共查询到20条相似文献,搜索用时 31 毫秒
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Annie Yang Zhou Zhu Arminja Kettenbach Philipp Kapranov Frank McKeon Thomas R. Gingeras Kevin Struhl 《PloS one》2010,5(7)
Background
The p53 homologs, p63 and p73, share ∼85% amino acid identity in their DNA-binding domains, but they have distinct biological functions.Principal Findings
Using chromatin immunoprecipitation and high-resolution tiling arrays covering the human genome, we identify p73 DNA binding sites on a genome-wide level in ME180 human cervical carcinoma cells. Strikingly, the p73 binding profile is indistinguishable from the previously described binding profile for p63 in the same cells. Moreover, the p73∶p63 binding ratio is similar at all genomic loci tested, suggesting that there are few, if any, targets that are specific for one of these factors. As assayed by sequential chromatin immunoprecipitation, p63 and p73 co-occupy DNA target sites in vivo, suggesting that p63 and p73 bind primarily as heterotetrameric complexes in ME180 cells.Conclusions
The observation that p63 and p73 associate with the same genomic targets suggest that their distinct biological functions are due to cell-type specific expression and/or protein domains that involve functions other than DNA binding. 相似文献3.
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Andrew N. Sharp Alexander E. P. Heazell Dora Baczyk Caroline E. Dunk Helen A. Lacey Carolyn J. P. Jones Jonathan E. Perkins John C. P. Kingdom Philip N. Baker Ian P. Crocker 《PloS one》2014,9(1)
Background
Preeclampsia (PE) is characterized by exaggerated apoptosis of the villous trophoblast of placental villi. Since p53 is a critical regulator of apoptosis we hypothesized that excessive apoptosis in PE is mediated by abnormal expression of proteins participating in the p53 pathway and that modulation of the p53 pathway alters trophoblast apoptosis in vitro.Methods
Fresh placental villous tissue was collected from normal pregnancies and pregnancies complicated by PE; Western blotting and real-time PCR were performed on tissue lysate for protein and mRNA expression of p53 and downstream effector proteins, p21, Bax and caspases 3 and 8. To further assess the ability of p53 to modulate apoptosis within trophoblast, BeWo cells and placental villous tissue were exposed to the p53-activator, Nutlin-3, alone or in combination with the p53-inhibitor, Pifithrin-α (PFT- α). Equally, Mdm2 was knocked-down with siRNA.Results
Protein expression of p53, p21 and Bax was significantly increased in pregnancies complicated by PE. Conversely, Mdm2 protein levels were significantly depleted in PE; immunohistochemistry showed these changes to be confined to trophoblast. Reduction in the negative feedback of p53 by Mdm2, using siRNA and Nutlin-3, caused an imbalance between p53 and Mdm2 that triggered apoptosis in term villous explants. In the case of Nutlin, this was attenuated by Pifithrin-α.Conclusions
These data illustrate the potential for an imbalance in p53 and Mdm2 expression to promote excessive apoptosis in villous trophoblast. The upstream regulation of p53 and Mdm2, with regard to exaggerated apoptosis and autophagy in PE, merits further investigation. 相似文献6.
Cristina Lanni Lavinia Nardinocchi Rosa Puca Serena Stanga Daniela Uberti Maurizio Memo Stefano Govoni Gabriella D'Orazi Marco Racchi 《PloS one》2010,5(4)
Background
Homeodomain interacting protein kinase 2 (HIPK2) is an evolutionary conserved serine/threonine kinase whose activity is fundamental in maintaining wild-type p53 function, thereby controlling the destiny of cells when exposed to DNA damaging agents. We recently reported an altered conformational state of p53 in tissues from patients with Alzheimer''s Disease (AD) that led to an impaired and dysfunctional response to stressors.Methodology/Principal Findings
Here we examined the molecular mechanisms underlying the impairment of p53 activity in two cellular models, HEK-293 cells overexpressing the amyloid precursor protein and fibroblasts from AD patients, starting from recent findings showing that p53 conformation may be regulated by HIPK2. We demonstrated that beta-amyloid 1–40 induces HIPK2 degradation and alters HIPK2 binding activity to DNA, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus. Expression of HIPK2 was analysed by western blot experiments, whereas HIPK2 DNA binding was examined by chromatin immunoprecipitation analysis. In particular, we evaluated the recruitment of HIPK2 onto some target promoters, including hypoxia inducible factor-1α and metallothionein 2A.Conclusions/Significance
These results support the existence of a novel amyloid-based pathogenetic mechanism in AD potentially leading to the survival of injured dysfunctional cells. 相似文献7.
