The mitogen-activated protein kinase pathway mediates growth arrest or E1A-dependent apoptosis in SKBR3 human breast

Related Experiment Video

Updated: Oct 27, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

M V Blagosklonny1

  • 1Medicine Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. mikhailb@box-m.nih.gov

International Journal of Cancer
|October 31, 1998
PubMed

Insights

Phorbol ester (PMA) triggers cancer cell growth arrest via p21(WAF1/CIP1) and the Raf-1/MEK/MAPK pathway. The E1A oncoprotein can override this arrest, promoting proliferation and apoptosis in PMA-treated cancer cells.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Phorbol ester (PMA) induces p21(WAF1/CIP1)-dependent growth arrest in breast and prostate cancer cells.
  • The Raf-1/MEK/MAPK pathway is implicated in PMA-mediated cellular responses.

Purpose of the Study:

  • To elucidate the role of the Raf-1/MEK/MAPK pathway in PMA-induced p21(WAF1/CIP1) expression and growth arrest.
  • To investigate the effect of the E1A oncoprotein on PMA-induced growth arrest and p21(WAF1/CIP1) regulation.

Main Methods:

  • Inhibition of Raf-1 kinase and MEK (using dominant-negative constructs, pharmacological depletion, and PD98059).
  • Expression of H-ras oncogene and 12S E1A-expressing adenovirus in SKBr3 cells.
  • Analysis of p21(WAF1/CIP1) induction, growth arrest, proliferation, and apoptosis.

Main Results:

  • Inhibition of Raf-1 or MEK blocked PMA-induced p21(WAF1/CIP1) and growth arrest.
  • H-ras activated p21(WAF1/CIP1) in SKBr3 cells, similar to PMA.
  • E1A abrogated PMA-induced growth arrest downstream of p21(WAF1/CIP1), promoting proliferation and apoptosis, with Rb- or p300-binding activity being partially sufficient.

Conclusions:

  • The Raf-1/MEK/MAPK pathway is essential for PMA-induced p21(WAF1/CIP1) expression and growth arrest.
  • E1A can overcome p21(WAF1/CIP1)-mediated growth arrest, suggesting therapeutic strategies targeting this pathway in PMA-sensitive cancers.

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