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Constitutive Activation (constitutive + activation)
Selected AbstractsConstitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2010Rogier Kersseboom Abstract B-cell receptor (BCR)-mediated signals provide the basis for B-cell differentiation in the BM and subsequently into follicular, marginal zone, or B-1 B-cell subsets. We have previously shown that B-cell-specific expression of the constitutive active E41K mutant of the BCR-associated molecule Bruton's tyrosine kinase (Btk) leads to an almost complete deletion of immature B cells in the BM. Here, we report that low-level expression of the E41K or E41K-Y223F Btk mutants was associated with reduced follicular B-cell numbers and significantly increased proportions of B-1 cells in the spleen. Crosses with 3-83,, and VH81X BCR Tg mice showed that constitutive active Btk expression did not change follicular, marginal zone, or B-1 B-cell fate choice, but resulted in selective expansion or survival of B-1 cells. Residual B cells were hyperresponsive and manifested sustained Ca2+ mobilization. They were spontaneously driven into germinal center-independent plasma cell differentiation, as evidenced by increased numbers of IgM+ plasma cells in spleen and BM and significantly elevated serum IgM. Because anti-nucleosome autoantibodies and glomerular IgM deposition were present, we conclude that constitutive Btk activation causes defective B-cell tolerance, emphasizing that Btk signals are essential for appropriate regulation of B-cell activation. [source] Constitutive activation of the neuregulin-1/ErbB receptor signaling pathway is essential for the proliferation of a neoplastic Schwann cell lineGLIA, Issue 2 2003Paul W. Frohnert Abstract Neuregulin-1 (NRG-1) proteins promote Schwann cell survival, differentiation and proliferation during development. High levels of an NRG-like activity are also present in some human peripheral nerve sheath tumors, suggesting that NRG-1 isoforms may be involved in the development of these neoplasms. We examined the expression of NRG-1 and its receptors, the erbB membrane tyrosine kinases, in JS1 cells, a rapidly proliferating line derived from a chemically induced rat malignant peripheral nerve sheath tumor (MPNST). Relative to nontransformed Schwann cells, JS1 cells overexpress the NRG-1 receptor erbB3 and its erbB2 coreceptor; JS1 erbB2 transcripts show no evidence of the activating mutation commonly found in N-ethyl-N-nitrosourea-induced neoplasms. JS1 cells do not express the epidermal growth factor receptor (EGFR), a kinase implicated in the pathogenesis of a major subset of MPNSTs. JS1 cells also express mRNAs encoding multiple , and , isoforms from the glial growth factor and sensory and motor neuron-derived factor NRG-1 subfamilies. Stimulation with NRG-1, in the presence of forskolin produces a dose-dependent increase in JS1 DNA synthesis. Even in unstimulated JS1 cells, however, erbB2 and erbB3 are constitutively tyrosine phosphorylated. Reducing this constitutive phosphorylation with the specific erbB inhibitor PD158780 markedly impairs JS1 DNA synthesis. These observations support the hypothesis that NRG-1 isoforms and erbB kinases act in an autocrine and/or paracrine fashion to promote mitogenesis in JS1 cells. The absence of EGFR expression in JS1 cells suggests that constitutive activation of the NRG-1/erbB signaling pathway is an alternative means of inducing Schwann cell neoplasia. © 2003 Wiley-Liss, Inc. [source] Bone Regeneration Is Regulated by Wnt Signaling,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2007Jae-Beom Kim Abstract Tissue regeneration is increasingly viewed as reactivation of a developmental process that, when misappropriated, can lead to malignant growth. Therefore, understanding the molecular and cellular pathways that govern tissue regeneration provides a glimpse into normal development as well as insights into pathological conditions such as cancer. Herein, we studied the role of Wnt signaling in skeletal tissue regeneration. Introduction: Some adult tissues have the ability to regenerate, and among these, bone is one of the most remarkable. Bone exhibits a persistent, lifelong capacity to reform after injury, and continual bone regeneration is a prerequisite to maintaining bone mass and density. Even slight perturbations in bone regeneration can have profound consequences, as exemplified by conditions such as osteoporosis and delayed skeletal repair. Here, our goal was to determine the role of Wnts in adult bone regeneration. Materials and Methods: Using TOPgal reporter mice, we found that damage to the skeleton instigated Wnt reporter activity, specifically at the site of injury. We used a skeletal injury model to show that Wnt inhibition, achieved through adenoviral expression of Dkk1 in the adult skeleton, prevented the differentiation of osteoprogenitor cells. Results: As a result, injury-induced bone regeneration was reduced by 84% compared with controls. Constitutive activation of the Wnt pathway resulting from a mutation in the Lrp5 Wnt co-receptor results in high bone mass, but our experiments showed that this same point mutation caused a delay in bone regeneration. In these transgenic mice, osteoprogenitor cells in the injury site were maintained in a proliferative state and differentiation into osteoblasts was delayed. Conclusions: When considered together, these data provide a framework for understanding the roles of Wnt signaling in adult bone regeneration and suggest a feasible approach to treating clinical conditions where enhanced bone formation is desired. [source] Constitutive activation of the mitogen-activated protein kinase pathway impairs vitamin D signaling in human prostate epithelial cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2010Zhentao Zhang We studied the effect of prolonged activation of mitogen-activated protein kinase (MAPK) signaling on 1,25 dihydroxyvitamin D (1,25(OH)2D3) action in the immortalized human prostate epithelial cell line RWPE1 and its Ki-Ras transformed clone RWPE2. 1,25(OH)2D3 -treatment caused growth arrest and induced gene expression in both cell lines but the response was blunted in RWPE2 cells. Vitamin D receptor (VDR) levels were lower in RWPE2 cells but VDR over-expression did not increase vitamin-D-mediated gene transcription in either cell line. In contrast, MAPK inhibition restored normal vitamin D transcriptional responses in RWPE2 cells and MAPK activation with constitutively active MEK1R4F reduced vitamin-D-regulated transcription in RWPE1 cells. 