ABSTRACT
p53 represents one of the most important tumor suppressors in mammalian cells, and the posttranslational modifications (PTMs) serve as a major strategy for fine-tuning of the functions of p53 in cells. Particularly, the acetylation regulates either the overall transactivity of p53 or the p53-dependent transcriptional selectivity, which plays key roles in modulating a variety of biological processes including cell cycle arrest, apoptosis, senescence, autophagy, and metabolism. This review, starting with the timeline of the researches on p53 acetylation, firstly summarizes how the site-specific acetylation of p53 is built up, including the acetyltransferases that catalyze p53 acetylation and their regulatory mechanism that influencing p53 functions. Secondly, this review summarizes pivotal deacetylases that erase p53 acetylation, and their contributions in modulating p53 cellular activities. Additionally, this review summarizes the reader proteins that specifically recognize and bind to acetylated/ unacetylated residues of p53, and their intimate interactions with p53 in manipulating downstream targets transcriptions. Meanwhile, this review sums up the crosstalk mechanisms between the acetylation and other PTMs in regulating p53 biological functions. Lastly, this review proposes a perspective on the studies of p53 acetylation in the field of molecular biomedicine in future.
ABSTRACT
OBJECTIVE To study the effect of tumor suppressor gene p53 on valproic acid (VPA)-caused radiosensitivity of breast cancer cells MCF7 and its mechanism of homologous recombination (HR) repair. METHODS By infecting breast cancer cells MCF7 with PLKO.1 and p53 shRNA lentiviral particle solution, the isogenic pairing MCF7 cells with down-regulated p53 expression, including MCF7/wild-type p53 (MCF7/wtp53) and MCF7/defective p53 (MCF7/dp53) cells, were established. By infecting MCF7/pDR-GFP cells, the MCF7/pDR-GFP/wfp53 and MCF7/pDR-GFP/cfp53 cells were established. MCF7/wtp53 and MCF7/dp53 cells were divided into control group, VPA group (VPA 0.5mmol«L-1 treatment for 24 h), ionizing radiation (IR, 8 Gy) group and VPA+IR group (VPA 0.5 mmol • L-1 pretreatment for 24 h combined with IR). The expression level of protein P53 was detected by Western blotting, while the nucleus tail length and percentage of cells containing phosphorylated histone (yH2AX) focus formation were detected by comet assay and immunofluorescence assay. The clone formation rate was detected by cell clone formation assay. The HR repair efficiency was detected by flow cytometry, and the percentage of cells containing breast cancer susceptibility gene 1 (BRCA1) and recombinase 51 (Rad51) focus formation was detected by immunofluorescence assay. RESULTS Western blotting results showed that the expression of P53 protein was observed in MCF7/wtp53 cells, however, it was decreased in bACF7/dp53 cells significantly (P<0.05). Comet assay and immunofluorescence assay results showed that in WiCF7/wtp53 cells, the nucleus tail length and percentage of cells containing yH2AX focus formation in the VPA+IR group increased compared with the IR group (P<0.05). In MCF7/dp53 cells, the nucleus tail length and percentage of cells containing yH2AX focus formation in VPA + IR group increased compared with the IR group (P<0.05), but still lower than those of the VPA + IR group in MCF7lwtp53 cells (P<0.05). Cell clone formation assay showed that in MCF7/w?p53 cells, the cell viability of the VPA+IR group was lower than that of the IR group (P<0.05). In MCF7Idp53 cells, the cell viability of the VPA+IR group was lower than that of the IR group, but still higher than that of the VPA+IR group in MCF7/wtp53 cells (P<0.05). Flow cytometry results showed that in MCF7/pDR-GFPIwtp53 cells, compared with cell control group, the HR efficiency of VPA group decreased (P<0.05). In MCF7/pDR-GFP/dp53 cells, the HR efficiency of the VPA group was lower than that of the cell control group, but higher than the VPA group in MCF7/pDR-GFP/wtp53 cells (P<0.05). Immunofluorescence assay results showed that in MCF7/wtp53 cells, the percentage of cells containing BRCA1 and Rad51 focus formation in the VPA+IR group was lower than in the IR group respectively (P<0.05). In MCF7/dp53 cells, the percentage of cells containing BRCA1 and Rad51 focus formation in VPA+IR group was lower than in the IR group respectively (P<0.05), but higher than that of VPA + IR group in MCF7/wtp53 cells (P< 0.05). CONCLUSION VPA can enhance the sensitivity of breast cancer cells to IR and is capable of radio sensitization. The inhibition of p53 expression can down-regulate the radiosensitization of VPA, which is associated with the BRCA1-Rad51-mediated over-enhancement of the HR mechanism.
ABSTRACT
The bursa of Fabricius (BF) is the acknowledged central humoral immune organ in birds. Bursal septpeptide II (BSP-II) is an immunomodulatory bioactive peptide isolated from BF. To understand the effects of BSP-II on immune induction, gene expression profiles of hybridoma cells treated with BSP-II were evaluated. Pathway analysis showed that regulated genes were involved in cytokine-cytokine receptor interactions, T cell receptor signaling pathway, and pathway in cancer. It was observed that BSP-II reduced tumor cells proliferation and stimulated p53 expression. These results indicate potential mechanisms underlying the effects of the humoral immune system on immune induction, including antitumor activities. Our study has provided a novel insight into immunotherapeutic strategies for treating human tumors.