p300 regulates p53-dependent apoptosis after DNA damage in colorectal cancer cells by modulation of PUMA/p21 levels.
Activation of the tumor suppressor p53 by DNA damage induces either cell cycle arrest or apoptosis, but what determines the choice between cytostasis and death is not clear. In this report, we show that the E1A-binding p300 nucleoprotein is a key determinant of p53-dependent cell fate in colorectal cancer cells: absence of p300 increases apoptosis in response to DNA damage. In addition, p300-deficient (p300(-)) cells fail to undergo G(1)/S arrest after UV irradiation. These abnormalities are associated with prolongation of p53 stability, reduced p53-acetylation, blunting of MDM2 activation, failure to transactivate p21, and a disproportionate increase in PUMA levels. When xenografted, p300(-) cells are more sensitive to chemotherapy with doxorubicin. These results show that p300 is a key regulator of the p53 response and suggest that p300 inhibition could be used to modulate chemotherapy.
Iyer
N Gopalakrishna
NG
Cancer Genomics Program, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 2XZ, United Kingdom.
Chin
Suet-Feung
SF
Ozdag
Hilal
H
Daigo
Yataro
Y
Hu
De-En
DE
Cariati
Massimiliano
M
Brindle
Kevin
K
Aparicio
Samuel
S
Caldas
Carlos
C
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004249:DNA Damage; D017931:DNA Primers; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015534:Trans-Activators / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D017931:DNA Primers; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)