共查询到20条相似文献,搜索用时 31 毫秒
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2.
Schreiber S Rignall B Braeuning A Marx-Stoelting P Ott T Buchmann A Hammad S Hengstler JG Schwarz M Köhle C 《Journal of molecular histology》2011,42(5):393-400
The gene CTNNB1 encoding β-catenin is mutated in about 30% of hepatocellular carcinoma, generally often combined with other genetic alterations.
In transgenic mice, it has been shown that activation of β-catenin in more than 70% of all hepatocytes causes immediate proliferation
leading to hepatomegaly. In this study we established a novel mouse model where β-catenin is activated only in individual,
dispersed hepatocytes. Hepatocyte-specific expression of activated point-mutated β-catenin (human β-cateninS33Y) was established using the Cre/loxP system. Expression of several downstream targets of β-catenin signaling such as glutamine
synthetase and several cytochrome P450 isoforms was confirmed by immunostaining. Only a minor portion of hepatocytes expressed
the β-cateninS33Y transgene, which were mainly positioned as dispersed individual cells within the normal liver parenchyma. The hepatocytes
with activated β-catenin did not show increased proliferation and the mice did not develop hepatomegaly. In conclusion, activated
β-catenin in single hepatocytes induces a gene expression pattern in hepatocytes which is similar to that of Ctnnb1-mutated mouse liver tumors, but is apparently not sufficient to induce increased cell proliferation. Therefore, onset of
proliferation seems to require concomitant activation of β-catenin in clusters of hepatocytes, suggesting a role of cell–cell
communication in this process. 相似文献
3.
Axil, a Member of the Axin Family, Interacts with Both Glycogen Synthase Kinase 3β and β-Catenin and Inhibits Axis Formation of Xenopus Embryos
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Hideki Yamamoto Shosei Kishida Takaaki Uochi Satoshi Ikeda Shinya Koyama Makoto Asashima Akira Kikuchi 《Molecular and cellular biology》1998,18(5):2867-2875
Using a yeast two-hybrid method, we identified a novel protein which interacts with glycogen synthase kinase 3β (GSK-3β). This protein had 44% amino acid identity with Axin, a negative regulator of the Wnt signaling pathway.We designated this protein Axil for Axin like. Like Axin, Axil ventralized Xenopus embryos and inhibited Xwnt8-induced Xenopus axis duplication. Axil was phosphorylated by GSK-3β. Axil bound not only to GSK-3β but also to β-catenin, and the GSK-3β-binding site of Axil was distinct from the β-catenin-binding site. Furthermore, Axil enhanced GSK-3β-dependent phosphorylation of β-catenin. These results indicate that Axil negatively regulates the Wnt signaling pathway by mediating GSK-3β-dependent phosphorylation of β-catenin, thereby inhibiting axis formation. 相似文献
4.
James M Wells Farzad Esni Gregory P Boivin Bruce J Aronow William Stuart Chelsea Combs Angela Sklenka Steven D Leach Andrew M Lowy 《BMC developmental biology》2007,7(1):4
Background
β-catenin is an essential mediator of canonical Wnt signaling and a central component of the cadherin-catenin epithelial adhesion complex. Dysregulation of β-catenin expression has been described in pancreatic neoplasia. Newly published studies have suggested that β-catenin is critical for normal pancreatic development although these reports reached somewhat different conclusions. In addition, the molecular mechanisms by which loss of β-catenin affects pancreas development are not well understood. The goals of this study then were; 1] to further investigate the role of β-catenin in pancreatic development using a conditional knockout approach and 2] to identify possible mechanisms by which loss of β-catenin disrupts pancreatic development. A Pdx1-cre mouse line was used to delete a floxed β-catenin allele specifically in the developing pancreas, and embryonic pancreata were studied by immunohistochemistry and microarray analysis. 相似文献5.
Establishment of the Dorso-ventral Axis in Xenopus Embryos Is Presaged by Early Asymmetries in β-Catenin That Are Modulated by the Wnt Signaling Pathway
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Carolyn A. Larabell Monica Torres Brian A. Rowning Cynthia Yost Jeffrey R. Miller Mike Wu David Kimelman Randall T. Moon 《The Journal of cell biology》1997,136(5):1123-1136
Eggs of Xenopus laevis undergo a postfertilization cortical rotation that specifies the position of the dorso-ventral axis and activates a transplantable dorsal-determining activity in dorsal blastomeres by the 32-cell stage. There have heretofore been no reported dorso-ventral asymmetries in endogenous signaling proteins that may be involved in this dorsal-determining activity during early cleavage stages. We focused on β-catenin as a candidate for an asymmetrically localized dorsal-determining factor since it is both necessary and sufficient for dorsal axis formation. We report that β-catenin displays greater cytoplasmic accumulation on the future dorsal side of the Xenopus embryo by the two-cell stage. This asymmetry persists and increases through early cleavage stages, with β-catenin accumulating in dorsal but not ventral nuclei by the 16- to 32cell stages. We then investigated which potential signaling factors and pathways are capable of modulating the steady-state levels of endogenous β-catenin. Steadystate levels and nuclear accumulation of β-catenin increased in response to ectopic Xenopus Wnt-8 (Xwnt-8) and to the inhibition of glycogen synthase kinase-3, whereas neither Xwnt-5A, BVg1, nor noggin increased β-catenin levels before the mid-blastula stage. As greater levels and nuclear accumulation of β-catenin on the future dorsal side of the embryo correlate with the induction of specific dorsal genes, our data suggest that early asymmetries in β-catenin presage and may specify dorso-ventral differences in gene expression and cell fate. Our data further support the hypothesis that these dorso-ventral differences in β-catenin arise in response to the postfertilization activation of a signaling pathway that involves Xenopus glycogen synthase kinase-3. 相似文献
6.
Adenomatous Polyposis Coli Tumor Suppressor Protein Has Signaling Activity in Xenopus laevis Embryos Resulting in the Induction of an Ectopic Dorsoanterior Axis 总被引:2,自引:0,他引:2
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Kris Vleminckx Ellen Wong Kathy Guger Bonnee Rubinfeld Paul Polakis Barry M. Gumbiner 《The Journal of cell biology》1997,136(2):411-420
Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are linked to both familial and sporadic human colon cancer. So far, a clear biological function for the APC gene product has not been determined. We assayed the activity of APC in the early Xenopus embryo, which has been established as a good model for the analysis of the signaling activity of the APC-associated protein β-catenin. When expressed in the future ventral side of a four-cell embryo, full-length APC induced a secondary dorsoanterior axis and the induction of the homeobox gene Siamois. This is similar to the phenotype previously observed for ectopic β-catenin expression. In fact, axis induction by APC required the availability of cytosolic β-catenin. These results indicate that APC has signaling activity in the early Xenopus embryo. Signaling activity resides in the central domain of the protein, a part of the molecule that is missing in most of the truncating APC mutations in colon cancer. Signaling by APC in Xenopus embryos is not accompanied by detectable changes in expression levels of β-catenin, indicating that it has direct positive signaling activity in addition to its role in β-catenin turnover. From these results we propose a model in which APC acts as part of the Wnt/β-catenin signaling pathway, either upstream of, or in conjunction with, β-catenin. 相似文献
7.