Background
Disruption of the nucleolus often leads to activation of the p53 tumor suppressor pathway through inhibition of MDM2 that is mediated by a limited set of ribosomal proteins including RPL11 and RPL5. The effects of ribosomal protein loss in cultured mammalian cells have not been thoroughly investigated. Here we characterize the cellular stress response caused by depletion of ribosomal protein S9 (RPS9).Methodology/Principal Findings
Depletion of RPS9 impaired production of 18S ribosomal RNA and induced p53 activity. It promoted p53-dependent morphological differentiation of U343MGa Cl2:6 glioma cells as evidenced by intensified expression of glial fibrillary acidic protein and profound changes in cell shape. U2OS osteosarcoma cells displayed a limited senescence response with increased expression of DNA damage response markers, whereas HeLa cervical carcinoma cells underwent cell death by apoptosis. Knockdown of RPL11 impaired p53-dependent phenotypes in the different RPS9 depleted cell cultures. Importantly, knockdown of RPS9 or RPL11 also markedly inhibited cell proliferation through p53-independent mechanisms. RPL11 binding to MDM2 was retained despite decreased levels of RPL11 protein following nucleolar stress. In these settings, RPL11 was critical for maintaining p53 protein stability but was not strictly required for p53 protein synthesis.Conclusions
p53 plays an important role in the initial restriction of cell proliferation that occurs in response to decreased level of RPS9. Our results do not exclude the possibility that other nucleolar stress sensing molecules act upstream or in parallel to RPL11 to activate p53. Inhibiting the expression of certain ribosomal proteins, such as RPS9, could be one efficient way to reinitiate differentiation processes or to induce senescence or apoptosis in rapidly proliferating tumor cells. 相似文献8.
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Beate B?hm Harald Burkhardt Steffen Uebe Maria Apel Frank Behrens André Reis Ulrike Hüffmeier 《Arthritis research & therapy》2012,14(2):R84-5
Introduction
In recent genome-wide association studies for psoriatic arthritis (PsA) and psoriasis vulgaris, common coding variants in the TRAF3IP2 gene were identified to contribute to susceptibility to both disease entities. The risk allele of p.Asp10Asn (rs33980500) proved to be most significantly associated and to encode a mutant protein with an almost completely disrupted binding property to TRAF6, supporting its impact as a main disease-causing variant and modulator of IL-17 signaling.Methods
To identify further variants, exons 2-4 encoding both known TNF-receptor-associated factor (TRAF) binding domains were sequenced in 871 PsA patients. Seven missense variants and one three-base-pair insertion were identified in 0.06% to 1.02% of alleles. Five of these variants were also present in 931 control individuals at comparable frequency. Constructs containing full-length wild-type or mutant TRAF3IP2 were generated and used to analyze functionally all variants for TRAF6-binding in a mammalian two-hybrid assay.Results
None of the newly found alleles, though, encoded proteins with different binding properties to TRAF6, or to the cytoplasmic tail of the IL-17-receptor α-chain, suggesting that they do not contribute to susceptibility.Conclusions
Thus, the TRAF3IP2-variant p.Asp10Asn is the only susceptibility allele with functional impact on TRAF6 binding, at least in the German population. 相似文献10.
