Apoptosis or growth arrest: Modulation of tumor suppressor p53's specificity by bacterial redox protein azurin
| Autor: | Tohru Yamada, Kazuhide Kimbara, Masateru Ikehata, Tapas K. Das Gupta, Yoshinori Hiraoka, Benjamin S. Avner, Ananda M. Chakrabarty |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Transcription Genetic Cell Mutant Apoptosis Biology Azurin Cell Line Tumor Cyclins medicine Humans E2F DNA Primers Cyclin Multidisciplinary Base Sequence Kinase Biological Sciences Molecular biology Cell biology medicine.anatomical_structure Cell culture Tumor Suppressor Protein p53 Oxidation-Reduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 101:4770-4775 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | The tumor suppressor protein p53 is known to induce either apoptosis or growth arrest depending on cellular background. We have previously reported that a bacterial redox protein azurin induces apoptosis in J774 cell line-derived macrophages whereas a site-directed mutant M44KM64E azurin shows very little cytotoxicity and fails to induce apoptosis in J774 cells. We now report that purified M44KM64E mutant azurin protein can enter both J774 cells as well as the human breast cancer MCF-7 cells. Entry of M44KM64E mutant azurin in J774 cells causes strong inhibition of cell-cycle progression at the G 1 to S phase and a higher level of transcription of the p21 gene. Corresponding to high p21 levels, the levels of cyclins and cyclin-dependent kinases were greatly lowered in M44KM64E mutant azurin-treated J774 cells. Interestingly, M44KM64E mutant azurin protein failed to elicit inhibition of cell-cycle progression in MCF-7 cells, presumably because of mutation at the retinoblastoma tumor suppressor protein that allows functional E2F formation in MCF-7 cells even in the presence of high intracellular p21 level. Thus, the WT azurin induces apoptosis but little inhibition of cell-cycle progression whereas the M44KM64E mutant azurin is deficient in the induction of apoptosis but mediates strong inhibition of cell-cycle progression, demonstrating the role of a single bacterial protein and its hydrophobic patch in modulating two important functions of p53. |
| Databáze: | OpenAIRE |
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