Hepatocytes in primary cultures de-differentiate and re-differentiate following addition of Engelbreth-Holm-Swarm mouse sarcoma
(matrigel) to the cultures. The Wnt/β-catenin pathway has been shown to be important in liver growth and development. Here,
we investigate changes in β-catenin and its mechanism, during matrigel-induced hepatocyte differentiation. Primary rat hepatocytes
were cultured for 8 days, and matrigel was added to half of the cultures. Total and nuclear protein and total RNA were extracted
at different days of culture and examined for β-catenin and other Wnt pathway components. A significant increase in total
β-catenin protein was observed upon matrigel addition, during hepatocyte differentiation, despite a decrease in β-catenin and frizzled-1 (Wnt receptor) expression. A concurrent decrease in the glycogen synthase kinase-3β (GSK3β), axin, and ser45/thr41-phosphorylated
β-catenin proteins was observed in matrigel-treated cultures, implying decreased degradation of β-catenin. Interestingly,
a decrease in nuclear β-catenin and total active β-catenin was observed in the presence of matrigel. Matrigel also induced
an increased association of β-catenin with Met (hepatocyte growth factor receptor), whereas association with E-cadherin remained
unchanged. This coexisted with decreased β-catenin tyrosine phosphorylation. Thus, β-catenin undergoes multifactorial regulation
during matrigel-induced hepatocyte differentiation and maturation; this induces its stabilization and membrane translocation,
possibly contributing to hepatocyte differentiation.
A. Micsenyi and M. Germinaro contributed equally to this work.
Grant Support: Rango's fund for Enhancement of Pathology Research, American Cancer Society Grant-RSG-03-141-01 and National
Institute of Health Grant 1RO1DK62277, to SPSM. 相似文献
8.
Characterization of a novel human CDK5 splicing variant that inhibits Wnt/β-catenin signaling 总被引:1,自引:0,他引:1
Qiang Li Xianghua Liu Mingjun Zhang Guangming Ye Qian Qiao Yichen Ling Yanhua Wu Yuanyuan Zhang Long Yu 《Molecular biology reports》2010,37(5):2415-2421
The cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases, playing an essential role in regulating cell-cycle
progression. In our present work, human CDK5 and a novel CDK5 splicing variant, named as CDK5-SV, were cloned from the cDNA library of human testis. CDK5-SV lacking the exon 7 of CDK5 encodes a protein of 260 amino acids. Through RT-PCR analysis in different human tissues, CDK5-SV was found to be expressed in testis, skeletal muscle, colon, bone marrow and ovary, while CDK5 was ubiquitously expressed. Immunofluorescence experiment in HeLa cells showed that the subcellular localizations of CDK5-SV
and CDK5 were totally different. CDK5 mainly located in the cytoplasm, while CDK5-SV accumulated in nucleus. Reporter gene
assay showed that when co-transfected with β-catenin, CDK5 and CDK5-SV could both strongly inhibit the Wnt/β-catenin signaling pathway. Consistently, CDK5-SV could also interact with β-catenin
as CDK5 does. Taken together, our findings suggest that CDK5-SV might also be a negative regulator of Wnt/β-catenin signaling
pathway. 相似文献
9.
Karin Geis Hermann Aberle Michael Kühl Rolf Kemler D. Wedlich 《Development genes and evolution》1998,207(7):471-481
The Armadillo family is formed by proteins which possess an Arm domain comprising multiple copies of a 42-amino-acid motif,
the Arm repeat, initially described for the Drosophila segment polarity gene product Armadillo. The Arm domain serves in protein-protein interactions which are required for the
family members Armadillo, β-catenin and plakoglobin to mediate cell-cell adhesion and Wnt/Wingless signalling. Similarily,
p120
cas
, the Arm domain containing src substrate, also binds to cadherins and becomes tyrosine phosphorylated in response to a variety
of stimuli. However, a putative function of p120
cas
in adhesion or signalling has not yet been demonstrated. It has also not been shown until now that an Arm domain is a common
signal transduction motif. Using Xenopus embryos we show by expression of murine p120
cas
1B (mp120
cas
1B) in ventral blastomeres that this catenin cannot replace β-catenin function in dorsal axis formation. Thus, the presence
of an Arm domain per se is not sufficient to activate the Wnt/Wg pathway. Indeed, injection of mp120
cas
1B into dorsal blastomeres led instead to delayed blastopore closure and posteriorized phenotypes with malformed head structures
indicative of disturbed gastrulation movements. Because neither convergent extension behaviour nor adhesion to fibronectin
was altered in the injected embryos we assume that mp120
cas
1B influences motility or orientation of migrating mesodermal cells.
Received: 29 September 1997 / Accepted: 15 November 1997 相似文献
10.
Involvement of Tcf/Lef in establishing cell types along the animal-vegetal axis of sea urchins 总被引:1,自引:0,他引:1
Huang L Li X El-Hodiri HM Dayal S Wikramanayake AH Klein WH 《Development genes and evolution》2000,210(2):73-81
Members of the Tcf/Lef family interact with β-catenin to activate programs of gene expression during development. Recently
β-catenin was shown to be essential for establishing cell fate along the animal-vegetal axis of the sea urchin embryo. To
examine the role of Tcf/Lef in sea urchins we cloned a Strongylocentrotus purpuratus Tcf/Lef homolog. Expression of SpTcf/Lef was maximal when β-catenin became localized to nuclei of vegetal blastomeres, consistent with its acting in combination with
β-catenin to specify vegetal cell fates. Expression of a dominant-negative SpTcf/Lef inhibited primary and secondary mesenchyma, endoderm, and aboral ectoderm formation in a manner similar to that observed
when nuclear accumulation of β-catenin was prevented. Our results suggest that SpTcf/Lef functions by interacting with β-catenin
to specify cell fates along the sea urchin animal-vegetal axis.
Received: 6 July 1999 / Accepted: 27 August 1999 相似文献
11.
Kajiura-Kobayashi H Yoshida N Sagata N Yamashita M Nagahama Y 《Development genes and evolution》2000,210(8-9):416-425
Mos plays a crucial role in meiotic cell division in vertebrates. In Xenopus, Mos is involved in the initiation of oocyte maturation as an initiator and in the arrest at the metaphase II stage (MII)
as a component of the cytostatic factor (CSF). The function of Mos is mediated by MAP kinase (MAPK). We investigated the function
of the Mos/MAPK pathway during goldfish oocyte maturation induced by 17α,20β-dihydroxy-4-pregnen-3-one (17α,20β-DP), a natural
maturation-inducing hormone in fishes. Mos was absent in immature goldfish oocytes. It appeared before the onset of germinal
vesicle breakdown (GVBD), increased to a maximum in mature oocytes arrested at MII and disappeared after fertilization. MAPK
was activated after Mos synthesis but before maturation-promoting factor (MPF) activation, and its activity reached maximum
at MII. Injection of either Xenopus or goldfish c-mos mRNA into one blastomere of 2-cell-stage Xenopus and goldfish embryos induced metaphase arrest, suggesting that goldfish Mos has a CSF activity. Injection of constitutively
active Xenopus c-mos mRNA into immature goldfish oocytes induced MAPK activation, but neither MPF activation nor GVBD occurred. Conversely, the
injection of goldfish c-mos antisense RNA inhibited both Mos synthesis and MAPK activation in the 17α,20β-DP-treated oocytes, but these oocytes underwent
GVBD. These results indicate that the Mos/MAPK pathway is not essential for initiating goldfish oocyte maturation despite
its general function as a CSF. We discuss the general role of Mos/MAPK during oocyte maturation, with reference to the difference
in contents of inactive MPF (pre-MPF) stored in immature oocytes.
Received: 10 February 2000 / Accepted: 25 April 2000 相似文献
12.
Signaling by members of TGF-β superfamily requires the activity of a family of site-specific endopeptidases, known as Subtilisin-like proprotein convertases (SPCs), which cleave these ligands into mature, active forms. To explore the role of SPCs in lateral plate mesoderm (LPM) differentiation in Xenopus, two SPC inhibitors, decanoyl-Arg-Val-Lys-Arg-chloromethylketone (Dec-RVKR-CMK) and hexa-arginine, were injected into the left and right LPM of Xenopus neurulae. Left-side injection caused heart-specific left–right reversal, and this phenotype was rescued by co-injection of mature Nodal protein. In contrast, right-side injection caused left–right reversal of both the heart and gut. Tailbud embryos were less sensitive to SPC inhibitors than neurula embryos. Injection of inhibitors into either side of neurula embryos completely abolished expression of the left-LPM-specific genes, Xnr-1, antivin, and pitx2. SPC1 enzyme (Furin) was injected into the left or right LPM of mid-neurula embryos to determine the effect of enhancing SPC activity. Left-side injection of SPC1 did not cause a significant left–right reversal of the internal organs. However, right-side injection of SPC1 strongly induced the expression of Xnr-1 and pitx2 in the right LPM, and caused 100% left–right reversal of both the heart and gut. These results suggest that moderate level of SPC activity in the right LPM of the neurulae is necessary for proper left–right specification. Taken together, SPC enzymatic activity must be present in both LPMs for expression of the left-handed genes and left–right axis determination of the heart and gut in Xenopus embryos. 相似文献
13.
Daniel Graf Paula M. Timmons Megan Hitchins Vasso Episkopou Gudrun Moore Takekito Ito Asao Fujiyama Amanda G. Fisher Matthias Merkenschlager 《Mammalian genome》2001,12(7):554-560
The twisted gastrulation gene (tsg) encodes a secreted protein required for the correct specification of dorsal midline cell fate during gastrulation in Drosophila. We report that tsg homologs from human, mouse, zebrafish, and Xenopus share 72–98% identity at the amino acid level and retain all 24 cysteine residues from Drosophila. In contrast to Drosophila where tsg expression is limited to early embryos, expression is found throughout mouse and human development. In Drosophila, tsg acts in synergy with decapentaplegic (dpp), a member of the TGF-β family of secreted proteins. The vertebrate orthologs of dpp, BMP-2 and -4, are crucial for gastrulation and neural induction, and aberrant signaling by BMPs and other TGF-β family members
results in developmental defects including holoprosencephaly (HPE). Interestingly, human TSG maps to the HPE4 locus on Chromosome
18p11.3, and our analysis places the gene within 5 Mbp of TG-interacting factor (TGIF).
Received: 21 August 2000 / Accepted: 9 March 2001 相似文献
14.
Dorsoventral patterning of the embryonic axis relies upon the mutual antagonism of competing signaling pathways to establish a balance between ventralizing BMP signaling and dorsal cell fate specification mediated by the organizer. In zebrafish, the initial embryo-wide domain of BMP signaling is refined into a morphogenetic gradient following activation dorsally of a maternal Wnt pathway. The accumulation of β-catenin in nuclei on the dorsal side of the embryo then leads to repression of BMP signaling dorsally and the induction of dorsal cell fates mediated by Nodal and FGF signaling. A separate Wnt pathway operates zygotically via Wnt8a to limit dorsal cell fate specification and maintain the expression of ventralizing genes in ventrolateral domains. We have isolated a recessive dorsalizing maternal-effect mutation disrupting the gene encoding Integrator Complex Subunit 6 (Ints6). Due to widespread de-repression of dorsal organizer genes, embryos from mutant mothers fail to maintain expression of BMP ligands, fail to fully express vox and ved, two mediators of Wnt8a, display delayed cell movements during gastrulation, and severe dorsalization. Consistent with radial dorsalization, affected embryos display multiple independent axial domains along with ectopic dorsal forerunner cells. Limiting Nodal signaling or restoring BMP signaling restores wild-type patterning to affected embryos. Our results are consistent with a novel role for Ints6 in restricting the vertebrate organizer to a dorsal domain in embryonic patterning. 相似文献
15.
