scholarly journals MAPK Signal Transduction Pathway Regulation: A Novel Mechanism of Rat HSC-T6 Cell Apoptosis Induced by FUZHENGHUAYU Tablet

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Qi Wang ◽  
Hongbo Du ◽  
Min Li ◽  
Yue Li ◽  
Shunai Liu ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Target Genes ◽  
Stellate Cell ◽  
Signal Transduction Pathway ◽  
Differentially Expressed ◽  
Mrna Levels ◽  
Protein Levels ◽  
Control Serum ◽  
Pathway Regulation ◽  
Induced Apoptosis

FUZHENGHUAYU Tablets have been widely used in the treatment of liver fibrosis in China. Here, we investigate the apoptotic effect of FUZHENGHUAYU Tablet in rat liver stellate cell line HSC-T6. HSC-T6 cells were incubated with control serum or drug serum from rats fed with 0.9% NaCl or FUZHENGHUAYU Tablet, respectively. Cells exposed to drug serum showed higher proportions of early and late apoptotic cells than controls. The mRNA levels of collagens I and III, TGF-β1 andα-SMA were reduced by drug serum compared to control serum. Differentially expressed mRNAs and miRNAs were analyzed by microarray and sequencing, respectively. We identified 334 differentially expressed mRNAs and also 60 GOs and two pathways related to the mRNAs. Seventy-five differentially expressed miRNAs were down-regulated by drug serum and 1963 target genes were predicted. 134 GOs up-regulated in drug serum group were linked to miRNA targets, and drug serum also regulated 43 miRNA signal transduction pathways. Protein levels were evaluated by Western blot. Drug serum down-regulated (phospho-SAPK/JNK)/(SAPK/JNK) and up-regulated phospho-p38/p38 ratios. The study showed that FUZHENGHUAYU Tablet induced apoptosis in rat HSC-T6 cells possibly in part by activating p38 and inhibiting SAPK/JNK.

scholarly journals Transcriptomic and epigenomic remodeling occurs during vascular cambium periodicity in Populus tomentosa

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Bo Chen ◽  
Huimin Xu ◽  
Yayu Guo ◽  
Paul Grünhofer ◽  
Lukas Schreiber ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Plant Hormone ◽  
Target Genes ◽  
Populus Tomentosa ◽  
Differentially Expressed ◽  
Vascular Cambium ◽  
Differentially Methylated Region ◽  
Gene Body Methylation ◽  
Transcription Analysis ◽  
Global Methylation

AbstractTrees in temperate regions exhibit evident seasonal patterns, which play vital roles in their growth and development. The activity of cambial stem cells is the basis for regulating the quantity and quality of wood, which has received considerable attention. However, the underlying mechanisms of these processes have not been fully elucidated. Here we performed a comprehensive analysis of morphological observations, transcriptome profiles, the DNA methylome, and miRNAs of the cambium in Populus tomentosa during the transition from dormancy to activation. Anatomical analysis showed that the active cambial zone exhibited a significant increase in the width and number of cell layers compared with those of the dormant and reactivating cambium. Furthermore, we found that differentially expressed genes associated with vascular development were mainly involved in plant hormone signal transduction, cell division and expansion, and cell wall biosynthesis. In addition, we identified 235 known miRNAs and 125 novel miRNAs. Differentially expressed miRNAs and target genes showed stronger negative correlations than other miRNA/target pairs. Moreover, global methylation and transcription analysis revealed that CG gene body methylation was positively correlated with gene expression, whereas CHG exhibited the opposite trend in the downstream region. Most importantly, we observed that the number of CHH differentially methylated region (DMR) changes was the greatest during cambium periodicity. Intriguingly, the genes with hypomethylated CHH DMRs in the promoter were involved in plant hormone signal transduction, phenylpropanoid biosynthesis, and plant–pathogen interactions during vascular cambium development. These findings improve our systems-level understanding of the epigenomic diversity that exists in the annual growth cycle of trees.

scholarly journals Birdsong Decreases Protein Levels of FoxP2, a Molecule Required for Human Speech

