p53 induction of heparin-binding EGF-like growth factor counteracts p53 growth suppression through activation of MAPK and PI3K/Akt signaling cascades.
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.
Fang
L
L
Derald H.Ruttenberg Cancer Center and Department of Pharmacology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Li
G
G
Liu
G
G
Lee
S W
SW
Aaronson
S A
SA
D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D004249:DNA Damage; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D009025:Morpholines / Q000494:pharmacology; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002867:Chromones; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D005419:Flavonoids; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016159:Tumor Suppressor Protein p53; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one