p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK.
Stimulation of the Ras/MAPK cascade can either activate p53 and promote replicative senescence and apoptosis, or degrade p53 and promote cell survival. Here we show that p53 can directly counteract the Ras/MAPK signaling by inactivating ERK2/MAPK. This inactivation is due to a caspase cleavage of the ERK2 protein and contributes to p53-mediated growth arrest. We found that in Ras-transformed cells, growth arrest induced by p53, but not p21(Waf1), is associated with a strong reduction in ERK2 activity, phosphorylation, and protein half-life, and with the appearance of caspase activity. Likewise, DNA damage-induced cell cycle arrest correlates with p53-dependent ERK2 downregulation and caspase activation. Furthermore, caspase inhibitors or expression of a caspase-resistant ERK2 mutant interfere with ERK2 cleavage and restore proliferation in the presence of p53 activation, indicating that caspase-mediated ERK2 degradation contributes to p53-induced growth arrest. These findings strongly point to ERK2 as a novel p53 target in growth suppression.
Marchetti
A
A
Molecular Oncogenesis Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, 00158 Rome, Italy.
Cecchinelli
B
B
D'Angelo
M
M
D'Orazi
G
G
Crescenzi
M
M
Sacchi
A
A
Soddu
S
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002461:Cell Line, Transformed; D004249:DNA Damage / Q000502:physiology; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D019950:Mitogen-Activated Protein Kinase 1; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases