p73 cooperates with DNA damage agents to induce apoptosis in MCF7 cells in a p53-dependent manner.
p73, a member of the p53 family, can induce apoptosis in cancer cells. Since p53-mediated apoptosis can be augmented by various cancer chemotherapeutic agents, it has been hypothesized that the status of the endogenous p53 gene in cancer cells is a key determinant in the outcome of cancer therapy. To determine whether p73 can sensitize cancer cells to apoptosis by DNA damage agents, several MCF7 adenocarcinoma cell lines that inducibly express p73 or p53 under a tetracycline-regulated promoter were generated. We found that at relevant physiological levels, p73, but not p53, is capable of sensitizing MCF7 cells to apoptosis induced by chemotherapeutic agents. In addition, we found that p73 can cooperate with the DNA damaging agent camptothecin to activate the initiator caspase 2. Furthermore, we found that p73 can cooperate with DNA damaging agents or p53 to induce some p53 target genes and activate their promoters. In contrast, in MCF7E6 cells that ectopically express the human papillomavirus E6 oncogene and are functionally p53-null, the ability of p73 to sensitize cells to apoptosis is abrogated. Taken together, these results suggest that a functional interaction between p53 and p73 in MCF7 cells leads to enhanced induction of apoptosis.
Zhu
J
J
Institute of Molecular Medicine and Genetics Medical College of Georgia, Augusta, Georgia, GA 30912, USA.
Nozell
S
S
Wang
J
J
Jiang
J
J
Zhou
W
W
Chen
X
X
D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000473:pathology*; D002166:Camptothecin / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013752:Tetracycline / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; D008156:Luciferases; D020169:Caspases; D013752:Tetracycline; D002166:Camptothecin