1,25(OH)2D3 -mediated transcription depends upon the VDR and its heterodimeric partner the retinoid X receptor (RXR) so we studied whether changes in the VDR,RXR transcription complex occur in response to MAPK activation. Mutation of putative phosphorylation sites in the activation function 1 (AF-1) domain (S32A, T82A) of RXR, restored 1,25(OH)2D3 -mediated transactivation in RWPE2 cells. Mammalian two-hybrid and co-immunoprecipitation assays revealed a vitamin-D-independent interaction between steroid receptor co-activator-1 (SRC-1) and RXR, that was reduced by MAPK activation and was restored in RWPE2 cells by mutating S32 and T82 in the RXR, AF-1 domain. Our data show that a common contributor to cancer development, prolonged activation of MAPK signaling, impairs 1,25(OH)2D3 -mediated transcription in prostate epithelial cells. This is due in part to the phosphorylation of critical amino acids in the RXR, AF-1 domain and impaired co-activator recruitment. J. Cell. Physiol. 224: 433,442, 2010. © 2010 Wiley-Liss, Inc. [source] Oncogenic KRAS provides a uniquely powerful and variable oncogenic contribution among RAS family members in the colonic epitheliumJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2007Jeffrey W. Keller Activating mutations of the RAS family of small GTPases are among the most common genetic events in human tumorigenesis. Constitutive activation of the three canonical family members, KRAS, NRAS, and HRAS segregate strongly by tissue type. Of these, KRAS mutations predominate in human tumors, including those arising from the colon and lung. We sought to compare the oncogenic contributions of different RAS isoforms in a comparable genetic setting and to explore downstream molecular changes that may explain the apparent differential oncogenic effects of the various RAS family members. We utilized colorectal cancer cell lines characterized by oncogenic KRAS in parallel with isogenically derived lines in which the mutant allele has been disrupted. We additionally attempted to reconstitute the isogenic derivatives with oncogenic forms of other RAS family members and analyze them in parallel. Pairwise analysis of HCT 116 and DLD-1 cell lines as well as their isogenic derivatives reveals distinct K-RASG13D signatures despite the genetic similarities of these cell lines. In DLD-1, for example, oncogenic K-RAS enhances the motility of these cells by downregulation of Rap1 activity, yet is not associated with increased ERK1/2 phosphorylation. In HCT 116, however, ERK1/2 phosphorylation is elevated relative to the isogenic derivative, but Rap1 activity is unchanged. K-RAS is uniquely oncogenic in the colonic epithelium, though the molecular aspects of its oncogenic contribution are not necessarily conserved across cell lines. We therefore conclude that the oncogenic contribution of K-RAS is a function of its multifaceted functionality and is highly context-dependent. J. Cell. Physiol. 210: 740,749, 2007. © 2006 Wiley-Liss, Inc. [source] Activation of Signal Transducers and Activators of Transcription 3 and Overexpression of its Target Gene CyclinD1 in Laryngeal Carcinomas,THE LARYNGOSCOPE, Issue 11 2008Bin Liu MD Abstract Objectives/Hypothesis: Constitutive activation of signal transducers and activators of transcription (STAT) 3 has been observed in many solid tumors including head and neck squamous cell carcinoma. Expression and activation of STAT3 in laryngeal carcinoma have not been fully understood. The study aims to investigate the expression and activation of STAT3 in laryngeal carcinoma, the relationship between activated STAT3 and its downstream target gene CyclinD1 and the related clinicopathological factors of activated STAT3. Study Design: Prospective. Methods: Sixty-four samples of laryngeal squamous cell carcinoma and 12 samples of control mucosa obtained from total laryngectomy cases were analyzed using Western blot analysis and reverse transcriptase-polymerase chain reaction. Statistical analysis was performed using SPSS. Results: The overexpression of both STAT3 and CyclinD1 mRNA was observed in all samples of laryngeal squamous cell carcinoma. The mRNA levels of STAT3 and CyclinD1 in carcinoma tissue were 2.1- and 2.3-fold higher than those in control mucosa, respectively; the differences were statistically significant (P < .01). The overexpression of STAT3, p-STAT3, and CyclinD1 protein was also observed in all tumor samples. The protein levels of STAT3, p-STAT3, and CyclinD1 in carcinoma tissue were 1.6-, 4.5-, and 2.0-fold higher than those in control mucosa respectively; the differences were statistically significant (P < .01). There was a positive correlation between p-STAT3 protein and CyclinD1 mRNA (Pearson correlation coefficient = 0.827, P < .01). There were significant correlations between the overexpression of p-STAT3 protein and clinical T stage (P < .01), and tumor size (P < .05). The p-STAT3 protein level of patients in T1, T2 was higher than that of patients in T3, T4. The p-STAT3 protein level of patients with tumor size within 20 mm was higher than that of patients with tumor size more than 20 mm. Conclusions: High expression and activation of STAT3 exist in laryngeal carcinomas. Activated STAT3 may take effect on promoting transcription of its downstream target gene CyclinD1. The role of activation of STAT3 in laryngeal carcinogenesis needs further research. [source] Constitutive activation of a CC-NB-LRR protein alters morphogenesis through the cytokinin pathway in ArabidopsisTHE PLANT JOURNAL, Issue 1 2008Kadunari Igari Summary Possible links between plant defense responses and morphogenesis have been postulated, but their molecular nature remains unknown. Here, we introduce the Arabidopsis semi-dominant mutant uni-1D with morphological defects. UNI encodes a coiled-coil nucleotide-binding leucine-rich-repeat protein that belongs to the disease resistance (R) protein family involved in pathogen recognition. The uni-1D mutation causes the constitutive activation of the protein, which is stabilized by the RAR1 function in a similar way as in other R proteins. The uni-1D mutation induces the upregulation of the Pathogenesis-related gene via the accumulation of salicylic acid, and evokes some of the morphological defects through the accumulation of cytokinin. The rin4 knock-down mutation, which causes the constitutive activation of two R proteins, RPS2 and RPM1, induces an upregulation of cytokinin-responsive genes and morphological defects similar to the uni-1D mutation, indicating that the constitutive activation of some R proteins alters morphogenesis through the cytokinin pathway. From these data, we propose that the modification of the cytokinin pathway might be involved in some R protein-mediated responses. [source] Constitutive activation of PI3K-Akt and NF-,B during prostate cancer progression in autochthonous transgenic mouse modelTHE PROSTATE, Issue 3 2005Sanjeev Shukla Abstract BACKGROUND Cancer progression is usually facilitated by independent growth signals that may lead to increased cell survival and evasion of apoptosis. Phosphatidylinositol 3,-OH kinase (PI3K)-Akt and