Significance of Wild-Type p53 Signaling in Suppressing Apoptosis in Response to Chemical Genotoxic Agents: Impact on Chemotherapy Outcome

• Published in: International journal of molecular sciences Vol. 18; no. 5; p. 928
• Main Authors: Mirzayans, Razmik, Andrais, Bonnie, Kumar, Piyush, Murray, David
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.04.2017; MDPI
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Apoptosis; Apoptosis - drug effects; Cell cycle; Cell Cycle Checkpoints - drug effects; Cellular Senescence - drug effects; Chemotherapy; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Deoxyribonucleic acid; DNA; DNA Damage - drug effects; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Review; Signal Transduction - drug effects; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; mutational processes; multinucleated giant cells; chemical genotoxic agents; DNAJB9; apoptosis; p53 signaling; premature senescence; p21WAF1 (CDKN1A)
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms18050928

Our genomes are subject to potentially deleterious alterations resulting from endogenous sources (e.g., cellular metabolism, routine errors in DNA replication and recombination), exogenous sources (e.g., radiation, chemical agents), and medical diagnostic and treatment applications. Genome integrity and cellular homeostasis are maintained through an intricate network of pathways that serve to recognize the DNA damage, activate cell cycle checkpoints and facilitate DNA repair, or eliminate highly injured cells from the proliferating population. The wild-type p53 tumor suppressor and its downstream effector p21WAF1 (p21) are key regulators of these responses. Although extensively studied for its ability to control cell cycle progression, p21 has emerged as a multifunctional protein capable of downregulating p53, suppressing apoptosis, and orchestrating prolonged growth arrest through stress-induced premature senescence. Studies with solid tumors and solid tumor-derived cell lines have revealed that such growth-arrested cancer cells remain viable, secrete growth-promoting factors, and can give rise to progeny with stem-cell-like properties. This article provides an overview of the mechanisms by which p53 signaling suppresses apoptosis following genotoxic stress, facilitating repair of genomic injury under physiological conditions but having the potential to promote tumor regrowth in response to cancer chemotherapy.