2008 ◽  
Vol 100 (4) ◽  
pp. 2015-2025 ◽  
Author(s):  
Julie E. Miller ◽  
Elizabeth Spiteri ◽  
Michael C. Condro ◽  
Ryan T. Dosumu-Johnson ◽  
Daniel H. Geschwind ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Target Genes ◽  
Expression Patterns ◽  
Vocal Learning ◽  
Brain Regions ◽  
Motor Deficits ◽  
Mrna Levels ◽  
Adult Males ◽  
Protein Levels ◽  
Area X

Cognitive and motor deficits associated with language and speech are seen in humans harboring FOXP2 mutations. The neural bases for FOXP2 mutation-related deficits are thought to reside in structural abnormalities distributed across systems important for language and motor learning including the cerebral cortex, basal ganglia, and cerebellum. In these brain regions, our prior research showed that FoxP2 mRNA expression patterns are strikingly similar between developing humans and songbirds. Within the songbird brain, this pattern persists throughout life and includes the striatal subregion, Area X, that is dedicated to song development and maintenance. The persistent mRNA expression suggests a role for FoxP2 that extends beyond the formation of vocal learning circuits to their ongoing use. Because FoxP2 is a transcription factor, a role in shaping circuits likely depends on FoxP2 protein levels which might not always parallel mRNA levels. Indeed our current study shows that FoxP2 protein, like its mRNA, is acutely downregulated in mature Area X when adult males sing with some differences. Total corticosterone levels associated with the different behavioral contexts did not vary, indicating that differences in FoxP2 levels are not likely attributable to stress. Our data, together with recent reports on FoxP2's target genes, suggest that lowered FoxP2 levels may allow for expression of genes important for circuit modification and thus vocal variability.

scholarly journals The Role of the FOXO1/β2-AR/p-NF-κB p65 Pathway in the Development of Endometrial Stromal Cells in Pregnant Mice under Restraint Stress

2021 ◽  
Vol 22 (3) ◽  
pp. 1478
Author(s):  
Jiayin Lu ◽  
Yaoxing Chen ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong
Keyword(s):  
Oxidative Stress ◽  
Stromal Cells ◽  
Restraint Stress ◽  
Target Genes ◽  
Mrna Levels ◽  
Endometrial Stromal Cells ◽  
Protein Levels ◽  
Pregnant Mice

Restraint stress causes various maternal diseases during pregnancy. β2-Adrenergic receptor (β2-AR) and Forkhead transcription factor class O 1 (FOXO1) are critical factors not only in stress, but also in reproduction. However, the role of FOXO1 in restraint stress, causing changes in the β2-AR pathway in pregnant mice, has been unclear. The aim of this research was to investigate the β2-AR pathway of restraint stress and its impact on the oxidative stress of the maternal uterus. In the study, maternal mice were treated with restraint stress by being restrained in a transparent and ventilated device before sacrifice on Pregnancy Day 5 (P5), Pregnancy Day 10 (P10), Pregnancy Day 15 (P15), and Pregnancy Day 20 (P20) as well as on Non-Pregnancy Day 5 (NP5). Restraint stress augmented blood corticosterone (CORT), norepinephrine (NE), and blood glucose levels, while oestradiol (E2) levels decreased. Moreover, restraint stress increased the mRNA levels of the FOXO family, β2-AR, and even the protein levels of FOXO1 and β2-AR in the uterus and ovaries. Furthermore, restraint stress increased uterine oxidative stress level. In vitro, the protein levels of FOXO1 were also obviously increased when β2-AR was activated in endometrial stromal cells (ESCs). In addition, phosphorylated-nuclear factor kappa-B p65 (p-NF-κB p65) and its target genes decreased significantly when FOXO1 was inhibited. Overall, it can be said that the β2-AR/FOXO1/p-NF-κB p65 pathway was activated when pregnant mice were under restraint stress. This study provides a scientific basis for the origin of psychological stress in pregnant women.

scholarly journals Genome-Wide Identification of Long Non-coding RNA in Trifoliate Orange (Poncirus trifoliata (L.) Raf) Leaves in Response to Boron Deficiency

