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1.
It is now clear that mitochondrial defects are associated with a plethora of clinical phenotypes in man and mouse. This is the result of the mitochondria''s central role in energy production, reactive oxygen species (ROS) biology, and apoptosis, and because the mitochondrial genome consists of roughly 1500 genes distributed across the maternal mitochondrial DNA (mtDNA) and the Mendelian nuclear DNA (nDNA). While numerous pathogenic mutations in both mtDNA and nDNA mitochondrial genes have been identified in the past 21 years, the causal role of mitochondrial dysfunction in the common metabolic and degenerative diseases, cancer, and aging is still debated. However, the development of mice harboring mitochondrial gene mutations is permitting demonstration of the direct cause-and-effect relationship between mitochondrial dysfunction and disease. Mutations in nDNA-encoded mitochondrial genes involved in energy metabolism, antioxidant defenses, apoptosis via the mitochondrial permeability transition pore (mtPTP), mitochondrial fusion, and mtDNA biogenesis have already demonstrated the phenotypic importance of mitochondrial defects. These studies are being expanded by the recent development of procedures for introducing mtDNA mutations into the mouse. These studies are providing direct proof that mtDNA mutations are sufficient by themselves to generate major clinical phenotypes. As more different mtDNA types and mtDNA gene mutations are introduced into various mouse nDNA backgrounds, the potential functional role of mtDNA variation in permitting humans and mammals to adapt to different environments and in determining their predisposition to a wide array of diseases should be definitively demonstrated. 相似文献
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Helicobacter hepaticus infection promotes colon tumorigenesis in the BALB/c-Rag2(-/-) Apc(Min/+) mouse 下载免费PDF全文
Nagamine CM Sohn JJ Rickman BH Rogers AB Fox JG Schauer DB 《Infection and immunity》2008,76(6):2758-2766
Adenomatous polyposis coli (APC) mutations are linked to human and mouse colorectal cancers. The Apc multiple intestinal neoplasia (Min) mouse mutation causes adenomas to develop throughout the small and large intestines. The BALB-Min (C.B6-Apc(Min/+)) congenic strain was generated by backcrossing into BALB/c the Apc(Min) allele from C57BL/6J-Apc(Min/+) mice. BALB-Min mice have a low tumor multiplicity (27.4 small intestine tumors/mouse) and a relatively long life span (>1 year) that makes them amenable to long-term studies. To investigate the interplay of the adaptive immune system and intestinal tumorigenesis, the immunodeficient compound mutant strain BALB-RagMin (C.Cg-Rag2(-/-) Apc(Min/+)) was generated. BALB-RagMin mice had a significant increase in tumors in the small, but not large, intestine relative to their BALB-Min counterparts (43.0 versus 24.0 tumors/mouse, respectively). The results suggest that the adaptive immune system plays a role in either the elimination or the equilibrium phase of cancer immunoediting in the small intestine in this model. We investigated the effect of the enterohepatic bacterial pathogen Helicobacter hepaticus on liver and intestine tumorigenesis in BALB-RagMin mice. H. hepaticus-infected BALB-RagMin mice developed moderate hepatitis, moderate typhlitis, and mild colitis. There were no differences in small intestine and cecal tumor multiplicity, regionality, or size relative to that in uninfected mice. However, H. hepaticus-infected BALB-RagMin mice had a significant increase in colon tumor incidence relative to uninfected BALB-RagMin mice (23.5% versus 1.7%, respectively). The data suggest that H. hepaticus, which is present in many research colonies, promotes colon tumorigenesis in the BALB-RagMin mouse and that it has the potential to confound colon tumorigenesis studies. 相似文献
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Mouse models for mitochondrial disease 总被引:9,自引:0,他引:9
Wallace DC 《American journal of medical genetics》2001,106(1):71-93
4.
