Georgetown University

About: Georgetown University is a education organization based out in Washington D.C., District of Columbia, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 23377 authors who have published 43718 publications receiving 1748598 citations. The organization is also known as: GU & Georgetown.

Gadd45 in stress signaling, cell cycle control, and apoptosis.

Abstract: The first identified Gadd45 gene, Gadd45a, encodes a ubiquitously expressed protein that is often induced by DNA damage and other stress signals associated with growth arrest and apoptosis. This protein and the other two members of this small gene family, Gadd45b and Gadd45g, have been implicated in a variety of the responses to cell injury including cell cycle checkpoints, apoptosis, and DNA repair. In vivo, many of the prominent roles for the Gadd45 proteins are associated with signaling mediated by p38 mitogen-activated protein kinases (MAPK). Gadd45 proteins can contribute to p38 activation either by activation of upstream kinase(s) or by direct interaction. In vivo, there are important tissue and cell-type-specific differences in the roles for Gadd45 in MAPK signaling. In addition to being p53-regulated, Gadd45a has been found to contribute to p53 activation via p38. Like other stress and signaling proteins, Gadd45 proteins show complex regulation and numerous effectors.

Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate

Abstract: The activity of the p53 gene product is regulated by a plethora of posttranslational modifications. An open question is whether such posttranslational changes act redundantly or dependently upon one another. We show that a functional interference between specific acetylated and phosphorylated residues of p53 influences cell fate. Acetylation of lysine 320 (K320) prevents phosphorylation of crucial serines in the NH2-terminal region of p53; only allows activation of genes containing high-affinity p53 binding sites, such as p21/WAF; and promotes cell survival after DNA damage. In contrast, acetylation of K373 leads to hyperphosphorylation of p53 NH2-terminal residues and enhances the interaction with promoters for which p53 possesses low DNA binding affinity, such as those contained in proapoptotic genes, leading to cell death. Further, acetylation of each of these two lysine clusters differentially regulates the interaction of p53 with coactivators and corepressors and produces distinct gene-expression profiles. By analogy with the “histone code” hypothesis, we propose that the multiple biological activities of p53 are orchestrated and deciphered by different “p53 cassettes,” each containing combination patterns of posttranslational modifications and protein–protein interactions.

In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease

Abstract: Neuroinflammation is a pathological hallmark of Alzheimer’s disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with 11C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer’s disease, patients with mild cognitive impairment and older control subjects were also scanned with 11C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer’s, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer’s disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, 11C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer’s disease, but not those with mild cognitive impairment, had greater 11C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. 11C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. 11C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater 11C-PBR28 binding than late-onset patients, and in parietal cortex and striatum 11C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between 11C-PBR28 and 11C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased 11C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer’s disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. 11C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer’s disease. * Abbreviations : MCI : mild cognitive impairment PIB : Pittsburgh compound B