2019 ◽  
Vol 20 (21) ◽  
pp. 5419 ◽  
Author(s):  
Gao-Feng Zhou ◽  
Li-Ping Zhang ◽  
Bi-Xian Li ◽  
Ou Sheng ◽  
Qing-Jiang Wei ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Plant Hormones ◽  
Target Genes ◽  
Expression Patterns ◽  
Poncirus Trifoliata ◽  
Differentially Expressed ◽  
Boron Deficiency ◽  
Trifoliate Orange ◽  
Genome Wide ◽  
A Genome

Long non-coding RNAs (lncRNAs) play important roles in plant growth and stress responses. As a dominant abiotic stress factor in soil, boron (B) deficiency stress has impacted the growth and development of citrus in the red soil region of southern China. In the present work, we performed a genome-wide identification and characterization of lncRNAs in response to B deficiency stress in the leaves of trifoliate orange (Poncirus trifoliata), an important rootstock of citrus. A total of 2101 unique lncRNAs and 24,534 mRNAs were predicted. Quantitative real-time polymerase chain reaction (qRT-PCR) experiments were performed for a total of 16 random mRNAs and lncRNAs to validate their existence and expression patterns. Expression profiling of the leaves of trifoliate orange under B deficiency stress identified 729 up-regulated and 721 down-regulated lncRNAs, and 8419 up-regulated and 8395 down-regulated mRNAs. Further analysis showed that a total of 84 differentially expressed lncRNAs (DELs) were up-regulated and 31 were down-regulated, where the number of up-regulated DELs was 2.71-fold that of down-regulated. A similar trend was also observed in differentially expressed mRNAs (DEMs, 4.21-fold). Functional annotation of these DEMs was performed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and the results demonstrated an enrichment of the categories of the biosynthesis of secondary metabolites (including phenylpropanoid biosynthesis/lignin biosynthesis), plant hormone signal transduction and the calcium signaling pathway. LncRNA target gene enrichment identified several target genes that were involved in plant hormones, and the expression of lncRNAs and their target genes was significantly influenced. Therefore, our results suggest that lncRNAs can regulate the metabolism and signal transduction of plant hormones, which play an important role in the responses of citrus plants to B deficiency stress. Co-expression network analysis indicated that 468 significantly differentially expressed genes may be potential targets of 90 lncRNAs, and a total of 838 matched lncRNA-mRNA pairs were identified. In summary, our data provides a rich resource of candidate lncRNAs and mRNAs, as well as their related pathways, thereby improving our understanding of the role of lncRNAs in response to B deficiency stress, and in symptom formation caused by B deficiency in the leaves of trifoliate orange.

Identification of genes differentially expressed in a strain of the moldAspergillus nidulanscarrying a loss-of-function mutation in thepalAgene

2008 ◽  
Vol 54 (10) ◽  
pp. 803-811 ◽  
Author(s):  
Emiliana M. Silva ◽  
Janaína S. Freitas ◽  
Diana E. Gras ◽  
Fábio M. Squina ◽  
Juliana Leal ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Stress Responses ◽  
Genome Stability ◽  
Sugar Content ◽  
Signal Transduction Pathway ◽  
Subtractive Hybridization ◽  
Differentially Expressed ◽  
Neutral Sugar ◽  
Loss Of Function ◽  
Secretion Signal

To identify genes differentially expressed in a strain of the mold Aspergillus nidulans carrying a loss-of-function mutation in palA, a gene in the pH-responsive signal transduction pathway, suppression subtractive hybridization was performed between RNA isolated from the biA1 and biA1 palA1 strains grown under limiting inorganic phosphate at pH 5.0. We have identified several genes upregulated in the biA1 palA1 mutant strain that play important roles in mitotic fidelity, stress responses, enzyme secretion, signal transduction mechanisms, development, genome stability, phosphate sensing, and transcriptional regulation among others. The upregulation of eight of these transcripts was also validated by Northern blot. Moreover, we show that a loss of function mutation in the palA gene drastically reduced the neutral sugar content of the acid phosphatase PacA secreted by the fungus A. nidulans grown at pH 5.0 compared with a control strain.

