Mechanisms of Cr(VI)-induced p53 activation: the role of phosphorylation, mdm2 and ERK.
The present study investigated the molecular mechanisms of p53 activation induced by Cr(VI), using human lung epithelial A549 cells. Cr(VI) increased both protein level and transactivation ability of p53 protein. The activation of p53 is at the protein level instead of the transcriptional level. The degradation of p53 was dramatically decreased upon stimulation by Cr(VI). In addition, Cr(VI) treatment decreased the interaction of p53 with mdm2 protooncoprotein, which blocks the transactivation ability of p53 and promotes the degradation of p53 protein. In response to Cr(VI) treatment, p53 protein became phosphorylated and acetylated at Ser15 and Lys382, respectively. The phosphorylation levels at either Ser20 or Ser392 did not show any significant alterations. Since previous studies report that it is Ser20 and not Ser15 phosphorylation that contributes to mdm2 dissociation from p53, the results obtained from the current investigation suggest a different mechanism: Ser15 instead of Ser20 may play a key role in the dissociation of mdm2 in response to Cr(VI). Erk, a member of mitogen-activated protein kinase, acts as the upstream kinase for the phosphorylation of the p53 Ser15 site.
Wang
S
S
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.
Shi
X
X
D002857:Chromium / Q000494:pharmacology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009687:Nuclear Proteins; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D002857:Chromium; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D020928:Mitogen-Activated Protein Kinases