inactivated during adenovirus infection. ..
  8. Thomas D, Schaack J, Vogel H, Javier R. Several E4 region functions influence mammary tumorigenesis by human adenovirus type 9. J Virol. 2001;75:557-68 pubmed
  9. Gupta A, Jha S, Engel D, Ornelles D, Dutta A. Tip60 degradation by adenovirus relieves transcriptional repression of viral transcriptional activator EIA. Oncogene. 2013;32:5017-25 pubmed publisher
    ..Thus, degradation of Tip60 by the adenoviral early proteins is important for efficient viral early gene transcription and for changes in expression of cellular genes. ..
  10. Mannervik M, Fan S, Ström A, Helin K, Akusjarvi G. Adenovirus E4 open reading frame 4-induced dephosphorylation inhibits E1A activation of the E2 promoter and E2F-1-mediated transactivation independently of the retinoblastoma tumor suppressor protein. Virology. 1999;256:313-21 pubmed
    ..Interestingly, E4-ORF4 did not inhibit the transactivation capacity of a Gal4-E2F hybrid protein. Instead, E4-ORF4 expression appears to result in reduced stability of E2F/DNA complexes. ..
  11. Evans J, Hearing P. Relocalization of the Mre11-Rad50-Nbs1 complex by the adenovirus E4 ORF3 protein is required for viral replication. J Virol. 2005;79:6207-15 pubmed
    ..These results illustrate the importance of nuclear organization in virus growth and suggest that E4 ORF3 regulates activities in both PML nuclear bodies and the MRN complex to stimulate the viral replication program. ..
  12. Dallaire F, Blanchette P, Groitl P, Dobner T, Branton P. Identification of integrin alpha3 as a new substrate of the adenovirus E4orf6/E1B 55-kilodalton E3 ubiquitin ligase complex. J Virol. 2009;83:5329-38 pubmed publisher
    ..e., very late activation antigen 3 alpha subunit). Preliminary analyses suggested that degradation of alpha3 may play a role in promoting release and spread of progeny virions. ..
  13. Li X, Zhang Y, Kim H, Bae K, Stantz K, Lee S, et al. Gene therapy for prostate cancer by controlling adenovirus E1a and E4 gene expression with PSES enhancer. Cancer Res. 2005;65:1941-51 pubmed
    ..These data show that adenoviral replication can be tightly controlled in a novel fashion by controlling adenoviral E1a and E4 genes simultaneously with a single enhancer. ..
  14. Orazio N, Naeger C, Karlseder J, Weitzman M. The adenovirus E1b55K/E4orf6 complex induces degradation of the Bloom helicase during infection. J Virol. 2011;85:1887-92 pubmed publisher
    ..We detected BLM localized at discrete foci around viral replication centers. These studies identify BLM as a new substrate for degradation by the adenovirus E1b55K/E4orf6 complex. ..
  15. Rafii S, Dias S, Meeus S, Hattori K, Ramachandran R, Feuerback F, et al. Infection of endothelium with E1(-)E4(+), but not E1(-)E4(-), adenovirus gene transfer vectors enhances leukocyte adhesion and migration by modulation of ICAM-1, VCAM-1, CD34, and chemokine expression. Circ Res. 2001;88:903-10 pubmed
    ..inflammatory responses by upregulating expression of adhesion molecules and enhancing migration through Advector-infected ECs and suggest that E1(-)E4(-) Advectors may be a better choice for gene-transfer strategies directed to the ECS: ..
  16. Dhurandhar E, Krishnapuram R, Hegde V, Dubuisson O, Tao R, Dong X, et al. E4orf1 improves lipid and glucose metabolism in hepatocytes: a template to improve steatosis & hyperglycemia. PLoS ONE. 2012;7:e47813 pubmed publisher
    ..Elucidating the underlying molecular mechanism may help develop therapeutic approaches for treating diabetes or non-alcoholic fatty liver disease(NAFLD). ..
  17. Lavoie J, Nguyen M, Marcellus R, Branton P, Shore G. E4orf4, a novel adenovirus death factor that induces p53-independent apoptosis by a pathway that is not inhibited by zVAD-fmk. J Cell Biol. 1998;140:637-45 pubmed
  18. Frese K, Lee S, Thomas D, Latorre I, Weiss R, Glaunsinger B, et al. Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein. Oncogene. 2003;22:710-21 pubmed
    ..From these results, we propose that the transforming and tumorigenic potentials of the adenovirus E4-ORF1 oncoprotein depend on its capacity to activate PI3K through a novel PDZ protein-dependent mechanism of action. ..
