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1.
Role of osteopontin in murine Lyme arthritis and host defense against Borrelia burgdorferi
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Potter MR Rittling SR Denhardt DT Roper RJ Weis JH Teuscher C Weis JJ 《Infection and immunity》2002,70(3):1372-1381
Several genetic loci in the mouse have been identified that regulate the severity of Lyme arthritis. The region of chromosome 5 including the osteopontin (OPN) gene (Opn) has been identified in intercross populations of C3H/HeN x C57BL/6 and C3H/HeJ x BALB/cAnN mice. OPN is of particular interest as it is involved in the maintenance and remodeling of tissue during inflammation, it regulates production of interleukin-10 (IL-10) and IL-12 (cytokines implicated in Lyme arthritis), it is necessary for host control of certain bacterial infections, and mice displaying different severities of Lyme arthritis possess different alleles of the OPN gene. Macrophages and splenocytes from OPN-deficient mice on mixed C57BL/6J-129S or inbred 129S backgrounds were stimulated with the Pam(3)Cys modified lipoprotein from Borrelia burgdorferi, OspA. OPN was not required for OspA-induced cytokine production; however, macrophages from 129S-Opn(-/-) mice displayed a reduced level of IL-10 production. OPN was also not required for resistance to severe arthritis, as B. burgdorferi-infected 129S-Opn(-/-) mice developed mild arthritis, as did their wild-type littermates. Arthritis was more severe in OPN-deficient mice on the mixed C57BL/6J-129S backgrounds than in inbred mice of either strain. This increase was most likely due to a gene(s) closely linked to Opn on chromosome 5 in conjunction with other randomly assorting genes. Deficiency in OPN did not influence the numbers of spirochetes in tissues from B. burgdorferi-infected mice, indicating OPN is not part of the host defense to this pathogen. Interestingly, there was no alteration in the B. burgdorferi-specific antibody isotypes in OPN-deficient mice, indicating that its effect on helper T-cell responses is not relevant to the host response to B. burgdorferi. 相似文献
2.
Keiko Danzaki Masashi Kanayama Oscar Alcazar Mari L. Shinohara 《European journal of immunology》2016,46(11):2669-2678
Osteopontin (OPN) is a protein, generally considered to play a pro‐tumorigenic role, whereas several reports have demonstrated the anti‐tumorigenic function of OPN during tumor development. These opposing anti‐ and pro‐tumorigenic functions are not fully understood. Here, we report that host‐derived OPN plays an anti‐tumorigenic role in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model and a TRAMP tumor transplant model. Tumor suppression mediated by OPN in Rag2?/? mice suggests that OPN is dispensable in the adaptive immune response. We found that host‐derived OPN enhanced infiltration of natural killer (NK) cells into TRAMP tumors. The requirement of OPN in NK cell migration towards TRAMP cells was confirmed by an ex vivo cell migration assay. In contrast to TRAMP cells, in vivo B16 tumor development was not inhibited by OPN, and B16 tumors did not show OPN‐mediated cell recruitment. It is possible that low levels of chemokine expression by B16 cells do not allow OPN to enhance immune cell recruitment. In addition to demonstrating the anti‐tumorigenic role of OPN in TRAMP tumor development, this study also suggests that the contribution of OPN to tumor development depends on the type of tumor as well as the source and isoform of OPN. 相似文献
3.
Tumor immunoevasion is an advanced phase of cancer immunosurveillance in which tumor cells acquire the ability to circumvent host immune systems and exploit protumorigenic inflammation. T-cell immunoglobulin mucin (TIM) gene family members have emerged as critical checkpoint proteins that regulate multiple immune response phases and maintain immune homeostasis. Accumulating evidence demonstrates that tumor cells exploit TIM gene family members to evade immunosurveillance, whereas TIM gene family members facilitate the prevention of inflammation-related tumor progression. Thus, a comprehensive analysis to clarify the relative contributions of TIM gene family members in tumor progression may elucidate immunosurveillance systems in cancer patients. 相似文献
4.