transcription factor NF-,B are important signaling molecules and key survival factors involved in the control of cell proliferation, apoptosis, and oncogenesis. Although PI3K-Akt and NF-,B have been implicated in the development and progression of prostate cancer, expression of these molecules during progression of autochthonous disease has not been elucidated. METHODS Prostate cancer growth and progression in autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and male non-transgenic littermates were observed by magnetic resonance imaging (MRI). Expression patterns of PI3K-Akt, NF-,B, I,B, and associated signaling molecules during different stages of cancer progression in these mice were examined by Western blot analysis, electrophoretic mobility shift assay (EMSA), enzyme-linked immunoabsorbent assay (ELISA), kinase assay, and immunohistochemistry. RESULTS Sequential MRI and gross analysis of prostate gland exhibited increasing prostate volume associated with the development and progression of prostatic adenocarcinoma in TRAMP mice, compared to male non-transgenic littermates. Differential protein expression of PI3K, phosphorylated-Akt (Ser473), I,B, and its phosphorylation, IKK kinase activity, NF-,B/p65, p50, DNA binding, and transcriptional-regulated genes, viz., Bcl2, cyclin D1, MMP-9, and VEGF were observed during prostate cancer progression in TRAMP mice, compared to male non-transgenic littermates. Expressions of these molecules were significantly increased during cancer progression observed at 24 and 32 weeks of age. CONCLUSIONS Differential expression pattern of PI3K-Akt, NF-,B and I,B during prostate cancer progression in TRAMP mice suggest that these molecules represent potential molecular targets for prevention and/or therapeutic intervention. © 2005 Wiley-Liss, Inc. [source] Constitutive activation of MAPK cascade in acute quadriplegic myopathyANNALS OF NEUROLOGY, Issue 2 2004Simone Di Giovanni MD Acute quadriplegic myopathy (AQM; also called "critical illness myopathy") shows acute muscle wasting and weakness and is experienced by some patients with severe systemic illness, often associated with administration of corticosteroids and/or neuroblocking agents. Key aspects of AQM include muscle atrophy and myofilament loss. Although these features are shared with neurogenic atrophy, myogenic atrophy in AQM appears mechanistically distinct from neurogenic atrophy. Using muscle biopsies from AQM, neurogenic atrophy, and normal controls, we show that both myogenic and neurogenic atrophy share induction of myofiber-specific ubiquitin/proteosome pathways (eg, atrogin-1). However, AQM patient muscle showed a specific strong induction of transforming growth factor (TGF),,/MAPK pathways. Atrophic AQM myofibers showed coexpression of TGF-, receptors, p38 MAPK, c-jun, and c-myc, including phosphorylated active forms, and these same fibers showed apoptotic features. Our data suggest a model of AQM pathogenesis in which stress stimuli (sepsis, corticosteroids, pH imbalance, osmotic imbalance) converge on the TGF-, pathway in myofibers. The acute stimulation of the TGF-,/MAPK pathway, coupled with the inactivity-induced atrogin-1/proteosome pathway, leads to the acute muscle loss seen in AQM patients. Ann Neurol 2004 [source] Exendin-4 protects pancreatic beta cells from human islet amyloid polypeptide-induced cell damage: potential involvement of AKT and mitochondria biogenesisDIABETES OBESITY & METABOLISM, Issue 9 2010R. Fan Aim: Glucagon-like peptide-1 (GLP-1) stimulates beta-cell proliferation and enhances beta-cell survival, whereas oligomerization of human islet amyloid polypeptide (hIAPP) may induce beta-cell apoptosis and reduce beta-cell mass. Type 2 diabetes is associated with increased expression of IAPP. As GLP-1-based therapy is currently developed as a novel antidiabetic therapy, we examined the potential protective action of the GLP-1 receptor agonist exendin-4 on hIAPP-induced beta-cell apoptosis. Methods: The study was performed in clonal insulinoma (INS-1E) cells. Both method of transcriptional and translational and sulphorhodamine B (SRB) assays were used to evaluate cell viability and cell mass. Western blot analysis was applied to detect protein expression. Transfection of constitutively active protein kinase B (PKB/AKT) was performed to examine the role of AKT. Mitochondrial biogenesis was quantified by mitogreen staining and RT-PCR. Results: First, we confirmed that hIAPP induced cell apoptosis and growth inhibition in INS-1E cells. These effects were partially protected by exendin-4 in association with partial recovery of the hIAPP-mediated AKT inhibition. Furthermore, AKT constitutive activation attenuated hIAPP-induced apoptosis, whereas PI3K/AKT inhibition abrogated exendin-4-mediated effects. These findings suggest that the antiapoptotic and proliferative effects of exendin-4 in hIAPP-treated INS-1E cells were partially mediated through AKT pathway. Moreover, hIAPP induced FOXO1 but inhibited pdx-1 nucleus translocation. These effects were restored by exendin-4. Finally, mitogreen staining and RT-PCR revealed enhanced mitochondrial biogenesis by exendin-4 treatment. Conclusions: Collectively, these results suggest that GLP-1 receptor agonist protects beta cells from hIAPP-induced cell death partially through the activation of AKT pathway and improved mitochondrial function. [source] Scanning mutagenesis of regions in the G, protein Gpa1 that are predicted to interact with yeast mating pheromone receptorsFEMS YEAST RESEARCH, Issue 1 2008Douglas P. Gladue Abstract The mechanism by which receptors activate heterotrimeric G proteins was examined by scanning mutagenesis of the Saccharomyces cerevisiae pheromone-responsive G, protein (Gpa1). The juxtaposition of high-resolution structures for rhodopsin and its cognate G protein transducin predicted that at least six regions of G, are in close proximity to the receptor. Mutagenesis was targeted to residues in these domains in Gpa1, which included four loop regions (,2,,3, ,2,,4, ,3,,5, and ,4,,6) as well as the N and C termini. The mutants displayed a range of phenotypes from nonsignaling to constitutive activation of the pheromone pathway. The constitutive activity of some mutants could be explained by decreased production of Gpa1, which permits unregulated signaling by G,,. However, the constitutive activity caused by the F344C and E335C mutations in the ,2,,4 loop and F378C in the ,3,,5 loop was not due to decreased protein levels, and was apparently due to defects in sequestering G,,. The strongest loss of the function mutant, which was not detectably induced by a pheromone, was caused by a K314C substitution in the ,2,,3 loop. Several other mutations caused weak signaling phenotypes. Altogether, these results suggest that residues in different interface regions of G, contribute to activation