“Oncogenic mutations inactivate the tumor suppressor p53 b


“Oncogenic mutations inactivate the tumor suppressor p53 by lowering

its stability or by weakening its binding to DNA Alkylating agents that reactivate OSI-027 ic50 mutant p53 are currently being explored for cancer therapy We have discovered ligands containing an alpha,beta-unsaturated double bond, characteristic of Michael acceptors, that bind covalently to generic cysteine sites in the p53 core domain They raised the melting temperature of the core domain of wild-type p53 and the hotspot mutants R175H, Y220C, G245S, R249S, and R282 by up to 3 degrees C Analysis of the relative reactivity of the cysteines in p53 by mass spectrometry found that C124 and C141 react first, followed by C135, https://www.selleckchem.com/products/CAL-101.html C182, and C277, and eventually C176 and C275 Post-translational modifications of cysteines are known to be involved in regulation of other transcription factors Modification of C277, which sits on the DNA-binding surface, may, for example, play

a role in regulating p53 activity in cells in response to environmental cues We found that the modifications progressively reduced DNA-binding activity of full-length p53 In light of these results, it is likely that the anticancer activity of the alkylating drugs works via a nontranscriptional activity of p53″
“Developmental exposure to endocrine disrupting drugs and environmental toxicants has been shown to alter a variety of physiological processes in mature offspring. Body (core) temperature (T-c) is a tightly regulated homeostatic system but is susceptible to disruptors of the hypothalamic pituitary thyroid (HPT) axis. We hypothesized that thermoregulation would be disrupted in adult offspring exposed perinatally to an HPT disruptor. Propylythiouracil (PTU) was used as a prototypical compound because of its well known antithyroidal properties. FLU was added to the drinking water of pregnant rats in concentrations of 0, 1, 2, 3, and 10 ppm from gestational day (GD) 6 through postnatal

day (PND) 21. Adult male offspring were implanted with radiotransmitters to monitor T-c and motor activity (MA) and were observed undisturbed at an Fedratinib chemical structure ambient temperature of 22 degrees C for 12 consecutive days. Data were averaged into a single 24 hour period to minimize impact of ultradian changes in T-c and MA. All treatment groups showed a distinct circadian temperature rhythm. Rats exposed to 10 ppm FLU exhibited a marked deviation in their regulated T-c with a reduction of approximately 0.4 degrees C below that of controls throughout the daytime period and a smaller reduction at night. Rats exposed to 1 or 2 ppm also had smaller but significant reductions in T-c. MA was unaffected by PTU. Overall, developmental exposure to moderate doses of an antithyroidal drug led to an apparent permanent reduction in T-c of adult offspring that was independent of changes in MA Published by Elsevier Inc.

Comments are closed.