Yasmine Zerdoumi Juliette Aury‐Landas Catherine Bonaïti‐Pellié Céline Derambure Richard Sesboüé Mariette Renaux‐Petel Thierry Frebourg Gaëlle Bougeard Jean‐Michel Flaman 《Human mutation》2013,34(3):453-461
In contrast to other tumor suppressor genes, the majority of TP53 alterations are missense mutations. We have previously reported that in the Li–Fraumeni syndrome (LFS), germline TP53 missense mutations are associated with an earlier age of tumor onset. In a larger series, we observed that mean age of tumor onset in patients harboring dominant negative missense mutations and clearly null mutations was 22.6 and 37.5 years, respectively. To assess the impact of heterozygous germline TP53 mutations in the genetic context of the patients, we developed a new functional assay of the p53 pathway on the basis of induction of DNA damage in Epstein–Barr‐virus‐immortalized lymphocytes, followed by comparative gene‐expression profiling. In wild‐type lymphocytes, we identified a core of 173 genes whose expression was induced more than twofold, of which 46 were known p53 target genes. In LFS lymphocytes with canonical missense mutations, the number of induced genes and the level of known p53 target genes induction were strongly reduced as compared with controls and LFS lymphocytes with null mutations. These results show that certain germline missense TP53 mutations, such as those with dominant negative effect, dramatically alter the response to DNA damage. This probably explains why TP53 alterations are predominantly missense mutations. 相似文献
5.
Luo L Chen J Du Q Dumanski J Blennow E Kockum I Luthman H Lindblom A 《International journal of molecular medicine》2002,9(4):405-409
The proportions of mutation of BRCA1 and BRCA2 detected in familial breast cancer vary in different regions. Most breast cancer families in Sweden cannot be explained by mutations in the known major susceptibility genes. Our previous studies have found a high frequency of LOH in the Tp53 region in familial breast cancer suggesting a putative tumor suppressor gene in this region, and the Tp53 gene was excluded as predisposing gene in these families by mutation screening. In order to identify other candidate tumor suppressor genes responsible for familial breast cancer, we performed LOH analysis in 98 paired tumor and blood samples from 91 breast cancer families using 11 microsatellite markers on chromosome 17p. Two loci with high frequency of LOH were found. One spanned the Tp53 gene, the other was distal to Tp53. Linkage studies were performed on 17p with 11 microsatellite markers in 102 breast cancer families with no detectable mutations in the BRCA1 and BRCA2 gene. The linkage analysis did not further support any of the regions suggested by the LOH study. However, since the Tp53 gene is already known to predispose to breast cancer as well as being involved in tumor progression, it is possible that also this region, close but distal to Tp53 contains a gene involved in familial and/or sporadic breast cancer development similar to Tp53. 相似文献
6.
Jennifer S Bennetts Nanna D Rendtorff Fiona Simpson Lisbeth Tranebjaerg Carol Wicking 《Developmental dynamics》2007,236(3):843-852
The locus for autosomal recessive infantile cerebellar ataxia (CLA3 or SCAR6) has been mapped to chromosome 20q11-q13 in a single Norwegian pedigree. We identified a relatively uncharacterised mouse gene Tp53inp2, and showed that its human orthologue mapped within this candidate interval. Tp53inp2 appears to encode a mammalian-specific protein with homology to the two Tp53inp1 isoforms that respond to cellular stress and interact with p53. We show that Tp53inp2 expression is highly restricted during mouse embryogenesis, with strong expression in the developing brain and spinal cord, as well as in the sensory and motor neuron tracts of the peripheral nervous system. Given this expression pattern, the neurological phenotype of CLA3 and the chromosomal localisation of TP53INP2, we searched the coding region for mutations in samples from individuals from the CLA3 pedigree. Our failure to detect causative mutations suggests that alterations in the coding region of TP53INP2 are not responsible for ataxia in this family, although we cannot rule out changes in non-coding elements of this gene. 相似文献
7.
Genomic and proteomic profiles reveal the association of gelsolin to TP53 status and bladder cancer progression 总被引:1,自引:0,他引:1
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Sanchez-Carbayo M Socci ND Richstone L Corton M Behrendt N Wulkfuhle J Bochner B Petricoin E Cordon-Cardo C 《The American journal of pathology》2007,171(5):1650-1658
8.
