Uterine Deletion of Trp53 Compromises Antioxidant Responses in the Mouse Decidua

Burnum, Kristin E.; Hirota, Yasushi; Baker, Erin; Yoshie, Mikihiro; Ibrahim, Yehia; Monroe, Matthew E.; Anderson, Gordon A.; Smith, Richard D.; Daikoku, Takiko; Dey, Sudhansu K.

doi:10.1210/en.2012-1335

Cited by 35 publications

(40 citation statements)

References 49 publications

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“…TRP53 polymorphisms have also been associated with aging and lifespan in humans (36,54). Our recent proteomics study showed that deciduae in Trp53 loxP/loxP Pgr Cre/+ females manifest an increased signature for oxidative stress, with downregulation of many antioxidant enzymes, including PRDX6 (24). PRDX6 plays a role during pregnancy in mice with deletion of Fkbp52, an immunophilin co-chaperone for nuclear PR, which show reduced uterine P 4 responsiveness (55-57).…”

Section: Figurementioning

confidence: 99%

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Cha¹,

Bartos²,

Egashira³

et al. 2013

J. Clin. Invest.

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There are currently more than 15 million preterm births each year. We propose that gene-environment interaction is a major contributor to preterm birth. To address this experimentally, we generated a mouse model with uterine deletion of Trp53, which exhibits approximately 50% incidence of spontaneous preterm birth due to premature decidual senescence with increased mTORC1 activity and COX2 signaling. Here we provide evidence that this predisposition provoked preterm birth in 100% of females exposed to a mild inflammatory insult with LPS, revealing the high significance of gene-environment interactions in preterm birth. More intriguingly, preterm birth was rescued in LPS-treated Trp53-deficient mice when they were treated with a combination of rapamycin (mTORC1 inhibitor) and progesterone (P 4 ), without adverse effects on maternal or fetal health. These results provide evidence for the cooperative contributions of two sites of action (decidua and ovary) toward preterm birth. Moreover, a similar signature of decidual senescence with increased mTORC1 and COX2 signaling was observed in women undergoing preterm birth. Collectively, our findings show that superimposition of inflammation on genetic predisposition results in high incidence of preterm birth and suggest that combined treatment with low doses of rapamycin and P 4 may help reduce the incidence of preterm birth in high-risk women.

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Section: Figurementioning

confidence: 99%

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Cha¹,

Bartos²,

Egashira³

et al. 2013

J. Clin. Invest.

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“…In mice, persistently high levels of senescent cells in uteri by tissue-specific deletion of the tumor protein p53 (Trp53) gene in progesterone receptor-expressing cells also reduced decidual growth without altering the number of implantation sites (Hirota et al 2010). Further proteomic analysis on these mice showed downregulated expression of a cluster of antioxidant enzymes in Trp53-deficient decidua (Burnum et al 2012), implicating the involvement of oxidative stress with increased presence of senescent cells in the uterus. Moreover, these tissue-specific Trp53-deficient mice have increased the incidence of preterm birth and neonatal deaths, partly due to the activation of a prostaglandinmediated pathway (Hirota et al 2010).…”

Section: Cellular Senescence and Uterine Agingmentioning

confidence: 99%

Positive and negative effects of cellular senescence during female reproductive aging and pregnancy

Velarde

Menon

2016

Journal of Endocrinology

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Cellular senescence is a phenomenon occurring when cells are no longer able to divide even after treatment with growth stimuli. Because senescent cells are typically associated with aging and age-related diseases, cellular senescence is hypothesized to contribute to the age-related decline in reproductive function. However, some data suggest that senescent cells may also be important for normal physiological functions during pregnancy. Herein, we review the positive and negative effects of cellular senescence on female reproductive aging and pregnancy. We discuss how senescent cells accelerate female reproductive aging by promoting the decline in the number of ovarian follicles and increasing complications during pregnancy. We also describe how cellular senescence plays an important role in placental and fetal development as a beneficial process, ensuring proper homeostasis during pregnancy.

