111 research outputs found

    TAp63 Is a Master Transcriptional Regulator of Lipid and Glucose Metabolism

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    SummaryTAp63 prevents premature aging, suggesting a link to genes that regulate longevity. Further characterization of TAp63−/− mice revealed that these mice develop obesity, insulin resistance, and glucose intolerance similar to those seen in mice lacking two key metabolic regulators, Silent information regulator T1 (Sirt1) and AMPK. While the roles of Sirt1 and AMPK in metabolism have been well studied, their upstream regulators are not well understood. We found that TAp63 is important in regulating energy metabolism by accumulating in response to metabolic stress and transcriptionally activating Sirt1, AMPKα2, and LKB1, resulting in increased fatty acid synthesis and decreased fatty acid oxidation. Moreover, we found that TAp63 lowers blood glucose levels in response to metformin. Restoration of Sirt1, AMPKα2, and LKB1 in TAp63−/− mice rescued some of the metabolic defects of the TAp63−/− mice. Our study defines a role for TAp63 in metabolism and weight control

    Infección por VPH en mujeres con artritis reumatoide

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    Antecedentes: el virus del papiloma humano (VPH) es el principal factor de riesgo de cáncer de cuello uterino, que sigue siendo la neoplasia más frecuente en nuestro país. Existen datos que muestran que los pacientes con inmunosupresión son más propensos a la infección por VPH. Objetivo: determinar la frecuencia de la infección por VPH en pacientes con artritis reumatoide comparada con mujeres pareadas por edad de población abierta. Material y métodos: estudio transversal, comparativo y observacional en mujeres con artritis reumatoide y mujeres sin enfermedad reumática a las que se les realizó citología cervical, detección y tipificación del VPH. Se analizaron los datos mediante las pruebas de la ji al cuadrado, exacta de Fisher, Mann Whitney y razón de momios. Resultados: se incluyeron 77 mujeres con artritis reumatoide comparadas con un grupo de 77 mujeres sin artritis reumatoide y de edad similar. Se encontró una frecuencia de infección por VPH en 37 pacientes con artritis reumatoide (48%) contra 17 mujeres sin ésta (22%) [OR 3.1551 IC 95%(1.56 – 6.35) p= 0.001]. Los tipos de VPH 83 y 59 fueron más frecuentes en las mujeres con artritis reumatoide mientras en los controles se encontró el 59, 81 y 54. No se encontró relación con la duración de la enfermedad, el uso de esteroides o inmunosupresión. Conclusiones: la infección por VPH es más frecuente en mujeres con artritis reumatoide comparada con las que no tienen esta enfermedad reumática

    Tumor predisposition in mice mutant for p63 and p73: Evidence for broader tumor suppressor functions for the p53 family

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    Summaryp63 and p73 are functionally and structurally related to the tumor suppressor p53. However, their own role in tumor suppression is unclear. Given the p53-like properties of p63 and p73, we tested whether they are involved in tumor suppression by aging mice heterozygous for mutations in all p53 family genes and scored for spontaneous tumors. We show here that p63+/−;p73+/− mice develop spontaneous tumors. Loss of p63 and p73 can also cooperate with loss of p53 in tumor development. Mice heterozygous for mutations in both p53 and p63 or p53 and p73 displayed higher tumor burden and metastasis compared to p53+/− mice. These findings provide evidence for a broader role for the p53 family than has been previously reported

    p73 is required for appropriate BMP-induced mesenchymal-to-epithelial transition during somatic cell reprogramming

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    The generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming holds great potential for modeling human diseases. However, the reprogramming process remains very inefficient and a better understanding of its basic biology is required. The mesenchymal-to-epithelial transition (MET) has been recognized as a crucial step for the successful reprogramming of fibroblasts into iPSCs. It has been reported that the p53 tumor suppressor gene acts as a barrier of this process, while its homolog p63 acts as an enabling factor. In this regard, the information concerning the role of the third homolog, p73, during cell reprogramming is limited. Here, we derive total Trp73 knockout mouse embryonic fibroblasts, with or without Trp53, and examine their reprogramming capacity. We show that p73 is required for effective reprogramming by the Yamanaka factors, even in the absence of p53. Lack of p73 affects the early stages of reprogramming, impairing the MET and resulting in altered maturation and stabilization phases. Accordingly, the obtained p73-deficient iPSCs have a defective epithelial phenotype and alterations in the expression of pluripotency markers. We demonstrate that p73 deficiency impairs the MET, at least in part, by hindering BMP pathway activation. We report that p73 is a positive modulator of the BMP circuit, enhancing its activation by DNp73 repression of the Smad6 promoter. Collectively, these findings provide mechanistic insight into the MET process, proposing p73 as an enhancer of MET during cellular reprogramming.Peer reviewe

    Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling

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    SummaryMany signals must be integrated to maintain self-renewal and pluripotency in embryonic stem cells (ESCs) and to enable induced pluripotent stem cell (iPSC) reprogramming. However, the exact molecular regulatory mechanisms remain elusive. To unravel the essential internal and external signals required for sustaining the ESC state, we conducted a short hairpin (sh) RNA screen of 104 ESC-associated phosphoregulators. Depletion of one such molecule, aurora kinase A (Aurka), resulted in compromised self-renewal and consequent differentiation. By integrating global gene expression and computational analyses, we discovered that loss of Aurka leads to upregulated p53 activity that triggers ESC differentiation. Specifically, Aurka regulates pluripotency through phosphorylation-mediated inhibition of p53-directed ectodermal and mesodermal gene expression. Phosphorylation of p53 not only impairs p53-induced ESC differentiation but also p53-mediated suppression of iPSC reprogramming. Our studies demonstrate an essential role for Aurka-p53 signaling in the regulation of self-renewal, differentiation, and somatic cell reprogramming

    TAp63 Prevents Premature Aging by Promoting Adult Stem Cell Maintenance

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    The cellular mechanisms that regulate the maintenance of adult tissue stem cells are still largely unknown. We show here that the p53 family member, TAp63, is essential for maintenance of epidermal and dermal precursors and that, in its absence, these precursors senesce and skin ages prematurely. Specifically, we have developed a TAp63 conditional knockout mouse and used it to ablate TAp63 in the germline (TAp63−/−) or in K14-expressing cells in the basal layer of the epidermis (TAp63fl/fl;K14cre+). TAp63−/− mice age prematurely and develop blisters, skin ulcerations, senescence of hair follicle-associated dermal and epidermal cells, and decreased hair morphogenesis. These phenotypes are likely due to loss of TAp63 in dermal and epidermal precursors since both cell types show defective proliferation, early senescence, and genomic instability. These data indicate that TAp63 serves to maintain adult skin stem cells by regulating cellular senescence and genomic stability, thereby preventing premature tissue aging

    ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression

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    Metastatic cancer is extremely difficult to treat, and the presence of metastases greatly reduces a cancer patient’s likelihood of long-term survival. The ZEB1 transcriptional repressor promotes metastasis through downregulation of microRNAs (miRs) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors. Given that each miR can target multiple genes with diverse functions, we posited that the prometastatic network controlled by ZEB1 extends beyond these processes. We tested this hypothesis using a mouse model of human lung adenocarcinoma metastasis driven by ZEB1, human lung carcinoma cells, and human breast carcinoma cells. Transcriptional profiling studies revealed that ZEB1 controls the expression of numerous oncogenic and tumor-suppressive miRs, including miR-34a. Ectopic expression of miR-34a decreased tumor cell invasion and metastasis, inhibited the formation of promigratory cytoskeletal structures, suppressed activation of the RHO GTPase family, and regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas. We identified several miR-34a target genes, including Arhgap1, which encodes a RHO GTPase activating protein that was required for tumor cell invasion. These findings demonstrate that ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression and provide a compelling rationale to develop miR-34a as a therapeutic agent in lung cancer patients.Young-Ho Ahn, Don L. Gibbons, Deepavali Chakravarti, Chad J. Creighton, Zain H. Rizvi, Henry P. Adams, Alexander Pertsemlidis, Philip A. Gregory, Josephine A. Wright, Gregory J. Goodall, Elsa R. Flores and Jonathan M. Kuri

    Risks to carbon storage from land-use change revealed by peat thickness maps of Peru

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    This work was funded by NERC (grant ref. NE/R000751/1) to I.T.L., A.H., K.H.R., E.T.A.M., C.M.A., T.R.B., G.D. and E.C.D.G.; Leverhulme Trust (grant ref. RPG-2018-306) to K.H.R., L.E.S.C. and C.E.W.; Gordon and Betty Moore Foundation (grant no. 5439, MonANPeru network) to T.R.B., E.N.H.C. and G.F.; Wildlife Conservation Society to E.N.H.C.; Concytec/British Council/Embajada Británica Lima/Newton Fund (grant ref. 220–2018) to E.N.H.C. and J.D.; Concytec/NERC/Embajada Británica Lima/Newton Fund (grant ref. 001–2019) to E.N.H.C. and N.D.; the governments of the United States (grant no. MTO-069018) and Norway (grant agreement no. QZA-12/0882) to K.H.; and NERC Knowledge Exchange Fellowship (grant ref no. NE/V018760/1) to E.N.H.C.Tropical peatlands are among the most carbon-dense ecosystems but land-use change has led to the loss of large peatland areas, associated with substantial greenhouse gas emissions. To design effective conservation and restoration policies, maps of the location and carbon storage of tropical peatlands are vital. This is especially so in countries such as Peru where the distribution of its large, hydrologically intact peatlands is poorly known. Here field and remote sensing data support the model development of peatland extent and thickness for lowland Peruvian Amazonia. We estimate a peatland area of 62,714 km2 (5th and 95th confidence interval percentiles of 58,325 and 67,102 km2, respectively) and carbon stock of 5.4 (2.6–10.6) PgC, a value approaching the entire above-ground carbon stock of Peru but contained within just 5% of its land area. Combining the map of peatland extent with national land-cover data we reveal small but growing areas of deforestation and associated CO2 emissions from peat decomposition due to conversion to mining, urban areas and agriculture. The emissions from peatland areas classified as forest in 2000 represent 1–4% of Peruvian CO2 forest emissions between 2000 and 2016. We suggest that bespoke monitoring, protection and sustainable management of tropical peatlands are required to avoid further degradation and CO2 emissions.PostprintPeer reviewe

    Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

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    This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin
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