p53 induction of heparin-binding EGF-like growth factor counteracts p53 growth suppression through activation of MAPK and PI3K/Akt signaling cascades

EMBO J. 2001 Apr 17;20(8):1931-9. doi: 10.1093/emboj/20.8.1931.

Abstract

Tumor suppressor p53 induction in response to cellular stresses activates the mitogen-activated protein kinase (MAPK) cascade through pathways involving Ras and RAF: p53's ability to activate this pathway is dependent on p53-mediated transcription. In order to investigate potential p53 target gene(s) involved, we utilized expression array analysis and identified heparin-binding epidermal growth factor-like growth factor (HB-EGF) as being markedly up-regulated by p53. In response to DNA damage, HB-EGF was induced in wild-type, but not in mutant p53-containing cells, implying its p53 dependence. HB-EGF neutralizing antibody and inhibitors of EGF receptor signaling abrogated p53-induced MAPK activation. Expression of HB-EGF was shown to protect cells from H(2)O(2)-induced apoptosis through MAPK activation. Additionally, the PI3K/Akt pathway was activated in response to p53 signaling through HB-EGF induction, and inhibition of MAPK and Akt activation after DNA damage decreased cell survival in wild-type p53-containing cells. All these findings point to a novel aspect of p53 function. Namely, p53-induced growth factors such as HB-EGF, which activate MAPK and Akt signaling, may be involved in a compensatory mechanism to alleviate adverse effects of cellular stresses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Survival
  • Chromones / pharmacology
  • DNA Damage
  • Epidermal Growth Factor / biosynthesis*
  • Epidermal Growth Factor / genetics
  • ErbB Receptors / antagonists & inhibitors
  • Flavonoids / pharmacology
  • Gene Expression Regulation
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • MAP Kinase Signaling System*
  • Morpholines / pharmacology
  • Oxidative Stress
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Chromones
  • Flavonoids
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Morpholines
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Epidermal Growth Factor
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one