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“…Identification and quantification of the detected peptide peaks were performed using the AMT tag approach (17,27,28). Both Q Exactive and IMS-MS analyses were utilized to populate the database with LC elution times, IMS drift times and accurate mass information for each peptide tag ( Fig.…”

Section: Experimental Design and Statistical Rational: Lc-ms And Lc-imentioning

confidence: 99%

“…Peptides observed in each instrument were compared, and only those agreeing with high mass accuracy (within 2 ppm) and LC elution time (Ͻ0.5%) were populated with IMS drift times in the PDX tumor database used in this work (28). The LC-MS and LC-IMS-MS raw data were processed using in-house developed informatics tools (publicly available at https://omics.pnl.gov/software) with algorithms for peak-picking and determining isotopic distributions and charge states for feature definition (30).…”

Section: Experimental Design and Statistical Rational: Lc-ms And Lc-imentioning

confidence: 99%

“…The detected features were then correlated (i.e. aligned) with the PDX tumor AMT tag database (28). Further downstream data analysis incorporated all possible detected peptides into the VIPER visualization program to associate LC-MS features and the peptide identifications in the AMT tag database (31).…”

Section: Experimental Design and Statistical Rational: Lc-ms And Lc-imentioning

confidence: 99%

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Simultaneous Proteomic Discovery and Targeted Monitoring using Liquid Chromatography, Ion Mobility Spectrometry, and Mass Spectrometry

Nie

Casey

Monroe

et al. 2016

Molecular & Cellular Proteomics

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Current proteomic approaches include both broad discovery measurements and quantitative targeted analyses. In many cases, discovery measurements are initially used to identify potentially important proteins (e.g. candidate biomarkers) and then targeted studies are employed to quantify a limited number of selected proteins. Both approaches, however, suffer from limitations. Discovery measurements aim to sample the whole proteome but have lower sensitivity, accuracy, and quantitation precision than targeted approaches, whereas targeted measurements are significantly more sensitive but only sample a limited portion of the proteome. Herein, we describe a new approach that performs both discovery and targeted monitoring (DTM) in a single analysis by combining liquid chromatography, ion mobility spectrometry and mass spectrometry (LC-IMS-MS). In DTM, heavy labeled target peptides are spiked into tryptic digests and both the labeled and unlabeled peptides are detected using LC-IMS-MS instrumentation. Compared with the broad LC-MS discovery measurements, DTM yields greater peptide/protein coverage and detects lower abundance species. DTM also achieved detection limits similar to selected reaction monitoring (SRM) indicating its potential for combined high quality discovery and targeted analyses, which is a significant step toward the convergence of discovery and targeted approaches. The application of both discovery and targeted proteomics approaches is increasingly important across many areas of biological research, such as elucidating molecular mechanism of disease progression and increasing the utility of clinical applications to facilitate early detection and prognostic classification (1, 2). Currently discovery and targeted approaches are performed separately, limiting sample throughput and requiring more material for thorough analyses. In the prevalent discovery-based shotgun approach (3-6), proteins are digested into peptides, separated by liquid chromatography (LC) 1 , and detected by mass spectrometry (MS), where specific peptides are further selected (typically by abundance) for successive tandem MS/MS for identification. The resulting spectra are then mapped to peptide or protein sequences using highly-evolved database search algorithms with results normally obtained for thousands of unique proteins. However, the large numbers of coeluting peptides and use of MS/MS inevitably limit proteomic measurement effectiveness by at least one of three key metrics: throughput, sensitivity, and proteome coverage. To increase proteome coverage additional fractionation steps and/or extended LC separations are often applied. Although this is advantageous for increasing the comprehensiveness and sensitivity of measurements, the reduced throughput greatly restricts the ability to account for both measurement and biological variability. Additionally, these broad discovery measurements still suffer deficiencies

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Uterine Deletion of Trp53 Compromises Antioxidant Responses in the Mouse Decidua

Cited by 35 publications

References 49 publications

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Positive and negative effects of cellular senescence during female reproductive aging and pregnancy

Simultaneous Proteomic Discovery and Targeted Monitoring using Liquid Chromatography, Ion Mobility Spectrometry, and Mass Spectrometry

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