A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1)

Konstantinos Alevizopoulos, Barbara Catarin, Jaromir Vlach, Bruno Amati

Research output: Contribution to journalArticle

Abstract

We show here that the adenovirus E1A oncoprotein prevents growth arrest by the CDK2 inhibitor p27(Kip1) (p27) in rodent fibroblasts. However, E1A neither binds p27 nor prevents inhibition of CDK2 complexes in vivo. In contrast, the amount of free p27 available to inhibit cyclin E/CDK2 is increased in E1A-expressing cells, owing to reduced expression of cyclins D1 and D3. Moreover, E1A allows cell proliferation in the presence of supraphysiological p27 levels, while c-Myc, known to induce a cellular p27-inhibitory activity, is only effective against physiological p27 concentrations. E1A also bypasses G1 arrest by roscovitine, a chemical inhibitor of CDK2. Altogether, these findings imply that E1A can act downstream of p27 and CDK2. Retinoblastoma (pRb)-family proteins are known CDK substrates; as expected, association of E1A with these proteins (but not with p300/CBP) is required for E1A to prevent growth arrest by either p27 or the CDK4/6 inhibitor p16(INK4a). Bypassing CDK2 inhibition requires an additional function of E1A: the mutant E1A Δ26-35 does not overcome p27-induced arrest, while it binds pRb-family proteins, prevents p16-induced arrest, and alleviates pRb-mediated repression of E2F-1 transcriptional activity (although E1A Δ26-35 fails to restore expression of E2F-regulated genes in p27-arrested cells). We propose that besides the pRb family, E1A targets specific effector(s) of CDK2 in G1-S control.

Original languageEnglish
Pages (from-to)5987-5997
Number of pages11
JournalEMBO Journal
Volume17
Issue number20
DOIs
Publication statusPublished - Oct 15 1998

Fingerprint

Adenoviridae
Growth
Cyclin D3
Cyclin E
Proteins
Retinoblastoma
Oncogene Proteins
Cyclin D1
Cell proliferation
Fibroblasts
Rodentia
Genes
Cell Proliferation
Substrates

Keywords

  • CDK2
  • E1A
  • E2F
  • p27(Kip1)
  • Retinoblastoma

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1). / Alevizopoulos, Konstantinos; Catarin, Barbara; Vlach, Jaromir; Amati, Bruno.

In: EMBO Journal, Vol. 17, No. 20, 15.10.1998, p. 5987-5997.

Research output: Contribution to journalArticle

Alevizopoulos, Konstantinos ; Catarin, Barbara ; Vlach, Jaromir ; Amati, Bruno. / A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1). In: EMBO Journal. 1998 ; Vol. 17, No. 20. pp. 5987-5997.
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