of signaling. [source] Secretion of matrix metalloproteinase-9 by the proinflammatory cytokine, IL-1,: a role for the dual signalling pathways, Akt and ErkGENES TO CELLS, Issue 6 2003A. R. M. Ruhul Amin Background: Matrix metalloproteinases including MMP-9 mediate matrix destruction during chronic inflammatory diseases such as arthritis and atherosclerosis. MMP-9 up-regulation by inflammatory cytokines involve interactions between several transcription factors including activator protein-1 and NF,B. The upstream regulatory pathways are less well understood. Results: To search for the mechanism of tissue destruction in the process of inflammatory disorders, we investigated the signalling pathway critical for the activation of MMP-9 expression and secretion by IL-1,. Treatment of Balb 3T3 cells with IL-1, activated MMP-9 transcription and subsequent secretion in a time- and dose-dependent manner. Concomitantly, IL-1, treatment of cells activated phosphorylation of Akt, Erk and p38. Treatment of cells with either LY294002, a PI3K inhibitor, or expression of a dominant negative form of Akt drastically suppressed the IL-1,-dependent secretion of MMP-9. Pretreatment of cells with a MEK1 inhibitor, U0126, also strongly inhibited IL-1,-dependent secretion of MMP-9. In contrast, pre-treatment with a specific p38 kinase inhibitor, SB203580, had no effect on IL-1,-dependent secretion of MMP-9. In addition, cells expressing constitutively active form of Akt or MEK1 showed no clear activation of MMP-9 secretion, whereas these cells responded well to IL-1, treatment. However, co-transfection of cells with both active Akt and MEK1 was sufficient to induce MMP-9 secretion without stimulation with IL-1,. Conclusion: Taken together, our results suggest that IL-1, stimulation of cells activates MMP-9 secretion by the activation of the dual signalling pathways, the PI3K-Akt and MEK1-Erk and constitutive activation of these pathways were sufficient to induce MMP-9 secretion. [source] Fusion gene-mediated truncation of RUNX1 as a potential mechanism underlying disease progression in the 8p11 myeloproliferative syndromeGENES, CHROMOSOMES AND CANCER, Issue 7 2007Helena Ågerstam The 8p11 myeloproliferative syndrome (EMS) is a chronic myeloproliferative disorder molecularly characterized by fusion of various 5, partner genes to the 3, part of the fibroblast growth factor receptor 1 (FGFR1) gene at 8p, resulting in constitutive activation of the tyrosine kinase activity contained within FGFR1. EMS is associated with a high risk of transformation to acute myeloid leukemia (AML), but the mechanisms underlying the disease progression are unknown. In the present study, we have investigated a case of EMS harboring a t(8;22)(p11;q11)/BCR-FGFR1 rearrangement as well as a t(9;21)(q34;q22) at the time of AML transformation. FISH and RT-PCR analyses revealed that the t(9;21) leads to a fusion gene consisting of the 5, part of RUNX1 (exons 1,4) fused to repetitive sequences of a gene with unknown function on chromosome 9, adding 70 amino acids to RUNX1 exon 4. The t(9;21) hence results in a truncation of RUNX1. No point mutations were found in the other RUNX1 allele. The most likely functional outcome of the rearrangement was haploinsufficiency of RUNX1, which thus may be one mechanism by which EMS transforms to AML. © 2007 Wiley-Liss, Inc. [source] Constitutive activation of the neuregulin-1/ErbB receptor signaling pathway is essential for the proliferation of a neoplastic Schwann cell lineGLIA, Issue 2 2003Paul W. Frohnert Abstract Neuregulin-1 (NRG-1) proteins promote Schwann cell survival, differentiation and proliferation during development. High levels of an NRG-like activity are also present in some human peripheral nerve sheath tumors, suggesting that NRG-1 isoforms may be involved in the development of these neoplasms. We examined the expression of NRG-1 and its receptors, the erbB membrane tyrosine kinases, in JS1 cells, a rapidly proliferating line derived from a chemically induced rat malignant peripheral nerve sheath tumor (MPNST). Relative to nontransformed Schwann cells, JS1 cells overexpress the NRG-1 receptor erbB3 and its erbB2 coreceptor; JS1 erbB2 transcripts show no evidence of the activating mutation commonly found in N-ethyl-N-nitrosourea-induced neoplasms. JS1 cells do not express the epidermal growth factor receptor (EGFR), a kinase implicated in the pathogenesis of a major subset of MPNSTs. JS1 cells also express mRNAs encoding multiple , and , isoforms from the glial growth factor and sensory and motor neuron-derived factor NRG-1 subfamilies. Stimulation with NRG-1, in the presence of forskolin produces a dose-dependent increase in JS1 DNA synthesis. Even in unstimulated JS1 cells, however, erbB2 and erbB3 are constitutively tyrosine phosphorylated. Reducing this constitutive phosphorylation with the specific erbB inhibitor PD158780 markedly impairs JS1 DNA synthesis. These observations support the hypothesis that NRG-1 isoforms and erbB kinases act in an autocrine and/or paracrine fashion to promote mitogenesis in JS1 cells. The absence of EGFR expression in JS1 cells suggests that constitutive activation of the NRG-1/erbB signaling pathway is an alternative means of inducing Schwann cell neoplasia. © 2003 Wiley-Liss, Inc. [source] p.Gln200Glu, a putative constitutively active mutant of rod ,-transducin (GNAT1) in autosomal dominant congenital stationary night blindness,,HUMAN MUTATION, Issue 7 2007Viktoria Szabo Abstract Congenital stationary night blindness (CSNB) is a non-progressive Mendelian condition resulting from a functional defect in rod photoreceptors. A small number of unique missense mutations in the genes encoding various members of the rod phototransduction cascade, e.g. rhodopsin (RHO), cGMP phosphodiesterase ,-subunit (PDE6B), and transducin ,-subunit (GNAT1) have been reported to cause autosomal dominant (ad) CSNB. While the RHO and PDE6B mutations result in constitutively active proteins, the only known adCSNB-associa-ted GNAT1 change (p.Gly38Asp) produces an ,-transducin that is unable to activate its downstream effector molecule in vitro. In a multigeneration Danish family with adCSNB, we identified a novel heterozygous C to G transversion (c.598C>G) in exon 6 of GNAT1 that should result in a p.Gln200Glu substitution in the evolutionarily highly conserved Switch 2 region of ,-transducin, a domain that has an important role in binding and hydrolyzing GTP. Computer modeling based on the known crystal structure of transducin suggests that the p.Gln200Glu mutant exhibits impaired GTPase activity, and thereby leads to constitutive activation of phototransduction. This assumption is in line with our results of trypsin protection assays as well as previously published biochemical data on mutants of this glutamine in the GTPase active site of ,-transducin