Heba Bassiony Salwa Sabet Taher A. Salah El-Din Mona M. Mohamed Akmal A. El-Ghor 《PloS one》2014,9(11)
Background
Magnetite nanoparticles (MNPs) have been widely used as contrast agents and have promising approaches in cancer treatment. In the present study we used Ehrlich solid carcinoma (ESC) bearing mice as a model to investigate MNPs antitumor activity, their effect on expression of p53 and p16 genes as an indicator for apoptotic induction in tumor tissues.Method
MNPs coated with ascorbic acid (size: 25.0±5.0 nm) were synthesized by co-precipitation method and characterized. Ehrlich mice model were treated with MNPs using 60 mg/Kg day by day for 14 injections; intratumorally (IT) or intraperitoneally (IP). Tumor size, pathological changes and iron content in tumor and normal muscle tissues were assessed. We also assessed changes in expression levels of p53 and p16 genes in addition to p53 protein level by immunohistochemistry.Results
Our results revealed that tumor growth was significantly reduced by IT and IP MNPs injection compared to untreated tumor. A significant increase in p53 and p16 mRNA expression was detected in Ehrlich solid tumors of IT and IP treated groups compared to untreated Ehrlich solid tumor. This increase was accompanied with increase in p53 protein expression. It is worth mentioning that no significant difference in expression of p53 and p16 could be detected between IT ESC and control group.Conclusion
MNPs might be more effective in breast cancer treatment if injected intratumorally to be directed to the tumor tissues. 相似文献11.
Wenrui Duan Li Gao Xin Wu Erinn M. Hade Jian-Xin Gao Haiming Ding Sanford H. Barsky Gregory A. Otterson Miguel A. Villalona-Calero 《PloS one》2009,4(5)
Background
Mutations in the P53 gene are among the most common genetic abnormalities in human lung cancer. Codon 273 in the sequence-specific DNA binding domain is one of the most frequently mutated sites.Methodology
To investigate the role of mutant p53 in lung tumorigenesis, a lung specific p53(273H) transgenic mouse model was developed. Rates of lung cancer formation in the transgenic animals and their littermates were evaluated by necropsy studies performed in progressive age cohorts ranging from 4 to 24 months. In order to establish the influence of other common genetic abnormalities in lung tumor formation in the animals, K-Ras gene mutation and p16INK4a (p16) promoter methylation were evaluated in a total of 281 transgenic mice and 189 non-transgenic littermates.Principal Findings
At the age extremes of 4–12 and 22–24 months no differences were observed, with very low prevalence of tumors in animals younger than 12 months, and a relatively high prevalence at age 22 months or older. However, the transgenic mice had a significant higher lung tumor rate than their non-transgenic counterparts during the age of 13–21 months, suggesting an age-related shift in lung tumor formation induced by the lung-specific expression of the human mutant p53. Histopathology suggested a more aggressive nature for the transgenic tumors. Older mice (>13 months) had a significantly higher rate of p16 promoter methylation (17% v 82%). In addition, an age related effect was observed for K-Ras codons 12 or 13 mutations, but not for codon 61 mutations.Conclusions/Significance
These results would suggest that the mutant p53(273H) contributes to an acceleration in the development of spontaneous lung tumors in these mice. Combination with other genetic and epigenetic alterations occurring after the age of 13 months is intimately linked to its oncogenic potential. 相似文献12.
