Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA) impeded monocyte to macrophage differentiation with respect to typical phenotypic modulation and certain phagocyte-related processes. The down-regulation of the porcine monocyte marker SWC1, and up-regulation of the SWC9 macrophage marker were retarded, but not inhibited, as was the differentiation-associated down-regulation of p53 and myeloperoxidase. Despite this clear impairment of macrophage differentiation, not all cellular functions were equally susceptible. Both agents inhibited phagocytosis, but not low-density lipoprotein receptor-associated endocytosis. Only LPS inhibited tartrate-resistant acid phosphatase up-regulation. In contrast, increase of vacuolar acidification rates was more susceptible to PMA. The activity of certain endosomal/lysosomal enzymes - esterase, nucleotidase, peroxidase and cathepsins - was generally enhanced by both LPS and PMA. This contrasted with autophagosomal activity, detected through the induction of an antiviral state. Disruption of autophagosomes and lysosomes (methionine-O-methyl ester), but not lysosomes alone (glycyl-L-phenylalanine) reversed LPS-induced inhibition of virus replication, without influencing the PMA-induced antiviral effect. Thus, PMA is similar to LPS in inhibiting monocyte to macrophage differentiation, when primary blood monocytes are employed, but not all pathways are equally susceptible. The analyses demonstrate that the pathways modulated during monocyte differentiation function somewhat independently. Moreover, certain functions of monocytic cells are more important with respect to the outcome of virus infection, with autophagosomal activities in particular favouring cell survival.
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PMID:Lipopolysaccharide and phorbol 12-myristate 13-acetate both impair monocyte differentiation, relating cellular function to virus susceptibility. 1152 40

The active sites of the membrane-bound nucleoside triphosphate diphosphohydrolases (NTPDases) regulate and are regulated by coordinated and spatially distant movements of their transmembrane helices, modulating enzyme activity, and substrate specificity. Using site-directed mutagenesis, the roles of the conserved proline residues (N-terminal: P52 and P53; C-terminal: P472, P476, P481, P484, and P485) of human NTPDase3, located in the "linker regions" that connect the N- and C-terminal transmembrane helices with the extracellular active site, were examined. Single cysteine substitutions were strategically placed in the transmembrane domain (N-terminal helix: V42C; C-terminal helix: G489C) to serve as cross-linking "sensors" of helical interactions. These "sensor" background mutant proteins (V42C and G489C NTPDase3) are enzymatically active and are cross-linked by copper phenanthroline less efficiently in the presence of adenosine triphosphate (ATP). Proline to alanine substitutions at P53, P481, P484, and P485 in the V42C background, as well as P53, P481, and P484 in the G489C background, exhibited decreased nucleotidase activities. More importantly, alanine substitutions at P53 and P481 in the V42C background and P481 in the G489C background no longer exhibited the ATP-induced decrease in transmembrane cross-linking efficiency. Interestingly, the P485A mutation abolished oxidative cross-linking at G489C both in the presence and absence of ATP. Taken together, these results suggest a role for proline residues 53 and 481 in the linker regions of human NTPDase3 for coupling nucleotide binding at the enzyme active site to movements and/or rearrangements of the transmembrane helices necessary for optimal nucleotide hydrolysis.
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PMID:Proline residues link the active site to transmembrane domain movements in human nucleoside triphosphate diphosphohydrolase 3 (NTPDase3). 2110 16

Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients' first relapses, which disappeared in the post-allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children's post-allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post-allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.
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PMID:Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets. 3164 13