High Frequency of TP53 Mutations in Juvenile Pilocytic Astrocytomas Indicates Role of TP53 in the Development of These Tumors 总被引:1,自引:0,他引:1
Vanessa M. Hayes Clemens M.F. Dirven Anke Dam Edwin Verlind Willemina M. Molenaar Jan Jakob A. Mooij Robert M.W. Hofstra Charles H.C.M. Buys 《Brain pathology (Zurich, Switzerland)》1999,9(3):463-467
In adults, the TP53 tumor suppressor gene is frequently mutated in astrocytic brain tumors which is supposed to represent an early event in their development. In juvenile pilocytic and low-grade astrocytomas, however, TP53 mutations have until now been reported as rare, which has led to the suggestion that these tumors may follow a different molecular pathogenesis with an involvement of genes other than TP53. Our analysis of 20 pilocytic and two low-grade astrocytomas of childhood, based on a comprehensive denaturing gradient gel electrophoresis (DGGE) mutation detection assay of the entire coding region, including all splice site junctions of TP53, showed mutations considered as causative in 7 of the 20 (35%) pilocytic astrocytomas and in one of the two low-grade astrocytomas. Our finding is significantly different from the mutation frequency of 1.3% (2/155) previously reported for these tumor types. This may be attributed to the mutation detection system used, which also detects mutations occurring outside the evolutionary conserved region of TP53. Our results suggest that, contrary to the present notion, TP53 mutations may well play a role in the development of juvenile astrocytomas. Furthermore, no mutations were found in tumors of patients with progression of residual tumor after postoperative follow-up. This suggests that TP53 mutations may be associated with less aggressive forms of juvenile astrocytomas, analogous to the situation in adult astrocytomas. 相似文献
9.
van Boxtel R Kuiper RV Toonen PW van Heesch S Hermsen R de Bruin A Cuppen E 《The American journal of pathology》2011,179(4):1616-1622
The TP53 tumor suppressor gene is mutated in the majority of human cancers. Inactivation of p53 in a variety of animal models results in early-onset tumorigenesis, reflecting the importance of p53 as a gatekeeper tumor suppressor. We generated a mutant Tp53 allele in the rat using a target-selected mutagenesis approach. Here, we report that homozygosity for this allele results in complete loss of p53 function. Homozygous mutant rats predominantly develop sarcomas with an onset of 4 months of age with a high occurrence of pulmonary metastases. Heterozygous rats develop sarcomas starting at 8 months of age. Molecular analysis revealed that these tumors exhibit a loss-of-heterozygosity of the wild-type Tp53 allele. These unique features make this rat highly complementary to other rodent p53 knockout models and a versatile tool for investigating tumorigenesis processes as well as genotoxic studies. 相似文献
10.
Attwooll CL McGown G Thorncroft M Stewart FJ Birch JM Varley JM 《Cancer Genetics and Cytogenetics》2002,135(2):165-172
The majority of families with classic Li-Fraumeni Syndrome (LFS) and a significant proportion of Li-Fraumeni-like (LFL) families have a germline mutation in the TP53 tumor suppressor gene. However around 20% of LFS and 60% of LFL families have no identifiable genetic defect in the coding region or splice junctions of TP53, and the genetic basis for cancer susceptibility in these families remains largely uncharacterized. To determine whether promoter mutations could be responsible for the Li-Fraumeni phenotype, we sequenced the TP53 promoter in index cases from members of classic LFS and LFL families without detectable TP53 mutations. We identified an identical single nucleotide deletion within the C/EBP- like site of the promoter in two out of eighteen such families (11%), compared to only one of a total of 366 control samples (0.3%). Although this result is highly significant (P=0.006, Fischer's exact test), the mutation did not affect the expression of TP53 in our hands. We provide evidence that this site is not utilized in the wild type TP53 promoter and further, that mutation of this site in LFS/LFL does not have a functional effect. We conclude that the sequence variant is a rare polymorphism arising within the TP53 promoter. However, the significantly increased frequency of this variant in LFS/LFL remains intriguing. 相似文献
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Michael J. Anderson Clare L. Fasching Eric J. Stanbridge Graham Casey 《Genes, chromosomes & cancer》1994,9(4):266-281
The specific transfer of normal chromosomes via microcell fusion has been instrumental in identifying putative tumor suppressor gene loci in a variety of human cancers. Using this same technique it has been proposed that the tumorigenicity of the human fibrosarcoma cell line HT1080 is controlled by functionally distinct tumor suppressor genes on human chromosomes 1 and 11. To address these results and perhaps further localize the suppressive effect to particular regions on these two chromosomes, we transferred into HTI080 seven different fibroblast-derived human chromosomes containing either intact or discrete portions of chromosome I or II. Interestingly, we found no evidence of genes on these chromosomes that could alter the growth of HT1080 either in vitro or in vivo. Based on these results we were left with the possibility that a gene, or genes, residing on an entirely different chromosome(s) was involved in the tumorigenesis of HTI080. Since TP53 mutation has been documented in a variety of human tumor types, and we found both copies of TP53 to be mutated in HTI080, we were prompted to examine its role by both cDNA transfection and chromosome transfer. Although by cDNA transfection we found that expression of exogenous wild-type TP53 was incompatible with continued proliferation of HTI080 cells in vitro, chromosome 17 transfer studies revealed that a more physiologic expression of exogenous wild-type TP53 could be tolerated in vitro while being completely incompatible with growth in vivo. These studies demonstrate a differential effect of TP53 growth inhibition and clearly show that TP53 tumor suppressing function can be independent from its potent growth suppressing effect in vitro. Genes Chrom Cancer 9:266-281 (1994). © 1994 Wiley-Liss, Inc. 相似文献
13.