The mouse provides an excellent in vivo system with which to model human diseases and to test therapies. Mutations in the Adenomatous polyposis coli (APC) gene are required to initiate familial adenomatous polyposis (FAP) and are also important in sporadic colorectal cancer tumorigenesis. The (multiple intestinal neoplasia Min) mouse contains a point mutation in the Apc gene, develops numerous adenomas and was the first model used to study the involvement of the Apc gene in intestinal tumorigenesis. The model has provided examples of modifying loci (called Modifiers of Min: Mom) in mice, demonstrating the principle of genetic modulation of disease severity. A spectrum of Apc mutant mice has since been developed, each with defining characteristics, some more able to accurately model human polyposis and colon cancer. We will focus our review on Apc mutant mouse models, the advent of models with concurrent or compound mutations and the importance of genetic background when modeling polyposis and cancer. Brief consideration will be given to the use of these models in drug testing. 相似文献
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Nguyen HT Dalmasso G Yan Y Laroui H Charania M Ingersoll S Ayyadurai S Zhang Y Sitaraman S Merlin D 《Laboratory investigation; a journal of technical methods and pathology》2012,92(8):1203-1212
The transmembrane glycoprotein CD98 regulates integrin signaling that in turn controls cell proliferation and survival. CD98 expression is upregulated in various carcinomas, including colorectal cancer. Recently, by generating gain- and loss-of-function mouse models featuring genetic manipulation of CD98 expression specifically in intestinal epithelial cells (IECs), we have explored the crucial role of CD98 in the regulation of intestinal homeostasis and inflammation-associated tumorigenesis. In the present study, we investigated the contribution of CD98 to intestinal tumorigenesis in Apc(Min/+) mice and the underlying mechanism of action. Mice featuring IEC-specific CD98 overexpression (Tg animals) were crossed with Apc(Min/+) mice, and the characteristics of intestinal adenoma formation were assessed. Compared with Apc(Min/+) mice, Tg/Apc(Min/+) animals exhibited increases in both intestinal tumor incidence and tumor size; these parameters correlated with enhanced proliferation and decreased apoptosis of IECs. IEC-specific CD98 overexpression resulted in increased synthesis of the oncogenic proteins c-myc and cyclin-D1 in Apc(Min/+) mice, independently of the Wnt-APC-β-catenin pathway, suggesting the implication of CD98 overexpression-mediated Erk activation. IEC-specific CD98 overexpression enhanced the production of proinflammatory cytokines and chemokines that are crucial for tumorigenesis. We validated our results in mice exhibiting IEC-specific CD98 downregulation (CD98(flox/+)VillinCre animals). IEC-specific CD98 downregulation efficiently attenuated tumor incidence and growth in Apc(Min/+) mice. The reduction of intestinal tumorigenesis upon IEC-specific CD98 downregulation was caused by the attenuation of IEC proliferation and cytokine/chemokine production. In conclusion, we show that CD98 exerts an oncogenic activity in terms of intestinal tumorigenesis, via an ability to regulate tumor growth and survival. 相似文献
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Aneuploidy arises at early stages of Apc-driven intestinal tumorigenesis and pinpoints conserved chromosomal loci of allelic imbalance between mouse and human 下载免费PDF全文
Alberici P de Pater E Cardoso J Bevelander M Molenaar L Jonkers J Fodde R 《The American journal of pathology》2007,170(1):377-387
Although chromosomal instability characterizes the majority of human colorectal cancers, the contribution of genes such as adenomatous polyposis coli (APC), KRAS, and p53 to this form of genetic instability is still under debate. Here, we have assessed chromosomal imbalances in tumors from mouse models of intestinal cancer, namely Apc(+/1638N), Apc(+/1638N)/KRAS(V12G), and Apc(+/1638N)/Tp53-/-, by array comparative genomic hybridization. All intestinal adenomas from Apc(+/1638N) mice displayed chromosomal alterations, thus confirming the presence of a chromosomal instability defect at early stages of the adenoma-carcinoma sequence. Moreover, loss of the Tp53 tumor suppressor gene, but not KRAS oncogenic activation, results in an increase of gains and losses of whole chromosomes in the Apc-mutant genetic background. Comparative analysis of the overall genomic alterations found in mouse intestinal tumors allowed us to identify a subset of loci syntenic with human chromosomal regions (eg, 1p34-p36, 12q24, 9q34, and 22q) frequently gained or lost in familial adenomas and sporadic colorectal cancers. The latter indicate that, during intestinal tumor development, the genetic mechanisms and the underlying functional defects are conserved across species. Hence, our array comparative genomic hybridization analysis of Apc-mutant intestinal tumors allows the definition of minimal aneuploidy regions conserved between mouse and human and likely to encompass rate-limiting genes for intestinal tumor initiation and progression. 相似文献
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Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers 总被引:4,自引:0,他引:4
Colnot S Niwa-Kawakita M Hamard G Godard C Le Plenier S Houbron C Romagnolo B Berrebi D Giovannini M Perret C 《Laboratory investigation; a journal of technical methods and pathology》2004,84(12):1619-1630
Murine models of familial adenomatous polyposis harbor a germinal heterozygous mutation on Apc tumor suppressor gene. They are valuable tools for studying intestinal carcinogenesis, as most human sporadic cancers contain inactivating mutations of APC. However, Apc(+/-) mice, such as the well-characterized Apc(Min/+) model, develop cancers principally in the small intestine, while humans develop mainly colorectal cancers. We used a Cre-loxP strategy to achieve a new model of germline Apc invalidation in which exon 14 is deleted. We compared the phenotype of these Apc(Delta14/+) mice to that of the classical Apc(Min/+). The main phenotypic difference is the shift of the tumors in the distal colon and rectum, often associated with a rectal prolapse. Thus, the severity of the colorectal phenotype is partly due to the particular mutation Delta14, but also to environmental parameters, as mice raised in conventional conditions developed more colon cancers than those raised in pathogen-free conditions. All lesions, including early lesions, revealed Apc LOH and loss of Apc gene expression. They accumulated beta-catenin, overexpressed the beta-catenin target genes cyclin D1 and c-Myc, and the distribution pattern of glutamine synthetase, a beta-catenin target gene recently identified in the liver, was mosaic in intestinal adenomas. The Apc(Delta14/+) model is thus a useful new tool for studies on the molecular mechanisms of colorectal tumorigenesis. 相似文献
10.
