Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells

A mechanism involving the p38 MAP kinase and phosphorylation of ATF-2

Joan S. Lewis, Veena Vijayanathan, T. J. Thomas, Richard G. Pestell, Chris Albanese, Michael A. Gallo, Thresia Thomas

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Estradiol (E2) and the naturally occurring polyamines (putrescine, spermidine, and spermine) play important roles in breast cancer cell growth and differentiation. We examined the effects of E2 and spermine on the phosphorylation and DNA binding of activating transcription factor-2 (ATF-2) in MCF-7 breast cancer cells. ATF-2 is a transcription factor involved in estrogenic regulation of cyclin D1 gene, and thereby cell cycle progression. DNA affinity immunoblot assays showed a six- to eightfold increase in the binding of ATF-2 to a 74-mer ATF/CRE oligonucleotide (ODN1) from cyclin D1 promoter in the presence of 4 nM E2 and 0.5 mM spermine, compared to untreated control. Individual treatments with E2 or spermine caused a twofold or lower increase in ATF-2 binding to ODN1. Immunoblotting with phospho-ATF-2 antibody showed that increased DNA binding of ATF-2 was associated with its phosphorylation. A p38 MAP kinase inhibitor, PD169316, inhibited ATF-2 phosphorylation. In contrast, the MEK-ERK1/2 inhibitor, PD98059, or the JNK inhibitor, SP600125, had no significant effect on DNA binding of ATF-2. Cyclin D1 promoter (-1745CD1) activity increased by approximately 12-fold (above control) in the presence of E2 and spermine, compared to a sixfold increase in the presence of E2 alone and a twofold increase with spermine. Cells transfected with a dominant negative mutant of ATF-2 showed decreased transactivation of cyclin D1 promoter in response to E2 and spermine. These results indicate that spermine can enhance E 2-induced cell signaling and cyclin D1 transcription by activation of the p38 MAP kinase and phosphorylation of ATF-2, contributing to breast cancer cell proliferation.

Original languageEnglish (US)
Pages (from-to)113-128
Number of pages16
JournalOncology Research
Volume15
Issue number3
StatePublished - 2005
Externally publishedYes

Fingerprint

Activating Transcription Factor 2
Spermine
Cyclin D1
p38 Mitogen-Activated Protein Kinases
Estradiol
Phosphorylation
Breast Neoplasms
DNA
Transcriptional Activation
bcl-1 Genes
Putrescine
Spermidine
Mitogen-Activated Protein Kinase Kinases
Polyamines
Immunoblotting
Oligonucleotides
Cell Differentiation
Cell Cycle
Transcription Factors

Keywords

  • ATF-2
  • Cyclin D1
  • Estradiol
  • MCF-7 cells
  • Polyamines

ASJC Scopus subject areas

  • Cancer Research

Cite this

Lewis, J. S., Vijayanathan, V., Thomas, T. J., Pestell, R. G., Albanese, C., Gallo, M. A., & Thomas, T. (2005). Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: A mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. Oncology Research, 15(3), 113-128.

Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells : A mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. / Lewis, Joan S.; Vijayanathan, Veena; Thomas, T. J.; Pestell, Richard G.; Albanese, Chris; Gallo, Michael A.; Thomas, Thresia.

In: Oncology Research, Vol. 15, No. 3, 2005, p. 113-128.

Research output: Contribution to journalArticle

Lewis, JS, Vijayanathan, V, Thomas, TJ, Pestell, RG, Albanese, C, Gallo, MA & Thomas, T 2005, 'Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: A mechanism involving the p38 MAP kinase and phosphorylation of ATF-2', Oncology Research, vol. 15, no. 3, pp. 113-128.
Lewis, Joan S. ; Vijayanathan, Veena ; Thomas, T. J. ; Pestell, Richard G. ; Albanese, Chris ; Gallo, Michael A. ; Thomas, Thresia. / Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells : A mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. In: Oncology Research. 2005 ; Vol. 15, No. 3. pp. 113-128.
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