Cameron CE 《Infection and immunity》2003,71(5):2525-2533
Host extracellular matrix (ECM) components represent ideal microbial adhesion targets that many pathogens use for colonization of tissues and initiation of infection. This study investigated the interaction of the spirochete Treponema pallidum with the ECM component laminin. To identify candidate laminin-binding adhesins, the T. pallidum genome was analyzed to predict open reading frames that encode putative outer membrane proteins, as these proteins interact directly with host ECM components. Subsequent recombinant expression of these proteins and analysis of their laminin-binding potential identified one protein, Tp0751, that demonstrated specific attachment to laminin. Tp0751 attached to laminin in a dose-dependent, saturable manner but did not attach to the ECM component collagen type I or IV or to the negative control proteins fetuin or bovine serum albumin. Sodium metaperiodate treatment of laminin reduced the Tp0751-laminin interaction in a concentration-dependent manner, suggesting that oligosaccharides play a role in this interaction. In addition, Tp0751-specific antibodies were detected in serum samples collected from both experimental and natural syphilis infections, indicating that Tp0751 is expressed in vivo during the course of infection. Collectively, these experiments identified Tp0751 as a laminin-binding protein that is expressed during infection and may be involved in attachment of T. pallidum to host tissues. 相似文献
14.
Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice 总被引:2,自引:0,他引:2
Miyazaki T Ono M Qu WM Zhang MC Mori S Nakatsuru S Nakamura Y Sawasaki T Endo Y Nose M 《European journal of immunology》2005,35(5):1510-1520
Potentially, autoimmune diseases develop from a combination of multiple genes with allelic polymorphisms. An MRL/Mp-Fas(lpr) (/) (lpr) (MRL/lpr) strain of mice develops autoimmune diseases, including lupus nephritis, but another lpr strain, C3H/HeJ-Fas(lpr) (/) (lpr) (C3H/lpr) does not. This indicates that MRL polymorphic genes are involved in the development of the diseases. By quantitative trait loci (QTL) analysis using 527 of the (MRL/lpr x C3H/lpr)F(2) mice, we identified a novel locus for susceptibility to lupus nephritis at map position D5Mit115 on chromosome 5, the same alias of the osteopontin (Opn) gene (LOD score =4.0), susceptible in the MRL allele. In functional analyses of the MRL and C3H Opn alleles using synthetic osteopontin (OPN) made with a new method "cell-free system" with wheat germ ribosomes, the MRL-OPN induced higher expression and production of immunoglobulins as well as cytokines including TNF-alpha, IL-1beta and IFN-gamma in splenocytes and/or macrophages than that of the C3H allele. These findings suggest that allelic polymorphism of OPN causes the functional differences in antibody production and macrophage activation between MRL and C3H strains, possibly involved in the development of lupus nephritis. 相似文献
15.