ARNT Mediates Chemotherapy Resistance by Modulating the Response to Oxidative Stress in AML Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2737-2737
Author(s):  
Richard A. Wells ◽  
Chunhong Gu ◽  
Joelle dela Paz
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cell Lines ◽  
Akt Signaling ◽  
Mrna Levels ◽  
Antioxidant Genes ◽  
Protein Levels ◽  
Exogenous Expression ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis

Abstract Abstract 2737 Poster Board II-713 Background Although patients with acute myelogenous leukaemia (AML) typically respond well to initial therapy, with over 75% of patients achieving complete remission, in the great majority the disease ultimately relapses. This is thought to be due to the inherent resistance of leukaemia stem cells to the effects of chemotherapy. While some mechanisms of chemoresistance, e.g. TP53 mutation and upregulation of P-glycoprotein expression, have been well characterized, this phenomenon remains incompletely understood and is a significant barrier to improving patient outcomes. Methods and results The thiazolidindione drug troglitazone (TG) induces apoptosis in AML cells via generation of intracellular reactive oxygen species (ROS), but the degree of sensitivity to TG is highly heterogeneous among AML cell lines. We studied expression of the transcription factor ARNT (aryl hydrocarbon nuclear translocator) in TG-sensitive and TG-resistant AML cell lines following TG treatment. In HL-60 cells, which are highly sensitive to induction of apoptosis by TG, ARNT mRNA levels remained constant following TG treatment and ARNT protein levels markedly decreased, while in U937 cells, which are TG resistant, ARNT mRNA levels increased and ARNT protein levels remained constant. We then tested the effect of exogenous expression of ARNT on the sensitivity of HL-60 cells to TG-induced apoptosis. HL-60 cells transduced with a retrovirus expressing ARNT became TG-resistant. Exogenous expression of ARNT also conferred resistance to induction of apoptosis by hydrogen peroxide, daunorubicin and etoposide. The cellular response to oxidative stress is governed by intracellular signaling pathways and through a transcriptional response through which expression of antioxidant genes is coordinated. HL-60 cells expressing ARNT had striking constitutive activation of AKT signaling, and treatment of these cells with a specific inhibitor of AKT signaling reversed their resistance to TG-induced apoptosis. The activation of AKT signaling by ARNT appears to be mediated by downregulation of expression of PP2A and alpha4, two key negative regulators of AKT phosphorylation. In addition, ARNT-transduced HL-60 cells showed increased expression of Nrf2, a key transcriptional regulator of the antioxidant response, and its target genes SOD2 and CAT. Conclusions The response to oxidative stress is heterogeneous in AML cells lines, and varies with expression of ARNT. ARNT activates expression of Nrf2, which stimulates expression of antioxidant genes resulting in an augmented adaptive response to ROS. Unexpectedly, ARNT also activates AKT signaling by repressing expression of the regulatory phosphatases PP2A and alpha4. These activities of ARNT result in increased resistance to the induction of apoptosis by TG, hydrogen peroxide, and chemotherapy. ARNT may play an important role in chemoresistance in and may be useful as a predictive or prognostic biomarker. Disclosures: No relevant conflicts of interest to declare.

Aspirin Induces Apoptosis in Human Leukemia Cells Independently of NF-κB and MAPKs through Alteration of the Mcl-1/Noxa Balance.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4825-4825
Author(s):  
Ana M Cosialls ◽  
Daniel Iglesias-Serret ◽  
Maria Piqué ◽  
Montserrat Barragán ◽  
Antonio F Santidrián ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Leukemia Cell ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Mrna Levels ◽  
Protein Levels ◽  
Human Leukemia Cells ◽  
Induced Apoptosis

Abstract Abstract 4825 Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in most cell types. We examined the mechanism of aspirin-induced apoptosis in human leukemia cells. Our results show that aspirin induced apoptosis in leukemia Jurkat T cells independently of NF-κB. Although aspirin induced p38 MAPK and c-Jun N-terminal kinase (JNK) activation, selective inhibitors of these kinases did not inhibit aspirin-induced apoptosis. We studied the regulation of Bcl-2 family members in aspirin-induced apoptosis. The mRNA levels of some pro-apoptotic members, such as BIM, NOXA, BMF or PUMA, were induced by aspirin. However, none of these pro-apoptotic proteins increased and the levels of Mcl-1 protein were reduced. Interestingly, in the presence of aspirin the protein levels of Noxa remained high. This alteration of the Mcl-1/Noxa balance was also found in other leukemia cell lines and primary chronic lymphocytic leukemia cells (CLL). Furthermore, in CLL cells aspirin induced an increase in the protein levels of Noxa. Knockdown of Noxa or Puma significantly attenuated aspirin-induced apoptosis. These results indicate that aspirin induces apoptosis through alteration of the Mcl-1/Noxa balance. Disclosures No relevant conflicts of interest to declare.

