Abstract
p53 is an important tumor suppressor gene, which is stimulated by cellular stress like ionizing radiation, hypoxia, carcinogens, and oxidative stress. Upon activation, p53 leads to cell-cycle arrest and promotes DNA repair or induces apoptosis via several pathways. p63 and p73 are structural homologs of p53 that can act similarly to the protein and also hold functions distinct from p53. Today more than 40 different isoforms of the p53 family members are known. They result from transcription via different promoters and alternative splicing. Some isoforms have carcinogenic properties and mediate resistance to chemotherapy. Therefore, expression patterns of the p53 family genes can offer prognostic information in several malignant tumors. Furthermore, the p53 family constitutes a potential target for cancer therapy. Small molecules (e.g., Nutlins, RITA, PRIMA-1, and MIRA-1 among others) have been objects of intense research interest in recent years. They restore pro-apoptotic wild-type p53 function and were shown to break chemotherapeutic resistance. Due to p53 family interactions small molecules also influence p63 and p73 activity. Thus, the members of the p53 family are key players in the cellular stress response in cancer and are expected to grow in importance as therapeutic targets.
Highlights
Human cells are constantly exposed to external and internal stressors, which cause damage to the integrity of the cell and to its genome
The p53 family plays a central role in cancer development and treatment response
Whereas p53 is often mutated in tumors, p63 and p73 function is preserved, yet altered by different expression patterns of their transcription–activation domain (TA) and ∆N isoforms
Summary
Human cells are constantly exposed to external and internal stressors, which cause damage to the integrity of the cell and to its genome. We would like to discuss the influence of cellular stress on tumor development as well as strategies in cancer therapy targeting pathways involved in cell-cycle control and apoptosis. Human tumor protein p53, often described as the “guardian of the genome,” and its target genes play key roles in cell-cycle control and induction of apoptosis.
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