  19. Evans J, Hearing P. Distinct roles of the Adenovirus E4 ORF3 protein in viral DNA replication and inhibition of genome concatenation. J Virol. 2003;77:5295-304 pubmed
    ..This function is distinct from the role of E4 ORF3 in the regulation of virus genome concatenation via inhibition of cellular double-strand break repair. ..
  20. Flint S, Gonzalez R. Regulation of mRNA production by the adenoviral E1B 55-kDa and E4 Orf6 proteins. Curr Top Microbiol Immunol. 2003;272:287-330 pubmed
    ..However, it should now be possible to address specific questions about the roles of potentially relevant properties of these viral proteins. ..
  21. Sohn S, Hearing P. Adenovirus regulates sumoylation of Mre11-Rad50-Nbs1 components through a paralog-specific mechanism. J Virol. 2012;86:9656-65 pubmed publisher
    ..Our findings suggest how E4-ORF3-mediated relocalization of the MRN complex influences the cellular DNA damage response. ..
  22. Nevels M, Tauber B, Spruss T, Wolf H, Dobner T. "Hit-and-run" transformation by adenovirus oncogenes. J Virol. 2001;75:3089-94 pubmed
    ..Our results strongly support the possibility that even tumors that lack any detectable virus-specific molecules can be of viral origin, which could have a significant impact on the use of adenoviral vectors for gene therapy. ..
  23. Kaplan J, Armentano D, Scaria A, Woodworth L, Pennington S, Wadsworth S, et al. Novel role for E4 region genes in protection of adenovirus vectors from lysis by cytotoxic T lymphocytes. J Virol. 1999;73:4489-92 pubmed
    ..Elements from both the E3 and the E4 regions were required for this effect, leading to the identification of a previously undescribed role for E4 gene products in resistance to cytolysis. ..
  24. O SHEA C, Klupsch K, Choi S, Bagus B, Soria C, Shen J, et al. Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication. EMBO J. 2005;24:1211-21 pubmed
    ..These data reveal that adenovirus has evolved proteins that activate the mTOR pathway, irrespective of the cellular microenvironment, and which play a requisite role in viral replication. ..
  25. Cheng C, Gilson T, Wimmer P, Schreiner S, Ketner G, Dobner T, et al. Role of E1B55K in E4orf6/E1B55K E3 ligase complexes formed by different human adenovirus serotypes. J Virol. 2013;87:6232-45 pubmed publisher
  26. Cheng C, Blanchette P, Branton P. The adenovirus E4orf6 E3 ubiquitin ligase complex assembles in a novel fashion. Virology. 2007;364:36-44 pubmed
    ..Thus E4orf6 appears to utilize a different mechanism for Cul5 selection, and, both in terms of interactions with Elongin B and C and with Cul5, assembles the E3 ligase complex in a highly novel fashion. ..
  27. Nevels M, Rubenwolf S, Spruss T, Wolf H, Dobner T. The adenovirus E4orf6 protein can promote E1A/E1B-induced focus formation by interfering with p53 tumor suppressor function. Proc Natl Acad Sci U S A. 1997;94:1206-11 pubmed
    ..Our data demonstrate that adenovirus type 5 encodes two different proteins, E1B-55kDa and E4orf6, that bind to p53 and contribute to transformation by modulating p53 transcriptional functions. ..
  28. Stracker T, Lee D, Carson C, Araujo F, Ornelles D, Weitzman M. Serotype-specific reorganization of the Mre11 complex by adenoviral E4orf3 proteins. J Virol. 2005;79:6664-73 pubmed
    ..These results reveal surprising differences among the highly conserved E4orf3 proteins from different serotypes in the ability to disrupt the Mre11 complex. ..
  29. Banerjee N, Rivera A, Wang M, Chow L, Broker T, Curiel D, et al. Analyses of melanoma-targeted oncolytic adenoviruses with tyrosinase enhancer/promoter-driven E1A, E4, or both in submerged cells and organotypic cultures. Mol Cancer Ther. 2004;3:437-49 pubmed
    ..These studies also demonstrate that organotypic cultures derived from mixtures of tumor and normal cells represent a promising new model for analysis of CRAd specificity and toxicity. ..
  30. Champagne C, Landry M, Gingras M, Lavoie J. Activation of adenovirus type 2 early region 4 ORF4 cytoplasmic death function by direct binding to Src kinase domain. J Biol Chem. 2004;279:25905-15 pubmed
    ..Nonetheless, both Src and PP2A enzymes are critical targets of E4orf4 that likely cooperate to trigger E4orf4-induced tumor cell killing and whose relative contributions may vary in function of the cellular background. ..