following in vitro expression, and observations that inappropriately activating mutants of various members of the rod phototransduction cascade represent one of the major molecular causes of adCSNB. © 2007 Wiley-Liss, Inc. [source] Functional characterization of the NF-,B transcription factor gene REL2 from Anopheles gambiaeINSECT SCIENCE, Issue 3 2007NGO T. HOA Abstract The REL2 gene plays an important role in innate immunity against both Gram (+) and Gram (-) bacteria and malaria parasites in Anopheles gambiae, the main vector of malaria in Africa. Through alternative splicing, REL2 produces two protein products, REL2F (with a Rel-homology domain as well as an inhibitory ankyrin repeat region) and REL2S (without the ankyrin repeats). In the immune-competent cell line Sua1B from An. gambiae, REL2 has been shown to be a key regulator for cecropin A (or CEC1). The high level expression of CEC1 in Sua1B was postulated to be the result of constitutive activation of REL2F. Here we showed that REL2F is indeed processed, albeit at a low level, in the Sua1B cell line. The primary cleavage requires residue 678 (an aspartic acid). Proteolytic cleavage of REL2F can be enhanced by challenge with bacteria Escherichia coli and Bacillus subtilis, but not with fungus Beauveria bassiana. The inducible cleavage can be substantially reduced by RNA interference against PGRP-LC and CASPL1. Over-expression of REL2S or a constitutively active form of REL2F (REL2F380C or REL2F678) in An. gambiae cell line can further increase expression of CEC1 and other antimicrobial peptide genes. Over-expression of these constitutive active proteins in an immune naive cell line, MSQ43, from Anopheles stephensi, results in even more dramatic increased expression of antimicrobial peptides. [source] Defining a role for Sonic hedgehog pathway activation in desmoplastic medulloblastoma by identifying GLI1 target genesINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Joon Won Yoon Abstract A subgroup of medulloblastomas shows constitutive activation of the Sonic hedgehog pathway with expression of GLI1. We identified the subset of GLI1 transforming target genes specifically expressed in medulloblastomas by comparing GLI1 targets in RK3E cells transformed by GLI1 with the gene expression profile of Sonic hedgehog signature medulloblastomas. We identified 1,823 genes whose expression was altered more than 2-fold in 2 independent RK3E + GLI1 cell lines. We identified 25 whose expression was altered similarly in medulloblastomas expressing GLI1. We identified potential GLI binding elements in the regulatory regions of 10 of these genes, confirmed that GLI1 binds the regulatory regions and activates transcription of select genes, and showed that GLI1 directly represses transcription of Krox-20. We identified upregulation of CXCR4, a chemokine receptor that plays roles in the proliferation and migration of granule cell neuron precursors during development, supporting the concept that reinitiation of developmental programs may contribute to medulloblastoma tumorigenesis. In addition, the targets suggest a pathway through which GLI1 may ultimately affect medulloblastoma cell proliferation, survival and genomic stability by converging on p53, SGK1, MGMT and NTRK2. We identify a p53 mutation in RK3E + GLI1 cells, suggesting that p53 mutations may sometimes shift the balance toward dysregulated tumor cell survival. © 2008 Wiley-Liss, Inc. [source] Chemoresistant tumor cell lines display altered epidermal growth factor receptor and HER3 signaling and enhanced sensitivity to gefitinibINTERNATIONAL JOURNAL OF CANCER, Issue 12 2008Tiziana Servidei Abstract Deregulated signaling through the epidermal growth factor receptor (EGFR) is involved in chemoresistance. To identify the molecular determinants of sensitivity to the EGFR inhibitor gefitinib (Iressa, ZD1839) in chemoresistance, we compared the response of matched chemosensitive and chemoresistant glioma and ovarian cancer cell lines. We found that chemoresistant cell lines were 2- to 3-fold more sensitive to gefitinib growth-inhibitory effects, because of decreased proliferation rather than survival. Sensitivity to gefitinib correlated with overexpression and constitutive phosphorylation of HER2 and HER3, but not EGFR, altered HER ligand expression, and enhanced activation of EGF-triggered EGFR pathway. No activating mutations were found in EGFR. Gefitinib fully inhibited EGF-induced and constitutive Akt activation only in chemoresistant cells. In parallel, gefitinib downregulated constitutively phosphorylated HER2 and HER3, and activated GSK3, with a concomitant degradation of cyclin D1. Ectopically overexpressed HER2 on its own was insufficient to sensitize chemonaive cells to gefitinib. pHER3 coimmunoprecipitated with p85-PI3K in chemoresistant cells and gefitinib dissociated these complexes. siRNA-mediated inhibition of HER3 decreased constitutive activation of Akt and sensitivity to gefitinib in chemoresistant cells. Our study indicates that in chemoresistant cells gefitinib inhibits both an enhanced EGF-triggered pathway and a constitutive HER3-mediated Akt activation, indicating that inhibition of HER3 together with that of EGFR could be relevant in chemorefractory tumors. Furthermore, in combination experiments gefitinib enhanced the effects of coadministered drugs more in chemoresistant than chemosensitive ovarian cancer cells. Combined treatment might be therapeutically beneficial in chemoresistant tumors from ovary and likely from other tissues. © 2008 Wiley-Liss, Inc. [source] A celecoxib derivative inhibits focal adhesion signaling and induces caspase-8-dependent apoptosis in human acute myeloid leukemia cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2008Isolda Casanova Abstract Most acute myeloid leukemias (AMLs), including those with c-Kit or FLT3 mutations, show enhanced anchorage independent growth associated with constitutive activation of focal adhesion proteins. Moreover, these alterations increase cell survival, inhibit apoptosis and are associated with poor prognosis and resistance to chemotherapy. Therefore, the induction of apoptosis by selective inhibition of focal adhesion signaling may represent a novel anti-AML therapy. Here, we have evaluated the antitumor effect and the mechanism of action of celecoxib and E7123, a non-Cox-2 inhibitor derivative, in a panel of human AML cell lines and bone marrow mononuclear cells from AML patients. Both compounds induce cell death by inhibiting focal adhesion signaling through p130Cas, FAK and c-Src, leading to caspase-8 dependent apoptosis. This mechanism of action differs from that of classical cytotoxic drugs or of other targeted therapies, and is amenable to rational drug development. Therefore, both drugs could be developed as AML therapeutics; nevertheless, E7123 shows more activity than