Because activation of p53 can trigger cell cycle arrest and apoptosis, it is necessary for a cell to suppress this activation until it is absolutely required for survival. The mechanisms underlying this important regulatory event are poorly understood. Here we show that nucleophosmin (NPM) acts as a natural repressor of p53 by setting a threshold for p53 activation in response to UV radiation. NPM binds to the p53 N terminus and inhibits p53 transcriptional activity by more than 70%. Our data indicate that the levels of NPM in a cell determine the UV dose at which the tumor suppressor p53 can be phosphorylated on Ser15. Moreover, we show that NPM is a substrate for the UV-activated protein kinase ATR and inhibits the UV-induced p53 phosphorylation at Ser15. In addition, NPM forms a complex with p53 and ATR in vivo. These data suggest that NPM is an early responder to DNA damage that prevents premature activation of p53. In normal cells, NPM could contribute to suppressing p53 activation until its functions are absolutely required while in cancer cells overexpression of NPM could contribute to p53 inactivation and tumor progression.Activation of the tumor suppressor p53 in response to DNA damage is an important event that prevents a normal cell from undergoing cellular aberrations that can lead to cancer progression. Because p53 can trigger cell cycle arrest or apoptosis, it is fundamental that the activation of p53 remains in check until it is absolutely required for cellular homeostasis. The restraint on p53 must be sufficient to allow normal growth and development while allowing it to retain the capacity for rapid induction in response to stress associated with tumor progression (28). In recent years, much emphasis has been put on the mechanisms that activate p53 in response to genotoxic stress, but little is known about how p53 functions are kept on hold under normal or low-stress conditions. Here we show data indicating that nucleophosmin (NPM) is a natural repressor of p53 that sets a threshold for p53 response to UV radiation.NPM, also known as B23, NO38, and numatrin (30), is a nucleolar protein that was initially identified as an important player in ribosome biogenesis (5). Since then a number of cellular activities associated with NPM indicate that the protein has multiple functions, especially in cell proliferation. For example, in anaplastic large-cell lymphoma NPM is fused to a receptor tyrosine kinase (anaplastic lymphoma kinase [ALK]) and works as an oncogene (10). NPM protein levels are 20 times higher in Novikoff hepatoma and 5 times higher in hypertrophic rat liver than in normal rat liver (5). NPM binds to pRb and synergistically stimulates DNA polymerase ␣ (25). NPM also binds to interferon regulatory factor 1 (IRF-1) and inhibits its tumor suppression function, probably by preventing expression of p21 (19). Another indication of NPM's role in cell proliferation is its association with the nucleolar organizer regions. The nucleolar organizer regions correlate with cell proliferation and tumor ...
factors associated with prevalent and incident BV in women and their sexual partners. Data from the cross-sectional study will be presented. Methods WSW were recruited using internet, festival and mediabased promotion and were ineligible if they are postmenopausal, pregnant or had not had a female sex partner (FSP) in the last 18 months. Study-kits containing consent forms, questionnaires, swabs and slides were sent to participants and returned by post. At baseline, women self-collected three consecutive vaginal swabs and slides at weekly intervals and completed detailed demographic behavioural data via an online or paper-based questionnaire. Gramstained self-collected vaginal smears (SCVS) were scored by the Nugent method. Women were classified as having prevalent BV if $1 slides had a Nugent score (NS) of 7e10, intermediate flora if $1 slides had a NS¼4e6 and normal flora if all three slides had a NS¼0e3. Univariate and multivariate analyses were performed using SPSS to examine the association between BV and behavioural practices. Results In February 2011, 342 (86%) women had been recruited and 314 (92%) women had completed all cross-sectional requirements. Median age was 31 years (range 19e49), 309 (98%) reported a FSP in the last year, 253 (81%) had a current sexual partner (95% female) and 246 (78%) reported vaginal sex with a male in the past. The prevalence of BV was 29% (95% CI 20% to 38%) in women providing $1 SCVS. Two hundred and seventy-five (88%) women provided all three SCVS of which 178 (65%) had stable normal flora on all slides, 56 (20%) stable BV and 41 (15%) had unstable flora transitioning between $1 Nugent categories over the three slides. Multivariate analysis found that being a current smoker of cigarettes or marijuana (Adjusted OR AOR ¼2.2; 95% CI: 1.3% to 3.8%) and having >5 lifetime FSPs (AOR ¼1.8; 1.0 to 3.01) was significantly associated with prevalent BV. A borderline association with FSP receptive oral sex (AOR¼3.2; 0.9 to 11.0) was evident. BV was not associated with increased age or numbers of male partners. Conclusion Prevalent BV is common (30%) in WSW and is strongly associated with smoking and increasing numbers of FSPs but not male partners. A high proportion of WSW had stable vaginal flora (85%) over a 3 week period. This study aims to advance our understanding of epidemiology of BV in WSW.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.