The β-1,3-d-glucan binding protein (βGBP), one kind of the pattern recognition proteins (PRPs), was cloned and characterized from the
Chinese Shrimp Fenneropenaeus chinensis, and named as FcβGBP-HDL. The results indicated that the full length cDNA of 6713 bp had an open reading frame encoded a
polypeptide of 2139 amino acids with two glucanase-like motifs and one RGD motif, while without signal peptide. The calculated
molecular mass of mature protein was 240.7 kDa and theoretical pI was 5.95. Sequence comparison of the deduced amino acid
sequence of FcβGBP-HDL showed varied identity of 88, 54 and 53% with those of Litopenaeus vannamei βGBP-HDL, Pacifastacus leniusculus βGBP, and Pontastacus leptodactylus βGBP, respectively. qRT-PCR analysis indicated that FcβGBP-HDL was expressed in intestines, hepatopancreas, muscle, gill
and hemocytes, and its profile was modified post WSSV challenge. The differential expressions of FcβGBP-HDL in different tissues
post WSSV challenge suggested that FcβGBP-HDL might play an important role in shrimp immune and perform differently in different
tissues. These data would be helpful to better understand the WSSV-resistance mechanism of farming shrimp. 相似文献
16.
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18.
Yi-Ting Wu Che Yi Lin Ming-Yuan Tsai Yi-Hua Chen Yu-Fen Lu Chang-Jen Huang Chao-Min Cheng Sheng-Ping L Hwang 《Journal of biomedical science》2011,18(1):70
Background
β-Lapachone has antitumor and wound healing-promoting activities. To address the potential influences of various chemicals on heart development of zebrafish embryos, we previously treated zebrafish embryos with chemicals from a Sigma LOPAC1280™ library and found several chemicals including β-lapachone that affected heart morphogenesis. In this study, we further evaluated the effects of β-lapachone on zebrafish embryonic heart development. 相似文献19.
β-Catenin plays a crucial role in embryonic development and responds to the activation of several signal transduction pathways.
In this paper, in order to understand the functions of β-catenin gene in early embryonic development of Artemia sinica, the complete cDNA sequence was cloned for the first time using RACE technology, then the sequence was analyzed by some bioinformatic
methods. The expression of the β-catenin gene was investigated at various stages during the embryonic development using quantitative real-time PCR and immunohistochemistry
assay. Through the investigation, the result of real-time PCR illustrated that β-catenin gene might relate to the response of A. sinica’s immune system and osmotic pressure system in early embryonic developmental stage. Meanwhile, Immunohistochemistry assay
demonstrated that during embryonic development, β-catenin was mainly expressed in the cephalothorax. Besides, we discovered
that β-catenin might not be a maternal gene in A. sinica, and this new phenomenon may explain a constitutive and regional expression during the early embryonic development of A. sinica. 相似文献
20.
Accumulation of β-catenin by lithium chloride in porcine myoblast cultures accelerates cell differentiation 总被引:1,自引:0,他引:1
Yingjuan Yang Jinzeng Yang Rongxin Liu Huixia Li Xiao Luo Gongshe Yang 《Molecular biology reports》2011,38(3):2043-2049
The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation to determine cell fate during embryogenesis.
Lithium chloride (LiCl) is known to activate canonical Wnt signaling by inhibiting glycogen synthetase kinase-3β and consequently
stabilizing free cytosolic β-catenin. To understand the role of the Wnt/β-catenin pathway in the regulation of porcine myoblast
differentiation, we studied the effects of LiCl on cultured porcine myoblasts and β-catenin expression. A supplementation
of 25 mM LiCl induced myoblast differentiation into myotubes over 3 days of culture. By semi-quantitative RT-PCR analyses,
levels of mRNA encoding MyoD, Myogenin, Myf5 and several Wnt-responsive genes in the cultured myoblast cells were significantly
increased after LiCl treatment. Using Western blotting and immunofluorescence analysis, we found that the protein levels of
β-catenin were consistently increased by LiCl. Meanwhile, phosphorylated GSK-3β at Ser9 levels were also increased as an indicator
of GSK-3β inactivation. Additionally, the nuclear staining of endogenous β-catenin was also significantly increased in porcine
myoblasts 48 h after LiCl treatment. These results provided additional evidence that Wnt/β-catenin is a significant pathway
that regulates myogenic differentiation. An enhanced level of β-catenin plays a positive role in porcine myoblast differentiation. 相似文献