celecoxib against AML cells, and may not present its Cox-2 dependent cardiovascular toxicity. Finally, our results support the evaluation of celecoxib in AML patients, and the preclinical evaluation of E7123, before its possible clinical testing. © 2008 Wiley-Liss, Inc. [source] Rapamycin together with herceptin significantly increased anti-tumor efficacy compared to either alone in ErbB2 over expressing breast cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2007Lu-Hai Wang Abstract The objective of this study was to assess the anti-tumor efficacy of rapamycin alone or in combination with herceptin in breast cancer. A total of 20 human breast cancer lines were examined for expression of various receptor tyrosine kinases and activation of their down stream signaling molecules, as well as for their invasion and colony forming ability. The ErbB2 and PI3 kinase pathway inhibitors were tested for the inhibition on breast cancer cell growth and tumor development. Seven of the 20 lines displayed an elevated level of ErbB2, others had varying level of EGF, IGF-1 or insulin receptor. Over 30% of the lines also had constitutive activation of Akt and MAP kinase. The lines displayed a wide range of colony forming and invasion ability. The PI3 kinase pathway inhibitors LY294002 and rapamycin inhibited the colony forming ability of all of the lines with the ErbB2 overexpressing lines having a higher sensitivity. A similar trend was observed for inhibition of invasion by LY294002. Rapamycin alone and additively together with herceptin inhibited the breast cancer cell growth especially in ErbB2 overexpressing cells. Rapamycin and herceptin synergistically inhibited tumor growth and endpoint tumor load in a xenograft model using a MCF-7 subline and in a MMTV-ErbB2 transgenic model. Rapamycin and herceptin significantly reduced the level of cyclin D1 and D3 and increased the cleavage of caspase 3 suggesting an increased apoptosis. Our results suggest that rapamycin together with herceptin has an enhanced anti-cancer effect and could be developed as an improved therapeutic regimen for breast cancer. © 2007 Wiley-Liss, Inc. [source] PDK1 and PKB/Akt: Ideal Targets for Development of New Strategies to Structure-Based Drug DesignIUBMB LIFE, Issue 3 2003Thomas Harris Abstract Growth factor binding events to receptor tyrosine kinases result in activation of phosphatidylinositol 3-kinase (PI3K), and activated PI3K generates the membrane-bound second messengers phosphatidylinositol 3,4-diphosphate [PI(3,4)P2] and PI(3,4,5)P3, which mediate membrane translocation of the phosphoinositide-dependent kinase-1 (PDK1) and protein kinase B (PKB, also known as Akt). In addition to the kinase domain, PDK1 and PKB contain a pleckstrin homology (PH) domain that binds to the second messenger, resulting in the phosphorylation and activation of PKB by PDK1. Recent evidence indicates that constitutive activation of PKB contributes to cancer progression by promoting proliferation and increased cell survival. The indicating of PDK1 and PKB as primary targets for discovery of anticancer drugs, together with the observations that both PDK1 and PKB contain small-molecule regulatory binding sites that may be in proximity to the kinase active site, make PDK1 and PKB ideal targets for the development of new strategies to structure-based drug design. While X-ray structures have been reported for the kinase domains of PDK1 and PKB, no suitable crystals have been obtained for either PDK1 or PKB with their PH domains intact. In this regard, a novel structure-based strategy is proposed, which utilizes segmental isotopic labeling of the PH domain in combination with site-directed spin labeling of the kinase active site. Then, long-range distance restraints between the 15N-labeled backbone amide groups of the PH domain and the unpaired electron of the active site spin label can be determined from magnetic resonance studies of the enhancement effect that the paramagnetic spin label has on the nuclear relaxation rates of the amide protons. The determination of the structure and position of the PH domain with respect to the known X-ray structure of the kinase active site could be useful in the rational design of potent and selective inhibitors of PDK1 and PKB by 'linking' the free energies of binding of substrate (ATP) analogs with analogs of the inositol polar head group of the phospholipid second messenger. The combined use of X-ray crystallography, segmental isotopic and spin labeling, and magnetic resonance studies can be further extended to the study of other dynamic multidomain proteins and targets for structure-based drug design. IUBMB Life, 55: 117-126, 2003 [source] Origin matters: Differences in embryonic tissue origin and Wnt signaling determine the osteogenic potential and healing capacity of frontal and parietal calvarial bonesJOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2010Natalina Quarto Abstract Calvarial bones arise from two embryonic tissues, namely, the neural crest and the mesoderm. In this study we have addressed the important question of whether disparate embryonic tissue origins impart variable osteogenic potential and regenerative capacity to calvarial bones, as well as what the underlying molecular mechanism(s). Thus, by performing in vitro and in vivo studies, we have investigated whether differences exist between neural crest,derived frontal and paraxial mesodermal,derived parietal bone. Of interest, our data indicate that calvarial bone osteoblasts of neural crest origin have superior potential for osteogenic differentiation. Furthermore, neural crest,derived frontal bone displays a superior capacity to undergo osseous healing compared with calvarial bone of paraxial mesoderm origin. Our study identified both in vitro and in vivo enhanced endogenous canonical Wnt signaling in frontal bone compared with parietal bone. In addition, we demonstrate that constitutive activation of canonical Wnt signaling in paraxial mesodermal,derived parietal osteoblasts mimics the osteogenic potential of frontal osteoblasts, whereas knockdown of canonical Wnt signaling dramatically impairs the greater osteogenic potential of neural crest,derived frontal osteoblasts. Moreover, fibroblast growth factor 2 (FGF-2) treatment induces phosphorylation of GSK-3, and increases the nuclear levels of ,-catenin in osteoblasts, suggesting that enhanced activation of Wnt signaling might be mediated by FGF. Taken together, our data provide compelling evidence that indeed embryonic tissue origin makes a difference and that active canonical Wnt signaling plays a major role in contributing to the superior intrinsic osteogenic potential and tissue regeneration observed in neural crest,derived frontal bone. © 2010 American Society for Bone and Mineral Research [source] Mirk/Dyrk1B in cancerJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2007Eileen Friedman Abstract Mirk/Dyrk1B is a member of a conserved family of serine/threonine kinases which are activated by intramolecular tyrosine phosphorylation, and which mediate differentiation in different tissues,Mirk in skeletal muscle, Dyrk1A in the brain, etc. One role of Mirk in skeletal muscle differentiation is to block cycling myoblasts in the G0 quiescent state by modification of cell cycle regulators, while another role of Mirk is to limit apoptosis in fusing myoblasts. Amplification of the Mirk gene, upregulation of Mirk expression and/or constitutive activation of this kinase have been observed in several different types of cancer. If coupled with a stress condition such as serum starvation which induces a quiescent state, depletion of Mirk by RNA interference using either synthetic duplex RNAi's or pSilencer-encoded RNAi's have decreased colony formation of different cancer cell lines and enhanced apoptosis induced by chemotherapeutic drugs. Mirk is activated by phosphorylation by the stress-activated SAPK kinases MKK3 and MKK6. Our working hypothesis is that Mirk is activated by this pathway in response to various stresses, and then acts as a checkpoint kinase to arrest damaged tumor cells in a quiescent state and allow cellular repair. Pharmacological inhibition of Mirk may enhance the anti-tumor effect of chemotherapeutic drugs. J. Cell. Biochem. 102: 274,279, 2007. © 2007 Wiley-Liss, Inc. [source] Age-related differences in insulin-like growth factor-1 receptor signaling regulates Akt/FOXO3a and ERK/Fos pathways in vascular smooth muscle cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2008Muyao Li Advanced age is a major risk factor for atherosclerosis, but how aging per se influences pathogenesis is not clear. Insulin-like growth factor-1 receptor (IGF-1R) promotes aortic vascular smooth muscle cell (VSMC) growth, migration, and extracellular matrix formation, but how IGF-1R signaling changes with age in VSMC is not known. We previously found age-related differences in the activation of Akt/FOXO3a and ERK1/2 pathways in VSMC, but the upstream signaling remains unclear. Using explanted VSMC from Fischer 344/Brown Norway F1 hybrid rats shown to display age-related vascular pathology similar to humans, we compared IGF-1R expression in early passages of VSMC and found a constitutive activation of IGF-1R in VSMC from old compared to young rats, including IGF-1R expression and its tyrosine kinase activity. The link between IGF-1R activation and the Akt/FOXO3a and ERK pathways was confirmed through the induction of IGF-1R with IGF-1 in young cells and attenuation of IGF-1R with an inhibitor in old cells. The effects of three kinase inhibitors: AG1024, LY294002, and TCN, were compared in VSMC from old rats to differentiate IGF-1R from other upstream signaling that could also regulate the Akt/FOXO and ERK pathways. Genes for p27kip-1, catalase and MnSOD, which play important roles in the control of cell cycle arrest and stress resistance, were found to be FOXO3a-targets based on FOXO3a-siRNA treatment. Furthermore, IGF-1R signaling modulated these genes through activation of the Akt/FOXO3a pathway. Therefore, activation of IGF-1R signaling influences VSMC function in old rats and may contribute to the increased risk for atherosclerosis. J. Cell. Physiol. 217: 377,387, 2008. © 2008 Wiley-Liss, Inc. [source] Tyrosine-phosphorylated STAT5 accumulates on podosomes in Hck-transformed fibroblasts and chronic myeloid leukemia cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2007Renaud Poincloux In chronic myeloid leukemia (CML), the transforming activity of Bcr/Abl involves constitutive activation of the phagocyte specific Src-family tyrosine kinase Hck, which in turn directly activates the signal transducer and activator of transcription 5 (STAT5). The effect of Hck on STAT5 was first explored independently of Bcr/Abl by expressing the constitutively active Hck mutant (Hckca) in MEF3T3-TetOff fibroblasts. As previously reported, Hckca -expressing cells form podosomes which are actin-rich structures involved in trans-tissular cell migration and found in the few cell types able to cross anatomic boundaries. We demonstrated that in these cells, the tyrosine-phosphorylated form of STAT5 (PY-STAT5) increased and preferentially localized on podosomes together with Hck, instead of translocating to the nucleus as observed with conventional stimuli such as IFN,. To examine whether similar results were obtained in the presence of Bcr/Abl, the CML cell line K562 was used. We observed that (i) podosomal structures are present in these cells in contrast to Bcr/Abl-negative leukemic cells, (ii) podosome formation was inhibited by Bcr/Abl- and Src-kinase inhibitors, and (iii) PY-STAT5 mainly colocalized with Hck on these structures. The presence of podosomes was not sufficient to trap STAT5 since in normal macrophages which spontaneously form podosomes and express regulated Hck, PY-STAT5 is in the nucleus. In conclusion, this is the first report showing that PY-STAT5 associates to podosomes in a process dependent on constitutive activation of Hck. We propose that STAT5, previously classified as a transcription factor, could play another role outside the nucleus, elicited by the Bcr/Abl-Hck transforming pathway. J. Cell. Physiol. 213: 212,220, 2007. © 2007 Wiley-Liss, Inc. [source] Inhibition of nuclear factor ,B and phosphatidylinositol 3-kinase/Akt is essential for massive hepatocyte apoptosis induced by tumor necrosis factor , in miceLIVER INTERNATIONAL, Issue 5 2003Motoaki Imose Abstract: Background/aims: Tumor necrosis factor (TNF)-, itself does not induce liver injury in normal mice or hepatocytes. Rather, this event, especially in vitro, is explained by the fact that the TNF-,/TNF receptor system not only triggers downstream signals leading to apoptosis but also induces an antiapoptotic pathway through the activation of nuclear factor (NF)-,B. The aim of this study was to determine whether inhibition of antiapoptotic pathways influences the susceptibility of mice to TNF-,. Here, we focused on the roles of NF-,B and phosphatidylinositol 3-kinase (PI3K)-regulated serine/threonine kinase Akt. Methods: TNF-, was administered to BALB/c mice after treatment with an adenovirus expressing a mutant form I,B, (Ad5I,B), the PI3K inhibitor wortmannin, or both. Liver injury was assessed biochemically and histologically. The expression of Bcl-2 family members and caspase activity were examined. Results: In the mice livers, treatment with Ad5I,B or the wortmannin suppressed the activation of NF-,B or Akt, respectively. Suppression of either NF-,B or Akt showed a slight increase in transaminase levels and focal liver cell death after TNF-, administration. However, in mice treated with both Ad5I,B and wortmannin, TNF-, administration resulted