Dillon LM Williams SL Hida A Peacock JD Prolla TA Lincoln J Moraes CT 《Human molecular genetics》2012,21(10):2288-2297
Aging is an intricate process that increases susceptibility to sarcopenia and cardiovascular diseases. The accumulation of mitochondrial DNA (mtDNA) mutations is believed to contribute to mitochondrial dysfunction, potentially shortening lifespan. The mtDNA mutator mouse, a mouse model with a proofreading-deficient mtDNA polymerase γ, was shown to develop a premature aging phenotype, including sarcopenia, cardiomyopathy and decreased lifespan. This phenotype was associated with an accumulation of mtDNA mutations and mitochondrial dysfunction. We found that increased expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a crucial regulator of mitochondrial biogenesis and function, in the muscle of mutator mice increased mitochondrial biogenesis and function and also improved the skeletal muscle and heart phenotypes of the mice. Deep sequencing analysis of their mtDNA showed that the increased mitochondrial biogenesis did not reduce the accumulation of mtDNA mutations but rather caused a small increase. These results indicate that increased muscle PGC-1α expression is able to improve some premature aging phenotypes in the mutator mice without reverting the accumulation of mtDNA mutations. 相似文献
11.
Mette Soerensen Ricardo Gredilla Mathis Müller-Ohldach Alexandra Werner Vilhelm A. Bohr Heinz D. Osiewacz Tinna Stevnsner 《Mechanisms of ageing and development》2009,130(8):487-496
The free radical theory of ageing states that ROS play a key role in age-related decrease in mitochondrial function via the damage of mitochondrial DNA (mtDNA), proteins and lipids. In the sexually reproducing ascomycete Podospora anserina ageing is, as in other eukaryotes, associated with mtDNA instability and mitochondrial dysfunction. Part of the mtDNA instabilities may arise due to accumulation of ROS induced mtDNA lesions, which, as previously suggested for mammals, may be caused by an age-related decrease in base excision repair (BER).Alignments of known BER protein sequences with the P. anserina genome revealed high homology. We report for the first time the presence of BER activities in P. anserina mitochondrial extracts. DNA glycosylase activities decrease with age, suggesting that the increased mtDNA instability with age may be caused by decreased ability to repair mtDNA damage and hence contribute to ageing and lifespan control in this ageing model.Additionally, we find low DNA glycosylase activities in the long-lived mutants grisea and ΔPaCox17::ble, which are characterized by low mitochondrial ROS generation.Overall, our data identify a potential role of mtDNA repair in controlling ageing and life span in P. anserina, a mechanism possibly regulated in response to ROS levels. 相似文献
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Mitochondrial dysfunction is a profound feature of cancer cells and is also known to cause several mitochondrial diseases. Mutations in mitochondrial DNA (mtDNA) have been reported frequently in these diseases. Although many environmental agents are known to cause damage to mitochondria, rapid methods need to be developed for testing agents that cause mitochondrial dysfunction and are involved in the development of mitochondrial and other diseases. Using Saccharomyces cerevisiae, we describe the development of a colorimetric method that identifies both physical and chemical agents that cause mitochondrial dysfunction and mutation of the mitochondrial genome. This method utilizes the previously reported ade2 mutant of S.cerevisiae that produces red colonies. However, when they lose mitochondrial function the colonies turn white. This colorimetric method has helped quantify the vulnerability of mtDNA to oxidative agents. Our study reveals that the oxidative agent adriamycin causes both mutation and extensive damage to mtDNA, which leads to loss of mtDNA. Our study also reveals that the lost mtDNA fragments migrate to the nucleus and integrate into the nuclear genome. Furthermore, our analysis reveals that loss of mtDNA leads to resistance to oxidative agents. The method described in this paper should aid in the rapid identification of environmental and other agents that cause mitochondrial dysfunction and mutagenesis, agents that may be involved in the development of mitochondrial and other diseases. 相似文献
14.
