p53 Modulates Radiation Sensitivity Independent of p21 Transcriptional Activation

Abstract

Cellular sensitivity to ionizing radiation (IR) treatment is a complex biologic phenomenon that is affected by several processes, namely the ability of the cell to detect and repair DNA damage, regulate cell cycle division, and execute apoptosis. Because the p53 tumor suppressor protein is implicated in the regulation of each of these processes, radiation sensitivity of H1299 p53-null human lung carcinoma cells was evaluated after restoration of wild-type p53. Expression of wild-type p53 in radiation-resistant H1299 cells reinstated a radiation-sensitive phenotype that was not fully explained by cell death resulting from p53-mediated apoptosis. In addition, we show that p53 alters radiation sensitivity only in the G1 phase of the cell cycle, whereas S- and G2/M-phase cells were unaffected by p53 status. To determine the mechanism of p53-induced G1-phase radiation sensitivity, we investigated the G1/S checkpoint response to IR in H1299/p53 cells. We show that H1299/p53 cells arrest in the G1 phase in a p53-dependent manner as a result of transcriptional activation of p21WAF1/Cip1. To determine if p53-induced radiation sensitivity was the result of a reproductive death from accumulated p21 protein expression, p21 was independently induced in H1299 parental cells. However, induction of p21 was not sufficient to account for the enhanced radiation sensitivity in H1299/p53 cells. Together, these data indicate that p53 modulates radiation sensitivity in the G1 phase of the cell cycle through mechanisms independent of p53-mediated transcriptional activation of p21 and cell cycle arrest.

WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells

“…In the absence of DNA damage, WTp53 is very unstable and is rapidly turned over via the ubiquitin-proteasome pathway, whereas increased stability is one of the hallmarks of MTp53. A similar result has been observed with the murine p53 A135V mutant (41,51).…”

Genetic polymorphisms in DNA repair and damage response genes and late normal tissue complications of radiotherapy for breast cancer

“…This mechanism indicates a possible combined effect of polymorphisms in the two genes. However, p53 may modulate response to radiation damage in the G1 phase of the cell cycle through mechanisms independent of p53-mediated transcriptional activation of p21 and cell-cycle arrest (Mazzatti et al, 2005). We did not observe a significant effect of p21 Ser31Arg polymorphism on the risk of late skin toxicity.…”

Time-course analysis of DNA damage response-related genes afterin vitroradiation in H460 and H1229 lung cancer cell lines

“…oligonucleotide causes human cancer cells to become radiosensitive (Zhang et al, 2004;Mazzatti et al, 2005), suggesting that the lack of p53 function allows cell proliferation rather than apoptosismediated elimination. Thus, it is plausible that a different p53 status may be primarily devoted to the radiosensitivity of H460 and H1299.…”