in massive hepatocyte apoptosis and hemorrhagic liver destruction in mice. The combination of Ad5I,B, wortmannin, and TNF-, markedly increased the activation of caspase-3 and -9, and activated caspase-8 to a lesser degree, suggesting that TNF-,-induced hepatocyte apoptosis is dependent on type II cell death signaling pathway, probably through the mitochondria. Inhibition of the NF-,B and PI3K/Akt pathways had no effect on expression of Bcl-2 families. Conclusion: The inducible activation of NF-,B and constitutive activation of Akt regulate hepatocyte survival against TNF-,, which occurs independent of Bcl-2 families. [source] Immune manipulation of advanced breast cancer: An interpretative model of the relationship between immune system and tumor cell biologyMEDICINAL RESEARCH REVIEWS, Issue 3 2009Andrea Nicolini Abstract This review summarizes some recent clinical immunological approaches with cytokines and/or antibodies for therapy of advanced breast cancer. It considers the recent advances in genetics and molecular tumor biology related to impaired immunosurveillance involving cytokines and growth factors to explain clinical results. Evasion of the host immune attack might be induced by the following groups of mechanisms: (a) tumor dependent (genomic instability, HLA class I antigen abnormalities, upregulation of fetal type nonclassical HLA class I molecules, epitope immunodominance, apoptosis inhibition by defective death receptor signaling, apoptosis of activated T cells, tumor cannibalism and constitutive activation of signal transducer, and activator of transcription-3 (Stat 3) and nuclear factor-,B (NF-kB) signaling); (b) host dependent (CD4+CD25+ regulatory T cells (T reg), CD4+ T cells anergy, Th2 antitumor immunity diversion and myeloid suppressor cells); (c) tumor and host dependent (lack of co-stimulation molecules, immunosuppressive cytokines (vascular endothelial growth factor (VEGF), interleukin (IL)-10, prostaglandin (PG)E2, transforming growth factor (TGF)-,)). Cytokines and growth factors are involved in virtually all three types of mechanisms. These mechanisms are integrated with the current knowledge of tumor growth and inhibited apoptosis primarily mediated by cytokines and growth factors to propose an interpretation of the relationships among tumor cells, tumor stroma, and tumor-infiltrating lymphocytes. Tumor growth, defective immunorecognition and immunosuppression are the three principal effects considered responsible for immune evasion. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 3, 436-471, 2009 [source] Melanoma development and pigment cell transformation in xiphophorusMICROSCOPY RESEARCH AND TECHNIQUE, Issue 6 2002Claudia Wellbrock As early as 1927, it was recognised that hybridisation of platyfish (Xiphophorus maculatus) and swordtails (Xiphophorus helleri) results in offspring that develop tumours according to Mendelian laws. Most obviously, the primary event, namely the cell lineage-specific overexpression of a structurally altered receptor tyrosine kinase, finds its parallel in many tumours of birds and mammals. Once expressed at high levels, this receptor, the Xiphophorus melanoma inducing receptor kinase Xmrk, shows constitutive activation. By using different pathways, Xmrk induces both proliferative as well as anti-apoptotic signalling in pigment cells finally leading to cell transformation, tumour induction, and progression. Analyses of the different signalling cascades induced by the Xmrk-receptor led to the identification of the src-kinase Fyn, the MAP kinases ERK1 and ERK2, the "Signal Transducer and Activator of Transcription" STAT5, and the PI3-kinase as its major downstream substrates. This review describes some of the genetic findings, as well as the results from the recent molecular analyses of the factors involved in the initiation and manifestation of pigment cell transformation and melanoma development in Xiphophorus. Microsc. Res. Tech. 58:456,463, 2002. © 2002 Wiley-Liss, Inc. [source] Activation of the RcsC/YojN/RcsB phosphorelay system attenuates Salmonella virulenceMOLECULAR MICROBIOLOGY, Issue 2 2004Chakib Mouslim Summary Bacterial pathogens have the ability to sense their presence in host tissues and to promote expression of their virulence factors in a time- and location-dependent manner. However, little is known about those genes whose expression is detrimental and thus suppressed during infection. Here we report that constitutive activation of the RcsC/YojN/RcsB system resulting from a mutation in the rcsC sensor gene dramatically attenuates Salmonella virulence. Mutation of the cognate response regulator gene rcsB restored full virulence to the rcsC constitutive mutant, indicating that virulence attenuation results from aberrant expression of RcsB-regulated genes. The virulence attenuation phenotype was partially dependent on the regulatory gene rcsA, which is necessary for transcription of certain RcsB-regulated genes, and on the RcsB- and RcsA-dependent colanic acid capsule synthesis cps operon. The rcsC constitutive mutant was phagocytized less efficiently by macrophages and it was defective for invasion of non-phagocytic cells and survival within macrophages; but it could protect mice upon challenge with wild-type Salmonella. Our results suggest that a successful infection demands that pathogens turn off expression of products that might interfere with virulence functions. [source] Mucosa-associated lymphoid tissue lymphoma: Molecular pathogenesis and clinicopathological significancePATHOLOGY INTERNATIONAL, Issue 8 2007Hiroshi Inagaki Mucosa-associated lymphoid tissue (MALT) lymphoma is a low-grade tumor closely associated with chronic inflammation such as that of Helicobacter pylori gastritis, Sjogren's syndrome, and Hashimoto's thyroiditis. Tumor regression by H. pylori eradication alone is well known in gastric MALT lymphoma, but some tumors occur in the absence of pre-existing chronic inflammation. The understanding of MALT lymphoma biology has significantly improved, and recurrent cytogenetic alterations have been detected. These include the trisomies 3 and 18, and the translocations t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). At least some of these alterations result in the constitutive activation of the nuclear factor (NF)-,B pathway, and may exert anti-apoptotic action. Apoptosis inhibitor 2,MALT lymphoma-associated translocation 1 (API12 - MALT1) fusion, resulting from t(11;18)(q21;q21), is specific to, and is the most common in, MALT lymphomas, and its clinicopathological significance has been studied extensively. The focus of the present review is on the recent progress made in elucidating MALT lymphomagenesis and its clinicopathological impact, especially in terms of the effect of API2-MALT1 fusion on this unique tumor. [source] | ||||||||||||||||||||||||||||||||||