Multiple lysine mutations in the C-terminus of p53 make it resistant to degradation mediated by MDM2 but not by human papillomavirus E6 and induce growth inhibition in MDM2-overexpressing cells.
We have recently shown that lysine mutations in p53's putative C-terminal acetylation sites result in increased stability and cytoplasmic distribution of the p53 protein in a human lung cancer cell line. In the present study, we showed that when lysine residues 372, 373, 381, and 382 of p53 were substituted with alanine, the resulting A4 protein was resistant to MDM2-mediated proteosomal degradation but was highly sensitive to human papillomavirus E6-mediated proteolysis. When A4 and wild-type p53 were transfected into MDM2-overexpressing MCF-7 cells, A4 significantly reduced colony formation in vitro, when compared with wild-type p53. Our results suggest that A4 exerts a growth-inhibitory effect more efficiently than wild-type p53 does in cell lines that overexpress MDM2 and may therefore be a better therapeutic tool than wild-type p53 for certain cancers in which MDM2 is amplified or overexpressed.
Nakamura
Seiichi
S
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 445, Houston, TX 77030, USA.
Roth
Jack A
JA
Mukhopadhyay
Tapas
T
D001483:Base Sequence; D002455:Cell Division; D006801:Humans; D008239:Lysine / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000494:pharmacology*; D027383:Papillomaviridae; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D008239:Lysine