  31. Aoyagi M, Higashino F, Yasuda M, Takahashi A, Sawada Y, Totsuka Y, et al. Nuclear export of adenovirus E4orf6 protein is necessary for its ability to antagonize apoptotic activity of BH3-only proteins. Oncogene. 2003;22:6919-27 pubmed
    ..These results suggest that E4orf6 is exported from the nucleus to the cytoplasm, enabling it to interact with BH3-only proteins, eventually leading to the inhibition of apoptotic activity. ..
  32. Ullman A, Reich N, Hearing P. Adenovirus E4 ORF3 protein inhibits the interferon-mediated antiviral response. J Virol. 2007;81:4744-52 pubmed
    ..We propose that the evolutionarily conserved function of the adenovirus E4 ORF3 protein is the inhibition of a host interferon response to viral infection via disruption of the PML oncogenic domain. ..
  33. Baker A, Rohleder K, Hanakahi L, Ketner G. Adenovirus E4 34k and E1b 55k oncoproteins target host DNA ligase IV for proteasomal degradation. J Virol. 2007;81:7034-40 pubmed
  34. Tauber B, Dobner T. Molecular regulation and biological function of adenovirus early genes: the E4 ORFs. Gene. 2001;278:1-23 pubmed
    ..Finally, we will discuss their role in Ad vector and adeno-associated virus infections. ..
  35. Stracker T, Carson C, Weitzman M. Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature. 2002;418:348-52 pubmed
    ..This targeting of cellular proteins involved in genomic stability suggests a mechanism for 'hit-and-run' transformation observed for these viral oncoproteins. ..
  36. Hernandez Alcoceba R, Pihalja M, Qian D, Clarke M. New oncolytic adenoviruses with hypoxia- and estrogen receptor-regulated replication. Hum Gene Ther. 2002;13:1737-50 pubmed
    ..These data indicate that the simultaneous regulation of E1A and E4 viral transcription units by the appropriate combination of promoters can increase the tumor selectivity of oncolytic adenoviruses. ..
  37. Harada J, Shevchenko A, Shevchenko A, Pallas D, Berk A. Analysis of the adenovirus E1B-55K-anchored proteome reveals its link to ubiquitination machinery. J Virol. 2002;76:9194-206 pubmed
    ..Lastly, we describe the identification and characterization of two novel E1B-55K interacting factors, importin-alpha 1 and pp32, that may also participate in the functions previously ascribed to E1B-55K and E4-orf6. ..
  38. Blanchette P, Cheng C, Yan Q, Ketner G, Ornelles D, Dobner T, et al. Both BC-box motifs of adenovirus protein E4orf6 are required to efficiently assemble an E3 ligase complex that degrades p53. Mol Cell Biol. 2004;24:9619-29 pubmed
    ..In addition, our data suggest that the interaction of E1B55K with E4orf6 depends on the ability of E4orf6 to form the E3 ligase complex and that such complex formation may be required for all E4orf6-E1B55K functions. ..
  39. Medghalchi S, Padmanabhan R, Ketner G. Early region 4 modulates adenovirus DNA replication by two genetically separable mechanisms. Virology. 1997;236:8-17 pubmed
    ..The effect of ORF4 on E2 expression is consistent with its ability to regulate levels of the transcription factor AP-1 (Müller et al., 1992, J. Virol. 66, 5867-5878); the mechanism by which ORFs 3 and 6 enhance replication is unknown. ..
  40. Mathew S, Bridge E. Nbs1-dependent binding of Mre11 to adenovirus E4 mutant viral DNA is important for inhibiting DNA replication. Virology. 2008;374:11-22 pubmed publisher
    ..Our results are consistent with a model in which physical interaction of Mre11 with viral DNA is mediated by Nbs1, and interferes with viral DNA replication. ..
  41. Andrews J, Kadan M, Gorziglia M, Kaleko M, Connelly S. Generation and characterization of E1/E2a/E3/E4-deficient adenoviral vectors encoding human factor VIII. Mol Ther. 2001;3:329-36 pubmed
    ..These data demonstrate that further attenuation of the adenoviral vector backbone by removal of the majority of the E4 coding region significantly diminished vector toxicity; however, the duration of transgene expression was reduced. ..
  42. Powell R, Parkhurst K, Brenowitz M, Parkhurst L. Marked stepwise differences within a common kinetic mechanism characterize TATA-binding protein interactions with two consensus promoters. J Biol Chem. 2001;276:29782-91 pubmed
    ..This detailed mechanistic comparison of two strong promoters interacting with TBP provides a foundation for subsequent comparison between consensus and variant promoter sequences reacting with TBP. ..
