title: The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells.
abstract: In some cell types either DNA damage or p53 expression leads to minimal cell death, while combining the two leads to a strong apoptotic response. To further understand features of p53 that contribute to this increased cell death we used clones of H1299 cells that express wild-type or several mutant forms of p53 under a tetracycline-regulated promoter. In these cells the induction of wild-type p53 leads to significant apoptosis only when combined with exposure to a number of chemotherapeutic agents. A common target of p53, p21, is itself not sufficient to cause apoptosis in the presence of these chemotherapeutic compounds. Many agents also effectively increase cell death when a transcriptionally-defective p53, p53([gln22ser23]), is induced, although a dramatic exception is treatment with 5-FU, which strongly cooperates with wild-type but not p53([gln22ser23]). Our results with 5-FU thus show that genetically separable functions of p53 are involved in its ability to respond to DNA-damaging agents to induce apoptosis. Notably as well, deleting the C-terminal 30 amino acids of p53 does not affect this cooperative effect with DNA-damaging agents. By contrast, a p53 mutant lacking the PXXP-domain between residues 60-90, while at least partially transcriptionally-competent, cannot be rendered apoptotic by any compounds that we tested. Thus the PXXP domain provides an essential component of the ability of p53 to respond to DNA-damaging agents to cause cell death.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Baptiste
authors.forename: Philip
authors.initials: P
authors.lastname: Friedlander
authors.forename: Xinbin
authors.initials: X
authors.lastname: Chen
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002166:Camptothecin / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D003078:Colchicine / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D003630:Daunorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D016158:Genes, p53; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008954:Models, Biological; D011392:Proline / Q000737:chemistry*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013329:Structure-Activity Relationship; D013752:Tetracycline / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D011392:Proline; D013752:Tetracycline; D003078:Colchicine; D005472:Fluorouracil; D002166:Camptothecin; D003630:Daunorubicin