Radiation-induced genomic instability (RIGI) challenges the long-standing notion that radiation's effects derive solely from nuclear impact. In RIGI it is the unirradiated progeny that can display phenotypic changes at delayed times after irradiation of the parental cell. RIGI might well provide the driving force behind the development of radiation-induced tumorigenesis as most cancer cells even in pre-neoplastic states display multiple genetic alterations. Thus, understanding RIGI may help elucidate the mechanisms underlying radiation-induced carcinogenesis. One characteristic of clones of genetically unstable cells is that many exhibit persistently increased levels of reactive oxygen species (ROS). Furthermore, oxidants enhance and antioxidants diminish radiation-induced instability. However, much about the mechanisms behind the initiation and perpetuation of RIGI remains unknown and we examine the evidence for the hypothesis that oxidative stress and mitochondrial dysfunction may be involved in perpetuating the unstable phenotype in some cell clones surviving ionizing radiation. 相似文献
15.
Rexhepaj R Rotte A Gu S Michael D Pasham V Wang K Kempe DS Ackermann TF Brücher B Fend F Föller M Lang F 《Pflügers Archiv : European journal of physiology》2011,461(5):527-536
Loss of function mutations of the tumor suppressor gene adenomatous polyposis coli (APC) underly the familial adenomatous polyposis. Mice carrying an inactivating mutation in the apc gene (apc (Min/+)) similarly develop intestinal polyposis. APC is effective at least in part by degrading β-catenin and lack of APC leads to markedly enhanced cellular β-catenin levels. β-Catenin has most recently been shown to upregulate the Na+/K+ ATPase. The present study, thus, explored the possibility that APC could influence intestinal transport. The abundance and localization of β-catenin were determined utilizing Western blotting and confocal microscopy, the activity of the electrogenic glucose carrier (SGLT1) was estimated from the glucose-induced current in jejunal segments utilizing Ussing chamber experiments and the Na+/H+ exchanger (NHE3) activity from Na+ -dependent re-alkalinization of cytosolic pH (ΔpH(i)) following an ammonium pulse employing BCECF fluorescence. As a result, β-catenin abundance in intestinal tissue was significantly higher in apc (Min/+) mice than in wild-type mice (apc (+/+)). The β-catenin protein was localized in the basolateral membrane. Both, the glucose-induced current and ΔpH(i) were significantly higher in apc (Min/+) mice than in apc (+/+) mice. In conclusion, intestinal electrogenic transport of glucose and intestinal Na+/H+ exchanger activity are both significantly enhanced in apc (Min/+) mice, pointing to a role of APC in the regulation of epithelial transport. 相似文献
16.
Smits R Hofland N Edelmann W Geugien M Jagmohan-Changur S Albuquerque C Breukel C Kucherlapati R Kielman MF Fodde R 《Genes, chromosomes & cancer》2000,29(3):229-239
The APC gene, originally identified as the gene for familial adenomatous polyposis (FAP), is now considered as the true "gatekeeper" of colonic epithelial proliferation. Its main tumor suppressing activity seems to reside in the capacity to properly regulate intracellular beta-catenin signaling. Most somatic APC mutations are detected between codons 1286 and 1513, the mutation cluster region (MCR). This clustering can be explained either by the presence of mutation-prone sequences within the MCR, or by the selective advantage provided by the resulting truncated polypeptides. Here, a Msh2-deficient mouse model (Msh2(delta 7N) ) was generated and bred with Apc(1638N) and Apc(Min) that allowed the comparison of the somatic mutation spectra along the Apc gene in the different allelic combinations. Mutations identified in Msh2(delta 7N/delta 7N) tumors are predominantly dinucleotide deletions at simple sequence repeats leading to truncated Apc polypeptides that partially retain the 20 a.a. beta-catenin downregulating motifs. In contrast, the somatic mutations identified in the wild type Apc allele of Msh2(delta 7N/delta 7N) /Apc(+/1638N) and Msh2(delta 7N/delta 7N) /Apc(+/Min) tumors are clustered more to the 5' end, thereby completely inactivating the beta-catenin downregulating activity of APC. These results indicate that somatic Apc mutations are selected during intestinal tumorigenesis and that inactivation of the beta-catenin downregulating function of APC is likely to represent the main selective factor. 相似文献
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Mark J. Sinnamon Kathy J. Carter Barbara Fingleton Lynn M. Matrisian 《International journal of experimental pathology》2008,89(6):466-475
