Distinct target genes and effector processes appear to be critical for p53-activated responses to acute DNA damage versus p53-mediated tumour suppression

Abstract

The p53 tumour suppressor is the most frequently mutated gene in human cancer. This transcription factor can be activated by diverse cellular stresses, including DNA damage and oncogene activation. Through transcriptional induction of appropriate target genes, p53 can stimulate activity in a broad range of effector pathways, most notably cell cycle arrest, cellular senescence and apoptotic cell death. Insensitivity to cell death-inducing signals and deregulated proliferation are two key hallmarks of cancer cells. Given that p53 inhibits proliferation and induces apoptosis, it was widely believed that these processes are the most critical ones for p53-mediated tumour suppression. However, this dogma has been challenged. In striking contrast to p53-deficient mice, which all develop tumours before 250 days of age, mutant mice in which expression of the p53 target genes that are critical for induction of cell cycle arrest and apoptosis is impaired or abrogated are not cancer-prone. This demonstrates that distinct effector processes are critical for the p53-mediated acute response to DNA damage versus p53-mediated tumour suppression. The discovery that cell cycle arrest, senescence and apoptosis are not essential for p53-mediated tumour suppression re-launches the search for the p53 target genes and effector processes that are critical to prevent tumour development, with coordination of DNA repair being a leading contender.

What is the potential of p53 isoforms as a predictive biomarker in the treatment of cancer?

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Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium

“…The p53 protein is a sequence-specific transcription factor that regulates the expression of many genes, including its own function (through MDM2, MDM4 ), cell cycle arrest and DNA repair ( CDKN1A [p21CIP1], CDK2, GADD45, TRIM22 ), senescence ( PML, PAI -1), apoptosis ( BAX, PUMA, NOXA , survivin), growth factors ( IGFBP -3, PTEN ), translation (Sestrin), autophagy (Sirtuin1), and innate immune receptors (TLRs) (Barsotti et al 2012; Hasty and Christy 2013; Kitagawa et al 2013; Klettner 2012; Purvis et al 2012; Suzuki et al 2009; Valente et al 2013; Valente and Strasser 2013; Vuong et al 2012). Activation of p53 can also directly initiate apoptosis via down regulation of anti-apoptotic BCL2 family proteins, including BCL2, BCLXL, and induction of mitochondrial outer membrane permeabilization.…”

Effect of KNDC1 overexpression on the senescence of human umbilical vein endothelial cells

“…In the present study, it was demonstrated that increased phosphorylated p53 levels compared with the control led to an increased production of ROS in a dose-dependent manner. Therefore, the activation of the p53 pathway may be in response to the ROS-induced DNA damage ( 32 ). p53 may downregulate the expression of antioxidant enzymes including SOD and GPx under physiological conditions when acutely stressed.…”