STAT3 Silencing as a Novel Therapeutic Strategy for Activated B Cell-Type Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 926-926
Author(s):  
Anna Scuto ◽  
Maciej Kujawski ◽  
Claudia Kowolik ◽  
Hua Yu ◽  
Stephen Forman ◽  
...  
Keyword(s):  
B Cell ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mrna Levels ◽  
Down Regulation ◽  
Protein Levels ◽  
Stat3 Signaling ◽  
Marrow Stroma ◽  
And Control

Abstract Abstract 926 Among the non-Hodgkin's lymphomas, the diffuse large B cell lymphoma (DLBCL) represents the most frequent (30%) of the aggressive lymphomas. Persistent STAT3 signaling contributes to malignant progression in many diverse human tumors. IL-6 and IL-10 are major activators of STAT3 signaling and are important in the pathophysiology of DLBCL. STAT3 has been found to be persistently active in activated B cells (ABC), which are non-germinal center-derived DLBCL cells. We studied the consequences of STAT3 inhibition on multiple biological functions in two representative human cell lines of this group, Ly3 and Ly10 cells. For this purpose, we established stably transduced STAT3 shRNA-expressing lentivirus Ly3 cells, control lentivirus Ly3 cells, STAT3 shRNA-expressing lentivirus Ly10 cells and control lentivirus Ly10 cells. The stable expression of STAT3 shRNA results in 40-50% reduction of total STAT3 protein levels in the STAT3 shRNA lentivirus Ly3 cells compared to the control lentivirus cells. STAT3 down-regulation induced inhibition of cell proliferation (approximately 40%). Ly3 cells respond to IL-10 more than to IL-6 in terms of proliferation; both cytokines induced less proliferation in the STAT3 shRNA lentivirus Ly3 cells compared to the control lentivirus Ly3 cells. Similar results were obtained in Ly10 cells, which respond more to IL-6 than to IL-10 in terms of proliferation. We analyzed by quantitative real-time PCR the mRNA levels of different STAT3 target genes and observed significant reduction in mRNA levels of Mcl-1, Bcl-xL and Survivin in STAT3 shRNA lentivirus Ly3 cells, as well as significant reduction of Cyclin D2 and up-regulation of STAT1 in shRNA lentivirus Ly10 cells. Comparison of these gene expression profiles with data obtained from other B-cell lymphoma cell lines revealed that silencing of STAT3 resulted in down-regulation of different STAT3 target genes in a cell-dependent manner. We also observed that both STAT3 and control lentivirus Ly3 cells have the same protein levels of c-Myc; nevertheless STAT3 silencing resulted in inhibition of IL-10-inducible upregulation of c-Myc. We next investigated the effect of STAT3 inhibition on adhesion to bone marrow stroma and chemotaxis. STAT3 shRNA lentivirus Ly3 cells adhered less to the stroma layer than control cells, and the longer they were cocultured with the stroma cells in the presence of serum-free media the more they lost the ability to adhere. Moreover, STAT3 shRNA lentivirus Ly3 cells had decreased capacity to migrate toward SDF-1 alpha, an important factor that mediates proliferation, survival, chemotaxis, migration and adhesion into bone marrow stroma. Radiation, in combination with chemotherapy, is one of the therapies used for DLBCL patients. We therefore investigated whether STAT3 down-regulation sensitized Ly3 cells to radiation. Radiation induced a higher accumulation of phospho-H2A.X (first sentinel event following DNA damage such as DSBs) and apoptosis in STAT3 shRNA lentivirus cells compared to control cells. Moreover, IL-6 and IL-10 protected the STAT3 shRNA lentivirus Ly3 cells less than the control cells from the induction of phospho-H2A.X following radiation. We further investigated the effect of STAT3 silencing in animal models of Ly3 lymphoma (Nude or NOD-SCID mice). Tumors in control lentivirus Ly3-bearing mice grew robustly, whereas tumors in STAT3 shRNA lentivirus Ly3-bearing mice regressed 5 days after injection. This tumor regression was associated with Caspase-3-dependent apoptosis, significant reduction of STAT3 target genes at the protein level such as Mcl-1, c-Myc and Survivin (approximately 40% to 60% inhibition), and reduction of cytokine production such as IL-10, IL-15, Leptin and Thrombopoietin. Taken together, these results suggest that inhibition of STAT3 is a potential promising approach in the therapy of ABC-type DLBCL. Disclosures: No relevant conflicts of interest to declare.