  43. Baxi M, Robertson J, Babiuk L, Tikoo S. Mutational analysis of early region 4 of bovine adenovirus type 3. Virology. 2001;290:153-63 pubmed
    ..0 kb. This is extremely useful for the construction of BAV3 vectors that express multiple genes and/or regulatory elements for gene therapy and vaccination...
  44. Jayaram S, Gilson T, Ehrlich E, Yu X, Ketner G, Hanakahi L. E1B 55k-independent dissociation of the DNA ligase IV/XRCC4 complex by E4 34k during adenovirus infection. Virology. 2008;382:163-70 pubmed publisher
    ..Expression of E4 34k alone was not sufficient to dissociate the ligase IV/XRCC4 complex, which indicates a requirement for an additional, as yet unidentified, factor in E1B 55k-independent dissociation of the ligase IV/XRCC4 complex. ..
  45. Hobom U, Dobbelstein M. E1B-55-kilodalton protein is not required to block p53-induced transcription during adenovirus infection. J Virol. 2004;78:7685-97 pubmed
    ..In conclusion, adenovirus does not need direct binding of E1B-55-kDa to inactivate p53, and forced p53 activity with consecutive apoptosis does not severely impair virus replication. ..
  46. Zhang F, Cheng J, Lam G, Jin D, Vincent L, Hackett N, et al. Adenovirus vector E4 gene regulates connexin 40 and 43 expression in endothelial cells via PKA and PI3K signal pathways. Circ Res. 2005;96:950-7 pubmed
    ..Taken together, these results suggest that AdE4+ may play an important role in the regulation of Cx expression in ECs, and that these effects are mediated by both the PKA/CREB and PI3K signaling pathways. ..
  47. Armentano D, Sookdeo C, Hehir K, Gregory R, St George J, Prince G, et al. Characterization of an adenovirus gene transfer vector containing an E4 deletion. Hum Gene Ther. 1995;6:1343-53 pubmed
    ..We describe the inclusion of the A2E4ORF6 modification in a recombinant adenovirus vector, Ad2/CFTR-2, for gene transfer of the human cystic fibrosis transmembrane regulator (CFTR). ..
  48. Shimizu K, Sakurai F, Tachibana M, Mizuguchi H. [Development of a novel adenovirus vector exhibiting microRNA-mediated suppression of the leaky expression of adenovirus genes]. Yakugaku Zasshi. 2012;132:1407-12 pubmed
    ..Incorporation of the miRNA-targeted sequences significantly suppressed the leaky expression of Ad genes in an miRNA-dependent manner. ..
  49. Horowitz B, Sharf R, Avital Shacham M, Pechkovsky A, Kleinberger T. Structure- and modeling-based identification of the adenovirus E4orf4 binding site in the protein phosphatase 2A B55? subunit. J Biol Chem. 2013;288:13718-27 pubmed publisher
  50. Fajas L, Paul C, Zugasti O, Le Cam L, Polanowska J, Fabbrizio E, et al. pRB binds to and modulates the transrepressing activity of the E1A-regulated transcription factor p120E4F. Proc Natl Acad Sci U S A. 2000;97:7738-43 pubmed
    ..Elevated levels of p120(E4F) have been shown to block growth of mouse fibroblasts in G(1). We find this requires pRB, because RB(-/-) fibroblasts are significantly less sensitive to excess p120(E4F). ..
  51. Jayaram S, Ketner G, Adachi N, Hanakahi L. Loss of DNA ligase IV prevents recognition of DNA by double-strand break repair proteins XRCC4 and XLF. Nucleic Acids Res. 2008;36:5773-86 pubmed publisher
    ..These data suggest that the intrinsic DNA-binding activities of XRCC4 and XLF may be subject to regulation and are down regulated in human cells that lack ligase IV. ..
  52. Lethbridge K, Scott G, Leppard K. Nuclear matrix localization and SUMO-1 modification of adenovirus type 5 E1b 55K protein are controlled by E4 Orf6 protein. J Gen Virol. 2003;84:259-68 pubmed
    ..Thus, this modification is favoured when 55K remains associated with the matrix but does not correlate with its stable association with ND10, many components of which are modified by SUMO-1. ..
  53. Rivera A, Davydova J, Schierer S, Wang M, Krasnykh V, Yamamoto M, et al. Combining high selectivity of replication with fiber chimerism for effective adenoviral oncolysis of CAR-negative melanoma cells. Gene Ther. 2004;11:1694-702 pubmed