Mutant p53 drives cancer chemotherapy resistance due to loss of function on activating transcription of PUMA
| Autor: | Lingling Zhang, Yeying Liu, Guang Luo, Shuaiyu Long, Jing Liu, Nannan Liu, Chuchu Zhang, Yuan Huang, Yingjie Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Tumor suppressor gene Transcription Genetic Cell Survival Mutant Apoptosis Biology 03 medical and health sciences 0302 clinical medicine Transcription (biology) Cyclin-dependent kinase Loss of Function Mutation Puma hemic and lymphatic diseases Proto-Oncogene Proteins Humans Molecular Biology bcl-2-Associated X Protein Kinase Cell Biology biology.organism_classification HCT116 Cells Gene Expression Regulation Neoplastic 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 Drug Resistance Neoplasm 030220 oncology & carcinogenesis Colonic Neoplasms Cancer research biology.protein Mutant Proteins biological phenomena cell phenomena and immunity Tumor Suppressor Protein p53 Apoptosis Regulatory Proteins Platelet-derived growth factor receptor Developmental Biology Research Paper |
| Zdroj: | Cell Cycle |
| Popis: | P53 is a critical tumor suppressor gene, activating p53 and its downstream targets to induce apoptosis is a promising way for cancer therapy. However, more than 50% of cancer patients have p53 mutations, which may cause cancer therapy resistance, and the underline mechanism is poorly understood. Here, we found that cell viability decrease and apoptosis induced by p53-dependent traditional drugs in colon cancer cells were eliminated in p53 mutant cells. Mutant p53 did not up-regulate the expression of its direct downstream targets PUMA and p21, due to the inhibition of PUMA transcription. Furthermore, mutant p53 could not bind to the promoter of PUMA to activate its transcription like WT p53 did, while overexpressed WT p53 rescued PUMA-induced subsequent apoptosis. In conclusion, our findings demonstrate mutant p53 may cause chemo-resistance of tumor because of inactivating PUMA transcription, which prompts some new insights for clinical therapy of cancer patients with mutant p53. Abbreviations: CRC: Colorectal cancer; CDKs: Cyclin-dependent kinases; PUMA: p53 up-regulated modulator of apoptosis; PDGF: the platelet-derived growth factor; WT p53: wild-type p53 protein; mutp53: mutant p53 proteins; BAX: Bcl-2-associated X protein; NOXA: Phorbol-12-myristate-13-acetate-induced protein 1. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|