Abstract
Activation of the p53 signaling pathway by DNA-damaging agents was originally proposed to result either in cell cycle checkpoint activation to promote survival or in apoptotic cell death. This model provided the impetus for numerous studies focusing on the development of p53-based cancer therapies. According to recent evidence, however, most p53 wild-type human cell types respond to ionizing radiation by undergoing stress-induced premature senescence (SIPS) and not apoptosis. SIPS is a sustained growth-arrested state in which cells remain viable and secrete factors that may promote cancer growth and progression. The p21WAF1 (hereafter p21) protein has emerged as a key player in the p53 pathway. In addition to its well-studied role in cell cycle checkpoints, p21 regulates p53 and its upstream kinase (ATM), controls gene expression, suppresses apoptosis, and induces SIPS. Herein, we review these and related findings with human solid tumor-derived cell lines, report new data demonstrating dynamic behaviors of p53 and p21 in the DNA damage response, and examine the gain-of-function properties of cancer-associated p53 mutations. We point out obstacles in cancer-therapeutic strategies that are aimed at reactivating the wild-type p53 function and highlight some alternative approaches that target the apoptotic threshold in cancer cells with differing p53 status.
Highlights
Extensive research has been directed towards targeting the p53 tumor suppressor and other key players in the DNA damage surveillance network in an attempt to improve the outcome of conventional cancer therapies [1]
The studies that have identified these targets were performed with different solid tumors and cell lines, the results are encouraging and warrant further indepth evaluation with a specific cancer type
We have further demonstrated for the first time that ionizing radiation triggers sequential waves of p21 in p53 wild-type human cancer cells
Summary
Extensive research has been directed towards targeting the p53 tumor suppressor and other key players in the DNA damage surveillance network in an attempt to improve the outcome of conventional cancer therapies [1]. This approach has met with limited success [2]. We will first review the current knowledge on the p53 signaling pathway that is activated in human solid tumor-derived cell lines after exposure to ionizing radiation, with a particular focus on the multiple functions of p21WAF1 (hereafter p21), a key downstream effector of p53. We will discuss the properties of mutant p53 commonly found in human cancers and will examine some promising pharmacological approaches for potentiating the radiosensitivity of cancer cells with differing p53 status
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
