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Adenovirus-5 E1A: paradox and paradigm

Nature Reviews Molecular Cell Biology volume 3, pages 441–452 (2002)Cite this article

Key Points

  • Adenovirus-2/5 E1A proteins have co-transformation activity in rodent cells, but this has not yet been shown in human cell lines.

  • The 243-amino-acid form of adenovirus-5 E1A has tumour-suppressive activity in several human tumour cell lines.

  • This E1A protein — acting chiefly through transcriptional mechanisms — sensitizes tumour cells to anoikis and converts them into an epithelial phenotype.

  • E1A proteins do not bind DNA directly.

  • The function of E1A proteins can be regulated by phosphorylation and acetylation.

  • E1A targets three histone acetyltransferase (HAT)-containing co-activator proteins — p300, CBP (CREB-binding protein) and PCAF (p300/CBP-associated factor) — and inhibits their function

  • This interaction promotes cell-cycle progression in rodent fibroblasts, but the exact mechanism is unclear. This interaction is, however, tumour suppressive in certain human tumour cell lines.

  • E1A also targets the co-repressor protein CtBP, which might be involved in anoikis-sensitization and epithelial conversion.

  • E1A targets components of a chromatin-remodelling complex known as TRRAP (transactivation/transformation-domain-associated protein) and p400, and these interactions might contribute to oncogenic co-transformation of rodent cells.

  • The interaction of E1A with retinoblastoma protein (pRB) might promote cell-cycle progression through displacement of pRB from complexes with E2F and/or BRG1/BRM chromatin-remodelling proteins. It might also promote the acetylation of pRB by p300, which affects MDM2 such that p53 accumulates, and provokes apoptosis.

  • E1A interacts with the Yak1 (yeast)/DYRK (mammalian; dual-specificity Yak1-related kinases) family of kinases, which might be involved in cell differentiation and cell-cycle control.

Abstract

The adenovirus early region 1A (E1A) proteins were described originally as immortalizing oncoproteins that altered transcription in rodent cells. Surprisingly, the 243-amino-acid form of adenovirus-5 E1A was found subsequently to reverse-transform many human tumour cells. Tumour suppression apparently results from the ability of E1A to re-programme transcription in tumour cells, and the molecular basis of this intriguing effect is now beginning to emerge. These discoveries have provided a tool with which to study the regulation of fundamental cellular processes.

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Figure 1: Map of the main E1A proteins and the regions required for selected E1A activities.
Figure 2: Function of CBP/p300 and effect of interaction with E1A.
Figure 3: The primary structure of p300/CBP-associated factor (PCAF).
Figure 4: Function of CtBP and disruption by E1A.
Figure 5: The primary structure of p400.
Figure 6: The primary structure of TRRAP.
Figure 7: E1A disrupts the interaction between retinoblastoma protein and E2F.
Figure 8: E1A increases acetylation of retinoblastoma protein by p300/CBP.

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Acknowledgements

We apologize to our colleagues for omitting references in this review due to space limitations. J.S.M. would like to acknowledge insightful discussion with members of his laboratory and with A. S. Turnell and L. Dagnino. J.S.M is supported by a Canadian Institutes of Health Scholarship and work in his laboratory is supported by funds from the Canadian Institutes of Health. S.M.F. is supported by the Army Breast Cancer Research Program and would like to acknowledge significant moral support from J. Folkman.

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Authors and Affiliations

  1. The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, 92037, California, USA

    Steven M. Frisch

  2. Departments of Oncology, London Regional Cancer Centre, The University of Western Ontario, Microbiology and Immunology, and Pharmacology and Toxicology, 790 Commissioners Road East, London, N6A 4L6, Ontario, Canada

    Joe S. Mymryk

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DATABASES

Flybase

cyclin E

mnb

Twist

LocusLink

VEGF

<i>Saccharomyces</i> Genome Database

Gcn5

Yak1

Swiss-Prot

ATF-2

ATM

BRCA1

BRG1

BRM

CBP

Cdk2

c-jun

c-myc

CtIP

E-cadherin

EID-1

granzyme B

HAT

HER2

HIF1

MDM2

MyoD

p19 ARF

p21Cip1/Waf1

p27Kip1

p53

p57Kip2

p107

PCAF

RACK1

SNF2

Sp1

Sug1

SUV39H1

TIP60

TRRAP

YAKA

Glossary

EPITHELIAL–MESENCHYMAL TRANSITION

(EMT). The transformation of an epithelial cell into a mesenchymal cell with migratory and invasive properties.

CREB

Cyclic AMP response-element-binding protein. A transcription factor that functions in glucose homeostasis and growth-factor-dependent cell survival, and has also been implicated in learning and memory.

HISTONE TAILS

The amino-terminal tails of the core histones, which are subject to several protein modifications.

BASIC HELIX–LOOP–HELIX

A transcription-factor motif that is involved in DNA binding and homo- or heterodimerization.

RNA HELICASE A

A core transcription factor that bridges RNA polymerase II with p300.

TFIIB

Core transcription factor IIB.

SMAD

A transforming growth factor (TGF)-β signal transducer that moves from cytoplasm to nucleus and regulates transcription.

EARLY-RESPONSE GENE

A gene, such as c-Jun and c-Fos, that is rapidly activated by growth factors.

SWI2/SNF2 HOMOLOGY REGION

A motif that is originally found in the yeast SWI/SNF chromatin-remodelling complex.

ENDOREDUPLICATION

A process in which DNA replication occurs without mitosis, and results in nuclear polyploidy.

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Frisch, S., Mymryk, J. Adenovirus-5 E1A: paradox and paradigm. Nat Rev Mol Cell Biol 3, 441–452 (2002). https://doi.org/10.1038/nrm827

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