Phosphorylation of p53 on Thr55 by ERK2 is necessary for doxorubicin-induced p53 activation and cell death.
We recently reported that exposure of human cervical carcinoma cells to doxorubicin results in extracellular signal-regulated kinase (ERK)2 activation, which in turn phosphorylates p53 on a previously uncharacterized site, Thr55. This study sought to clarify the biological significance of doxorubicin-induced Thr55 phosphorylation. In breast carcinoma MCF7 cells, doxorubicin (300 nM) activated ERK2 and induced phosphorylation of p53 on Thr55 residues. Pretreatment of MCF7 cells with an ERK2 chemical inhibitor, PD98059 or U0126, blocked doxorubicin-induced p53 activation and suppressed phosphorylation of p53Thr55. MCF55a cells were established by transfection of full-length p53 carrying Thr55 mutation (Thr to Ala) into MCF7 cells. Doxorubicin (500 nM) could not induce p53 activation in MCF55a cells, which showed significantly increased drug resistance toward doxorubicin. While the expression of the apoptotic protein, Bax, showed no difference between MCF7 and MCF55a cells, Bcl-2, an antiapoptotic protein, was constitutively expressed in MCF55a cells. The increase of Bcl-2 protein and/or Bcl-2/Bax ratio might at least partly contribute to the drug resistance of MCF55a cells. In summary, our results suggest that phosphorylation of p53Thr55 by ERK2 is important for doxorubicin-induced p53 activation and cell death.
Yeh
Pei Yen
PY
Department of Oncology, National Taiwan University Hospital, Taipei 10016, Taiwan, ROC.
Chuang
Shuang-En
SE
Yeh
Kun-Huei
KH
Song
Ying Chyi
YC
Chang
Lucia Ling-Yuan
LL
Cheng
Ann-Lii
AL
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D013912:Threonine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
D000903:Antibiotics, Antineoplastic; C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D013912:Threonine; D004317:Doxorubicin; D019950:Mitogen-Activated Protein Kinase 1