Abstract
p53 has a crucial role in governing cellular mechanisms in response to a broad range of genotoxic stresses. During DNA damage, p53 can either promote cell survival by activating senescence or cell-cycle arrest and DNA repair to maintain genomic integrity for cell survival or direct cells to undergo apoptosis to eliminate extensively damaged cells. The ability of p53 to execute these two opposing cell fates depends on distinct signaling pathways downstream of p53. In this study, we showed that under DNA damage conditions induced by chemotherapeutic drugs, gamma irradiation and hydrogen peroxide, p53 upregulates a novel protein, proline-rich acidic protein 1 (PRAP1). We identified functional p53-response elements within intron 1 of PRAP1 gene and showed that these regions interact directly with p53 using ChIP assays, indicating that PRAP1 is a novel p53 target gene. The induction of PRAP1 expression by p53 may promote resistance of cancer cells to chemotherapeutic drugs such as 5-fluorouracil (5-FU), as knockdown of PRAP1 increases apoptosis in cancer cells after 5-FU treatment. PRAP1 appears to protect cells from apoptosis by inducing cell-cycle arrest, suggesting that the induction of PRAP1 expression by p53 in response to DNA-damaging agents contributes to cancer cell survival. Our findings provide a greater insight into the mechanisms underlying the pro-survival role of p53 in response to cytotoxic treatments.
Highlights
The tumor-suppressor gene, p53, has a critical role in regulating the responses of mammalian cells to DNA damage
We demonstrate that in response to cellular stresses such as DNA damage, proline-rich acidic protein 1 (PRAP1) expression is significantly induced by p53, a key player mediating cellular responses to DNA damage
We identified two p53-response elements within intron 1 of the PRAP1 gene and show that these elements are responsive to p53 transcriptional activity during DNA damage conditions
Summary
The tumor-suppressor gene, p53, has a critical role in regulating the responses of mammalian cells to DNA damage. In response to DNA damage, p53 inhibits the entry of cells into the DNA synthesis phase of the cell cycle and activates DNA repair mechanisms.[4] Alternatively, extensively damaged cells are eliminated through apoptosis.[5] the mechanisms leading to the determination of cell fate resulting in either cell survival or death are still unclear. P53 may enhance the recovery of cancer cells by activating DNA repair pathways,[7] while on the other, it regulates apoptosis and has been shown to increase sensitivity of cells to chemotherapeutic agents.[8] The apparent discrepancy may be explained by genes targeted by p53 under different circumstances, resulting in different cell fates. Our data indicate that PRAP1 modulates cell fate downstream of p53 activation by DNA-damaging agents and suggest that PRAP1 may be an important determinant of cancer cell survival
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
