Cyclin E and c-Myc promote cell proliferation in the presence of p16(INK4a) of hypophosphorylated retinoblastoma family proteins

Konstantinos Alevizopoulos, Jaromir Vlach, Silke Hennecke, Bruno Amati

Research output: Contribution to journalArticle

183 Citations (Scopus)

Abstract

Retroviral expression of the cyclin-dependent kinase (CDK) inhibitor pl6(INK4a) in rodent fibroblasts induces dephosphorylation of pRb, p107 and p130 and leads to G1 arrest. Prior expression of cyclin E allows S-phase entry and long-term proliferation in the presence of p16. Cyclin E prevents neither the dephosphorylation of pRb family proteins, nor their association with E2F proteins in response to p16. Thus, cyclin E can bypass the pl6/pRb growth-inhibitory pathway downstream of pRb activation. Retroviruses expressing E2F-1, -2 or -3 also prevent pl6-induced growth arrest but are ineffective against the cyclin E-CDK2 inhibitor p27(Kip1), suggesting that E2F cannot substitute for cyclin E activity. Thus, cyclin E possesses an E2F-independent function required to enter S-phase, However, cyclin E may not simply bypass E2F function in the presence of p16, since it restores expression of E2F-regulated genes such as cyclin A or CDC2, Finally, c-Myc bypasses the pl6/pRb pathway with effects indistinguishable from those of cyclin E. We suggest that this effect of Myc is mediated by its action upstream of cyclin E-CDK2, and occurs via the neutralization of p27(Kip1) family proteins, rather than induction of Cdc25A. Our data imply that oncogenic activation of c-Myc, and possibly also of cyclin E, mimics loss of the pl6/pRb pathway during oncogenesis.

Original languageEnglish
Pages (from-to)5322-5333
Number of pages12
JournalEMBO Journal
Volume16
Issue number17
DOIs
Publication statusPublished - Sep 1 1997

Fingerprint

Cyclin E
Retinoblastoma Protein
Cell proliferation
Cell Proliferation
Proteins
S Phase
Chemical activation
E2F Transcription Factors
Cyclin-Dependent Kinase Inhibitor p27
Cyclin A
Cyclin-Dependent Kinases
Retroviridae
Fibroblasts
Growth
Rodentia
Carcinogenesis
Genes
Association reactions

Keywords

  • CDK
  • Cyclin
  • Myc
  • p16
  • Retinoblastoma

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Cyclin E and c-Myc promote cell proliferation in the presence of p16(INK4a) of hypophosphorylated retinoblastoma family proteins. / Alevizopoulos, Konstantinos; Vlach, Jaromir; Hennecke, Silke; Amati, Bruno.

In: EMBO Journal, Vol. 16, No. 17, 01.09.1997, p. 5322-5333.

Research output: Contribution to journalArticle

Alevizopoulos, Konstantinos ; Vlach, Jaromir ; Hennecke, Silke ; Amati, Bruno. / Cyclin E and c-Myc promote cell proliferation in the presence of p16(INK4a) of hypophosphorylated retinoblastoma family proteins. In: EMBO Journal. 1997 ; Vol. 16, No. 17. pp. 5322-5333.
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