Mechanisms of transcriptional regulation by p53

Abstract

p53 is a transcription factor that suppresses tumor growth through regulation of dozens of target genes with diverse biological functions. The activity of this master transcription factor is inactivated in nearly all tumors, either by mutations in the TP53 locus or by oncogenic events that decrease the activity of the wild-type protein, such as overexpression of the p53 repressor MDM2. However, despite decades of intensive research, our collective understanding of the p53 signaling cascade remains incomplete. In this review, we focus on recent advances in our understanding of mechanisms of p53-dependent transcriptional control as they relate to five key areas: (1) the functionally distinct N-terminal transactivation domains, (2) the diverse regulatory roles of its C-terminal domain, (3) evidence that p53 is solely a direct transcriptional activator, not a direct repressor, (4) the ability of p53 to recognize many of its enhancers across diverse chromatin environments, and (5) mechanisms that modify the p53-dependent transcriptional program in a context-dependent manner.

Targeted OMA1 therapies for cancer

“…a and 2 b with 2 c and 2 d ). Tumor protein p53 is a transcription factor, which controls cell cycle genes and other important tumor suppressor pathways . The MYC transcription factor is a proto oncogene, which can control mitochondrial biogenesis.…”

Diepoxybutane induces the expression of a novel p53‐target gene XCL1 that mediates apoptosis in exposed human lymphoblasts

“…It is activated in response to a variety of stresses to mediate various cellular responses, such as cell cycle arrest, DNA repair, and apoptosis [13] . The pleiotropy of p53 activity is due to its ability to transcriptionally activate different classes of p53 transcriptional target genes that play roles in different outcomes [14] . Thus, identification of p53 target genes is of paramount importance toward the understanding of pathways regulated by p53, such as those that control cell growth arrest and apoptosis [14] …”

Reviewing the future of the P53 field

“…The wild-type p53 protein is a transcription factor that selectively regulates the transcriptional activation of 4200 genes in diverse cells (reviewed in Engeland 3 and Sullivan et al 4 ). Activation of p53-mediated transcription by various stress signals results in the expression of a number of pathways that accomplish diverse phenotypes that include cell cycle arrest, 3 senescence, apoptosis and other types of cell death, metabolic alterations, DNA repair processes, and other prosurvival mechanisms and tumor suppression (reviewed in refs.…”

“…Activation of p53-mediated transcription by various stress signals results in the expression of a number of pathways that accomplish diverse phenotypes that include cell cycle arrest, 3 senescence, apoptosis and other types of cell death, metabolic alterations, DNA repair processes, and other prosurvival mechanisms and tumor suppression (reviewed in refs. [3][4][5][6][7]. There is an active debate about which p53-regulated genes and pathways are responsible for the tumor suppressor phenotype.…”

“…In vertebrates, this family of transcription factors has a critical role in protecting the host skin's protective barrier, inducing the innate immune response, preventing movement of retrotransposons in the genome and genomic instability, hypoxia, mitochondrial functions, regulating metabolic pathways and glucose and glutamine utilization, regulating the rates of cell division, maintaining epigenetic stability, monitoring centrosome fidelity and chromosomal segregation (aneuploidy), monitoring and inhibiting viral and bacterial infections, and many other responses to our environment. [3][4][5][6][7]9 Hidden in some of these functions are the processes of aging and death. 8 From germ line development, through fertilization, embryonic development, epigenetic programing, birth, organismic development, reproduction, aging, and death, the Tp53 family of genes, first observed over a billion years ago, has an important role throughout our lives by providing fidelity in spite of stress.…”