Chunmei Ye Shengzhe Lin Jingwen Hong Fang Liu Guoxiang Guo Shuping Chen Zhifeng Zhou Wansong Lin Jieyu Li Yunbin Ye 《European journal of immunology》2023,53(5):2250054
High-frequency mutation of the TP53 tumor suppressor gene is observed in multiple human cancers, which promotes cancer progression. However, the mutated gene-encoded protein may serve as a tumor antigen to elicit tumor-specific immune responses. In this study, we detected widespread expression of shared TP53-Y220C neoantigen in hepatocellular carcinoma with low affinity and low stability of binding to HLA-A0201 molecules. We substituted the amino acid sequences VVPCEPPEV with VLPCEPPEV in the TP53-Y220C neoantigen to yield a TP53-Y220C (L2) neoantigen. This altered neoantigen was found to increase affinity and stability and induce more cytotoxic T lymphocytes (CTLs), indicating improvements in immunogenicity. In vitro assays showed the cytotoxicity of CTLs stimulated by both TP53-Y220C and TP53-Y220C (L2) neoantigens against multiple HLA-A0201-positive cancer cells expressing TP53-Y220C neoantigens; however, the TP53-Y220C (L2) neoantigen showed higher cytotoxicity than the TP53-Y220C neoantigen against cancer cells. More importantly, in vivo assays demonstrated greater inhibition of hepatocellular carcinoma cell proliferation by TP53-Y220C (L2) neoantigen-specific CTLs relative to TP53-Y220C neoantigen in zebrafish and nonobese diabetic/severe combined immune deficiency mouse models. The results of this study demonstrate enhanced immunogenicity of the shared TP53-Y220C (L2) neoantigen, which has the potential as dendritic cells or peptide vaccines for multiple cancers. 相似文献
16.
Horie S Endo K Kawasaki H Terada T 《Virchows Archiv : an international journal of pathology》2000,437(1):25-30
Aberration of the p53 gene is thought to be the most frequent genetic alteration in human cancers. Tp53 protein may be inactivated by the binding
of the MDM2 protein. MDM2, the product of the mdm2 gene, is an oncoprotein that binds to Tp53 and inhibits the p53- mediated transactivation. MDM2 overexpression has been reported
in several human cancers, but not in intrahepatic cholangiocarcinoma (ICC). Therefore, we have evaluated the immunohistochemical
overexpression of MDM2 and the relationship between its expression and histological grade, clinicopathological features, Tp53
overexpression, and Ki-67 labeling index in 47 cases of ICC. MDM2 and Tp53 were found to be overexpressed in 38% and 57% of
the tumor, respectively. MDM2 and Tp53 were not expressed in non-tumorous liver tissue. There was no significant difference
between the MDM2 overexpression and ICC tumor grade. However, MDM2 overexpression correlated with the presence of metastases
(P<0.01) and advanced tumor stage (P<0.05). MDM2 overexpression also correlated with Tp53 overexpression (P<0.03) and Ki-67 labeling index (P<0.03). Our findings suggest that MDM2 overexpression may play a role in the late stage of human ICC.
Received: 6 October 1999 Accepted: 31 January 2000 相似文献
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Karim H Saba Valeria Difilippo Michal Kovac Louise Cornmark Linda Magnusson Jenny Nilsson Hilda van den Bos Diana CJ Spierings Mahtab Bidgoli Tord Jonson Vaiyapuri P Sumathi Otte Brosjö Johan Staaf Floris Foijer Emelie Styring Michaela Nathrath Daniel Baumhoer Karolin H Nord 《The Journal of pathology》2024,262(2):147-160
19.
Paolella BR Havrda MC Mantani A Wray CM Zhang Z Israel MA 《Stem cells (Dayton, Ohio)》2011,29(7):1090-1101
Neural progenitor cells (NPCs) have the capacity to proliferate and give rise to all major central nervous system cell types and represent a possible cell of origin in gliomagenesis. Deletion of the tumor suppressor gene Tp53 (p53) results in increased proliferation and self-renewal of NPCs and is a common genetic mutation found in glioma. We have identified inhibitor of DNA binding 2 (Id2) as a novel target gene directly repressed by p53 to maintain normal NPC proliferation. p53((-/-)) NPCs express elevated levels of Id2 and suppression of Id2 expression is sufficient to inhibit the increased proliferation and self-renewal which results from p53 loss. Elevated expression of Id2 in wild-type NPCs phenocopies the behavior of p53((-/-)) NPCs by enhancing NPC proliferation and self-renewal. Interestingly, p53 directly binds to a conserved site within the Id2 promoter to mediate these effects. Finally, we have identified elevated Id2 expression in glioma cell lines with mutated p53 and demonstrated that constitutive expression of Id2 plays a key role in the proliferation of glioma stem-like cells. These findings indicate that Id2 functions as a proproliferative gene that antagonizes p53-mediated cell cycle regulation in NPCs and may contribute to the malignant proliferation of glioma-derived tumor stem cells. 相似文献