Abnormally High Levels of E- and N-Cadherin Expression Add to Altered Regulation of b-Catenin In Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2982-2982
Author(s):  
Ya-Wei Qiang ◽  
Peter Stewart ◽  
Yu Chen ◽  
Bo Hu ◽  
John Shaughnessy ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Target Genes ◽  
Plasma Cells ◽  
Expression System ◽  
Mrna Levels ◽  
Hematopoietic Stem ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
Elevated Expression ◽  
E Cadherin

Abstract Abstract 2982 Gene expression profiling (GEP) of normal and malignant plasma cells and B-cells, revealed that MM is uniquely characterized by elevated expression of E- or N-cadherin. Classical cadherins are integral plasma membrane proteins, that together with a- and b-catenin form calcium-dependent adherent junctions. Homotypic interaction of N-cadherin+ hematopoietic stem cells and N-cadherin+ bone lining cells in the endosteal niche regulates HSC function. Adherent junctions contribute to the regulation of Wnt/b-catenin signaling by modulating the balance between membrane-bound and free cytosolic b-catenin, the latter of which is required for TCF transcriptional activity. Overexpression of DKK1 and suppression of Wnt/b-catenin osteoblasts causes a loss in self-renewal of HSC and only stromal cells with active nuclear b-catenin can support hematopoiesis in-vitro. On the other hand, disruption of adherent junctions and release of b-catenin contributes to epithelial-to-mesenchymal transition and solid tumor metastases. We, and others, have demonstrated that Wnt/β-catenin signaling is active in MM. However, emerging evidence suggests that loss of Wnt/b-catenin activity, rather than its activation, is central to MM pathogenesis. Nearly 90% of primary MM cells express and secrete DKK1 and/or SFRP3 or SFRP2, potent inhibitors of Wnt/b-catenin signaling. Moreover, loss-of-function mutations of APC or axin genes or gain-of-function mutations in the β-catenin gene common in colon cancer have not been found in MM. We therefore hypothesized that elevated expression of N/E-cadherin in MM cells contributes to the abnormally increase of b-catenin in MM. We first assessed the steady-state levels of β-catenin protein in MMCL with immunoblotting analysis. β-Catenin protein was expressed in all tested MMCL, with variable levels in individual lines. Interestingly, relative levels of β-catenin protein were comparable to N-cadherin expression in all eight tested myeloma cell lines. CD138-enriched plasma cells from the BM of 72 patients newly diagnosed MM revealed β-catenin protein levels are highly variable. After normalization of β-catenin with β-tubulin levels we segregated cases into three groups: 39% had low, 23% moderate, and 38% high levels of β-catenin. Analysis of correlation of b-catenin protein levels with U133Plus microarray data revealed there are striking positive correlations between N- or E-cadherin mRNA levels with levels of b-catenin protein. Importantly, b-catenin levels were not correlated with known Wnt/b-catenin target genes. To evaluate the role of N-cadherin in regulating β-catenin signaling in MM, we used a lentiviral expression system to express wild-type N-cadherin (NCadW/MMS1) or empty vector (EV/MMS1) in MMS1 cells. Significant increases in total and free b-catenin correlated with N-cadherin protein expression. These results indicate that N-cadherin protein modulates b-catenin levels MM cells. Results of experiments to determine whether N-cadherin-mediated regulation of b-catenin translates into altered TCF/b-catenin transcriptional activity in MM cells will be reported. Disclosures: Shaughnessy: Myeloma Health LLC: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Patents & Royalties; Millennium: Honoraria; Celgene: Honoraria; OrthoBiotech: Honoraria; Array BioPharma: Honoraria.

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