Background
Malignant gliomas represent one group of tumors that poorly respond to ionizing radiation (IR) alone or combined with chemotherapeutic agents because of the intrinsic or acquired resistance. In this study, TIP-1 was identified as one novel protein that confers resistance of glioma cells to IR.Methodology/Principal Findings
Meta-analysis indicated that high TIP-1 expression levels correlate with the poor prognosis of human malignant gliomas after radiotherapy. Studies with established human glioma cell lines demonstrated that TIP-1 depletion with specific shRNAs sensitized the cells to IR, whereas an ectopic expression of TIP-1 protected the glioma cells from the IR-induced DNA damage and cell death. Biochemical studies indicated that TIP-1 protein promoted p53 ubiquitination and resulted in a reduced p53 protein level. Furthermore, p53 and its ubiquitination are required for the TIP-1 regulated cellular response to IR. A yeast two-hybrid screening identified that TIP-1, through its single PDZ domain, binds to the carboxyl terminus of LZAP that has been studied as one tumor suppressor functioning through ARF binding and p53 activation. It was revealed that the presence of TIP-1 enhances the protein association between LZAP and ARF and modulates the functionality of ARF/HDM2 toward multi-ubiquitination of p53, while depleting TIP-1 rescued p53 from polyubiquitination and degradation in the irradiated glioma cells. Studies with a mouse xenograft model indicated that depleting TIP-1 within D54 cells improved the tumor growth control with IR.Conclusions/Significance
This study provided the first evidence showing that TIP-1 modulates p53 protein stability and is involved in the radioresistance of malignant gliomas, suggesting that antagonizing TIP-1 might be one novel approach to sensitize malignant gliomas to radiotherapy. 相似文献13.
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Chi-Jung Huang Shung-Haur Yang Chia-Long Lee Yu-Che Cheng Szu-Yun Tai Chih-Cheng Chien 《PloS one》2013,8(6)
Background
The development and progression of colorectal cancer (CRC) involve a complex process of multiple genetic changes. Tumor suppressor p53 is capable of determining the fate of CRC cells. However, the role of a p53-inducible modulator, ribosomal protein S27-like (RPS27L), in CRC is unknown.Methods
Here, the differential expression of RPS27L was examined in the feces and colonic tissues of CRC patients, to explore its possible correlation with patient survival and to investigate the cellular mechanisms underlying their clinical outcomes. Eighty intermediate-stage CRC patients (42 at stage II and 38 at stage III) were divided into two groups according to their fecal RPS27L mRNA levels. The survival probabilities of the groups were estimated using the Kaplan–Meier method. The RPS27L protein in the colonic tissues of stage III patients with different prognoses was further examined immunohistochemically. RPS27L expression in LoVo cells was manipulated to examine the possible cellular responses in vitro.Results
Elevated RPS27L expression, in either feces or tissues, was related to a better prognosis. In vitro, RPS27L-expressing LoVo cells ceased DNA synthesis and apoptotic activity while the expression of their DNA repair molecules was upregulated.Conclusions
Elevated RPS27L may improve the prognoses of certain CRC patients by enhancing the DNA repair capacity of their colonic cells, and can be determined in feces. By integrating clinical, molecular, and cellular data, our study demonstrates that fecal RPS27L may be a useful index for predicting prognoses and guiding personalized therapeutic strategies, especially in patients with intermediate-stage CRC. 相似文献18.
Background
The laminin receptors (LRs) play important roles in cell adhesion to the extracellular matrix, certain cell-cell adhesions, and the activation of many intracellular signaling pathways. Studies of LRs have primarily focused on mammals, while few studies of LRs in marine invertebrates have been reported. The functions of LRs in marine bivalve species are still unclear.Methodology/Principal Findings
In this study, we cloned and sequenced an LR gene, MmeLR, from the clam Meretrix meretrix. The MmeLR mRNA and protein detected by realtime PCR and western blots were primarily distributed in muscle tissues. Far-western analysis showed a specific interaction between recombinant MmeLR and the LR ligand laminin. The results of the binding assay suggested a role of LR in cell adhesion and apoptosis in cultured primary cells of mantle tissues from M. meretrix. The Bcl-2 mRNA expression level in primary cells cultured in matrigel (mainly laminin) coated plates was significantly higher than in cells cultured in non-coated plates at 48 h of culture, while the p53 mRNA expression pattern was inversely related to that of bcl-2, suggesting that MmeLR is involved in p53-dependent apoptosis, and the binding between MmeLR and laminin inhibits apoptosis during primary cell culture.Conclusions
Our results suggest that MmeLR may be involved in cell adhesion and apoptosis. This study may increase the understanding of the role of laminin receptor in cell adhesion and apoptosis and help to improve the culture of primary cells of marine invertebrates. 相似文献19.
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