Matrix metalloproteinases (MMPs) are a family of 23 extracellular proteases that are best known for their collective ability to degrade all components of the extracellular matrix. We previously demonstrated that genetic ablation of MMP‐7 reduced tumour multiplicity in multiple intestinal neoplasia (Min) mice possessing a genetic alteration in the adenomatous polyposis coli gene (APC). These mice, commonly referred to as APC‐Min mice, are a frequently used model of early intestinal tumourigenesis. To examine further the role of MMPs in intestinal tumour development, we generated APC‐Min mice genetically deficient in MMP‐2, ‐9, ‐12 or ‐19. Genetic ablation of MMP‐2, ‐12 or ‐19 did not affect multiplicity or size of intestinal tumours when crossed into the APC‐Min system. However, MMP‐9 deficient animals developed 40% fewer tumours than littermate controls, although tumour size distribution remained unaffected. Intestinal adenomas from MMP‐9 deficient mice demonstrated a 50% decrease in proliferating cells compared with control tissues, with no difference in apoptosis. To determine the cellular origin of MMP‐9 in these tumours, immunofluorescent co‐staining with markers for different leucocyte lineages was used to demonstrate that intratumoural MMP‐9 is largely a product of neutrophils. These studies extend the potential targets for chemoprevention of intestinal adenomas to MMP‐9 in addition to MMP‐7 and exclude MMP‐2,‐12,‐19 as attractive targets for intervention. 相似文献
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Mansouri A Muller FL Liu Y Ng R Faulkner J Hamilton M Richardson A Huang TT Epstein CJ Van Remmen H 《Mechanisms of ageing and development》2006,127(3):298-306
Mitochondrial function, hydrogen peroxide generation and oxidative damage were measured in hind-limb skeletal muscle from young (6-8 month) and old (27-29 month) wildtype and heterozygous Mn-superoxide dismutase (MnSOD) knockout mice (Sod2(+/-)). The reduction in MnSOD activity in the Sod2(+/-) mice makes these mice a good model to examine the implications of life-long elevated endogenous mitochondrial oxidative stress on mitochondrial function. ATP production was reduced approximately 30% with age in skeletal muscle mitochondria isolated from wildtype mice, and reduced 40-45% in mitochondria from both young and old Sod2(+/-) mice compared to the young wildtype mice. Release of hydrogen peroxide from skeletal muscle mitochondria increased 40-50% with age in both wildtype and Sod2(+/-) but was not higher in mitochondria from Sod2(+/-) mice. Activities of electron transport Complexes I and V were decreased 25-30% in both young and old Sod2(+/-) mice compared to wildtype mice, and were 25-30% lower in mitochondria from old wildtype and old Sod2(+/-) mice. DNA oxidative damage (oxo8dG levels) increased more than 45% with age and over 130% in the young Sod2(+/-) mice compared to the wildtype mice. These data show that mitochondrial oxidative stress in mouse skeletal muscle is increased with age, leading to alterations in mitochondrial function. In addition, increased oxidative stress generated by reduced activity of MnSOD does not exacerbate these alterations during aging. 相似文献
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Lewis W Day BJ Kohler JJ Hosseini SH Chan SS Green EC Haase CP Keebaugh ES Long R Ludaway T Russ R Steltzer J Tioleco N Santoianni R Copeland WC 《Laboratory investigation; a journal of technical methods and pathology》2007,87(4):326-335
POLG is the human gene that encodes the catalytic subunit of DNA polymerase gamma (Pol gamma), the replicase for human mitochondrial DNA (mtDNA). A POLG Y955C point mutation causes human chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease with eye muscle weakness and mtDNA defects. Y955C POLG was targeted transgenically (TG) to the murine heart. Survival was determined in four TG (+/-) lines and wild-type (WT) littermates (-/-). Left ventricle (LV) performance (echocardiography and MRI), heart rate (electrocardiography), mtDNA abundance (real time PCR), oxidation of mtDNA (8-OHdG), histopathology and electron microscopy defined the phenotype. Cardiac targeted Y955C POLG yielded a molecular signature of CPEO in the heart with cardiomyopathy (CM), mitochondrial oxidative stress, and premature death. Increased LV cavity size and LV mass, bradycardia, decreased mtDNA, increased 8-OHdG, and cardiac histopathological and mitochondrial EM defects supported and defined the phenotype. This study underscores the pathogenetic role of human mutant POLG and its gene product in mtDNA depletion, mitochondrial oxidative stress, and CM as it relates to the genetic defect in CPEO. The transgenic model pathophysiologically links human mutant Pol gamma, mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM. 相似文献