Blinded by the Light: The Growing Complexity of p53

The p53 protein regulates the transcription of many different genes in response to a wide variety of stress signals. Following DNA damage, p53 regulates key processes, including DNA repair, cell-cycle arrest, senescence and apoptosis, in order to suppress cancer. This Analysis article provides an overview of the current knowledge of p53-regulated genes in these pathways and others, and the mechanisms of their regulation. In addition, we present the most comprehensive list so far of human p53-regulated genes and their experimentally validated, functional binding sites that confer p53 regulation.

Transcriptional control of human p53-regulated genes

p53AIP1, a Potential Mediator of p53-Dependent Apoptosis, and Its Regulation by Ser-46-Phosphorylated p53

P53 is a transcription factor highly inducible by many stress signals such as DNA damage, oncogene activation, and nutrient deprivation. Cell-cycle arrest and apoptosis are the most prominent outcomes of p53 activation. Many studies showed that p53 cell-cycle and apoptosis functions are important for preventing tumor development. p53 also regulates many cellular processes including metabolism, antioxidant response, and DNA repair. Emerging evidence suggests that these noncanonical p53 activities may also have potent antitumor effects within certain context. This review focuses on the cell-cycle arrest and apoptosis functions of p53, their roles in tumor suppression, and the regulation of cell fate decision after p53 activation.

/pdf/the-cell-cycle-arrest-and-apoptotic-functions-of-p53-in-1iqggfnnv2.pdf

The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression

Transcriptional repression of the anti-apoptotic survivin gene by wild type p53.

There are two response elements for p53 in the promoter of the gene for the cyclin-dependent kinase inhibitor p21. The binding of p53 to the 5' site was enhanced by incubation with monoclonal antibody 421, whereas the binding of p53 to the 3' site was inhibited. Mutational analysis showed that a single-base change caused one element to behave like the other. A response element in the human cdc25C promoter is bound by p53 with properties similar to the 3' site. These results identify two classes of p53-binding sites and suggest a mechanism for target gene selectivity by p53.

/pdf/identification-of-a-novel-class-of-genomic-dna-binding-sites-4j6p0cke78.pdf

Identification of a novel class of genomic DNA-binding sites suggests a mechanism for selectivity in target gene activation by the tumor suppressor protein p53.

The cdc25C gene has been shown to be a novel target for transcriptional downregulation by p53. Two independent mechanisms contribute to the p53-dependent repression of the cdc25C gene. First, an element in the cdc25C promoter consisting of a binding site for p53 plus an adjacent 8 base pairs confers p53-dependent repression. Mutation of either the p53 binding site or the adjacent 8 bp sequence abolishes this effect. The element conferring p53-dependent repression also contains a binding site for the transcription factor Sp1 and a mutant p53 protein that retains the ability to interact with the p53-binding site is defective in mediating repression. Second, a minimal promoter lacking the p53 binding site but containing a previously characterized CDE/CHR element is also repressed by p53. This repression is abrogated when a 5 bp mutation is introduced in the CHR sequence. These results support a model for p53 downregulating cdc25C expression, in part, by direct binding to a promoter element that is likely to require cooperation with an additional cellular factor.

The Dual Specificity Phosphatase Cdc25C is a Direct Target for Transcriptional Repression by the Tumor Suppressor p53

INTRODUCTION: The integration of artificial intelligence (AI) and augmented reality (AR) technologies in spine navigation has the potential to minimize pedicle screw misplacement, decrease radiation exposure, and improve procedural efficiency, addressing some of the challenges associated with spinal instrumentation. METHODS: Sixty lumbosacral pedicle screws were placed by 4 Orthopedics surgeons in 6 cadavers using the AR/AI surgical navigation system. Two CT intraoperative scans (before and after screw placement) of the cadaveric specimens were obtained for the study to measure the 3D positional and angular discrepancies between virtual and real screws. The validation procedure consisted of 3 steps: (1) automatic registration and 3D coordinate transformation, where the preop CT scan was aligned with the postop scan to determine the virtual screw 3D positions and orientations in postop scan; (2) analysis of the postop scan to determine the real screw 3D positions and orientations as they appeared in the scan volume; (3) automatic comparison between the 3D positions and orientations of the virtual and real screws. RESULTS: A one-sample t-test statistical analysis yielded a mean positional error of 2.16 mm ± 1.00 mm (99% CI: 1.81-2.49 mm), and a mean angular error of 1.49± 0.73° (99% CI: 1.25-1.74°). These results were independent of anatomical level, side, and surgeon. CONCLUSIONS: This study indicates that this AR/AI surgical guidance system provides mean positional and angular errors lower than 3.0 mm and 3.0° respectively, thus complying with FDA-required regulatory acceptance criteria. The system was FDA-cleared as a US 510k Orthopedic Stereotaxic Instrument.

360 Assessment of Pedicle Screw Placement Accuracy Utilizing a Novel Augmented Reality and Artificial Intelligence Surgical Guidance System

https://www.cell.com/molecular-cell/pdf/S1097-2765(04)00675-6.pdf

DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter.

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Identification of a novel class of genomic DNA-binding sites suggests a mechanism for selectivity in target gene activation by the tumor suppressor protein p53.

The Dual Specificity Phosphatase Cdc25C is a Direct Target for Transcriptional Repression by the Tumor Suppressor p53

360 Assessment of Pedicle Screw Placement Accuracy Utilizing a Novel Augmented Reality and Artificial Intelligence Surgical Guidance System

DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter.