The Experts below are selected from a list of 486 Experts worldwide ranked by ideXlab platform
Xiangdong Zhou - One of the best experts on this subject based on the ideXlab platform.
-
interleukin 13 induces mucin 5ac production involving stat6 SPDEF in human airway epithelial cells
Cell Communication and Adhesion, 2010Co-Authors: Hongmei Yu, Vladimirovich Petr Kolosov, Juliy M Perelman, Xiangdong ZhouAbstract:AbstractMucus hypersecretion is commonly observed in many chronic airway inflammatory diseases. Mucin 5AC (MUC5AC) is a major airway mucin because of its high expression in goblet cells. Here, the authors identified a gene called SAM domain–containing prostate-derived Ets factor (SPDEF) that was induced by interleukin (IL)-13. Their results showed that specific knockdown of SPDEF reduced IL-13-induced MUC5AC expression in human airway epithelial cells. This finding was associated with decreased expression of anterior gradient 2 (AGR2) and Ca2+-activated Cl− channel (CLCA1), which regulate IL-13-mediated MUC5AC overproduction. Furthermore, transfection with SPDEF siRNA enhanced expression of forkhead box a2 (Foxa2), a key transcription factor that is known to prevent mucus production. The authors also demonstrated that the repression of STAT6 inhibited expression of SPDEF and MUC5AC induced by IL-13. These results show that SPDEF plays a critical role in regulating a transcriptional network mediating IL-13...
-
interleukin 13 induces mucin 5ac production involving stat6 SPDEF in human airway epithelial cells
Cell Communication and Adhesion, 2010Co-Authors: Vladimirovich Petr Kolosov, Juliy M Perelman, Xiangdong ZhouAbstract:Mucus hypersecretion is commonly observed in many chronic airway inflammatory diseases. Mucin 5AC (MUC5AC) is a major airway mucin because of its high expression in goblet cells. Here, the authors identified a gene called SAM domain-containing prostate-derived Ets factor (SPDEF) that was induced by interleukin (IL)-13. Their results showed that specific knockdown of SPDEF reduced IL-13-induced MUC5AC expression in human airway epithelial cells. This finding was associated with decreased expression of anterior gradient 2 (AGR2) and Ca(2+)-activated Cl(-) channel (CLCA1), which regulate IL-13-mediated MUC5AC overproduction. Furthermore, transfection with SPDEF siRNA enhanced expression of forkhead box a2 (Foxa2), a key transcription factor that is known to prevent mucus production. The authors also demonstrated that the repression of STAT6 inhibited expression of SPDEF and MUC5AC induced by IL-13. These results show that SPDEF plays a critical role in regulating a transcriptional network mediating IL-13-induced MUC5AC synthesis dependent on STAT6.
Jeffrey A Whitsett - One of the best experts on this subject based on the ideXlab platform.
-
SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1
2016Co-Authors: Mario Medvedovic, Jeffrey A Whitsett, Vladimir V. Kalinichenko, Tanya V. KalinAbstract:SAM-pointed domain-containing ETS transcription factor (SPDEF) is expressed in normal prostate epithelium. While its expression changes during prostate carcinogenesis (PCa), the role of SPDEF in prostate cancer remains controversial due to the lack of genetic mouse models. In present study, we generated transgenic mice with the loss- or gain-of-function of SPDEF in prostate epithelium to demonstrate that SPDEF functions as tumor suppressor in prostate cancer. Loss of SPDEF increased cancer progression and tumor cell proliferation, whereas over-expression of SPDEF in prostate epithelium inhibited carcinogenesis and reduced tumor cell proliferation in vivo and in vitro. Transgenic over-expression of SPDEF inhibited mRNA and protein levels of Foxm1, a transcription factor critical for tumor cell proliferation, and reduced expression of Foxm1 target genes, including Cdc25b, Cyclin B1, Cyclin A2, Plk-1, AuroraB, CKS1 and Topo2alpha. Deletion of SPDEF in transgenic mice and cultures prostate tumor cells increased expression of Foxm1 and its target genes. Furthermore, an inverse correlation between SPDEF and Foxm1 levels was found in human prostate cancers. The two-gene signature of low SPDEF and high FoxM1 predicted poor survival in prostate cancer patients. Mechanistically, SPDEF bound to, and inhibited transcriptional activity of Foxm1 promoter by interfering with the ability of Foxm1 to activate its own promoter through auto-regulatory site located in the 2745/2660 bp Foxm1 promoter region. Re-expression of Foxm1 restored cellular proliferation in the SPDEF-positive cancer cells and rescued progression of SPDEF-positive tumors in mous
-
airway epithelial SPDEF integrates goblet cell differentiation and pulmonary th2 inflammation
Journal of Clinical Investigation, 2015Co-Authors: Priya Rajavelu, Gang Chen, Thomas R Korfhagen, Joseph A Kitzmiller, Jeffrey A WhitsettAbstract:Epithelial cells that line the conducting airways provide the initial barrier and innate immune responses to the abundant particles, microbes, and allergens that are inhaled throughout life. The transcription factors SPDEF and FOXA3 are both selectively expressed in epithelial cells lining the conducting airways, where they regulate goblet cell differentiation and mucus production. Moreover, these transcription factors are upregulated in chronic lung disorders, including asthma. Here, we show that expression of SPDEF or FOXA3 in airway epithelial cells in neonatal mice caused goblet cell differentiation, spontaneous eosinophilic inflammation, and airway hyperresponsiveness to methacholine. SPDEF expression promoted DC recruitment and activation in association with induction of Il33, Csf2, thymic stromal lymphopoietin (Tslp), and Ccl20 transcripts. Increased Il4, Il13, Ccl17, and Il25 expression was accompanied by recruitment of Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. SPDEF was required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM) extract, as both were decreased in neonatal and adult SPDEF(-/-) mice compared with control animals. Together, our results indicate that SPDEF causes goblet cell differentiation and Th2 inflammation during postnatal development and is required for goblet cell metaplasia and normal Th2 inflammatory responses to HDM aeroallergen.
-
tgfβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium
Development, 2014Co-Authors: Heather A Mccauley, Jeffrey A Whitsett, Chiayang Liu, Aria C Attia, Kathryn A Wikenheiserbrokamp, Yujin Zhang, Geraldine GuaschAbstract:The ocular surface epithelia, including the stratified but non-keratinized corneal, limbal and conjunctival epithelium, in concert with the epidermal keratinized eyelid epithelium, function together to maintain eye health and vision. Abnormalities in cellular proliferation or differentiation in any of these surface epithelia are central in the pathogenesis of many ocular surface disorders. Goblet cells are important secretory cell components of various epithelia, including the conjunctiva; however, mechanisms that regulate goblet cell differentiation in the conjunctiva are not well understood. Herein, we report that conditional deletion of transforming growth factor β receptor II (Tgfbr2) in keratin 14-positive stratified epithelia causes ocular surface epithelial hyperplasia and conjunctival goblet cell expansion that invaginates into the subconjunctival stroma in the mouse eye. We found that, in the absence of an external phenotype, the ocular surface epithelium develops properly, but young mice displayed conjunctival goblet cell expansion, demonstrating that TGFβ signaling is required for normal restriction of goblet cells within the conjunctiva. We observed increased expression of SAM-pointed domain containing ETS transcription factor (SPDEF) in stratified conjunctival epithelial cells in Tgfbr2 cKO mice, suggesting that TGFβ restricted goblet cell differentiation directly by repressing SPDEF transcription. Gain of function of SPDEF in keratin 14-positive epithelia resulted in the ectopic formation of goblet cells in the eyelid and peripheral cornea in adult mice. We found that Smad3 bound two distinct sites on the SPDEF promoter and that treatment of keratin 14-positive cells with TGFβ inhibited SPDEF activation, thereby identifying a novel mechanistic role for TGFβ in regulating goblet cell differentiation.
-
SPDEF inhibits prostate carcinogenesis by disrupting a positive feedback loop in regulation of the foxm1 oncogene
PLOS Genetics, 2014Co-Authors: Xin-hua Cheng, Anusha Sridharan, Jeffrey A Whitsett, Markaisa Black, Vladimir Ustiyan, Logan Fulford, Mario Medvedovic, Vladimir V. Kalinichenko, Tanya V. KalinAbstract:SAM-pointed domain-containing ETS transcription factor (SPDEF) is expressed in normal prostate epithelium. While its expression changes during prostate carcinogenesis (PCa), the role of SPDEF in prostate cancer remains controversial due to the lack of genetic mouse models. In present study, we generated transgenic mice with the loss- or gain-of-function of SPDEF in prostate epithelium to demonstrate that SPDEF functions as tumor suppressor in prostate cancer. Loss of SPDEF increased cancer progression and tumor cell proliferation, whereas over-expression of SPDEF in prostate epithelium inhibited carcinogenesis and reduced tumor cell proliferation in vivo and in vitro. Transgenic over-expression of SPDEF inhibited mRNA and protein levels of Foxm1, a transcription factor critical for tumor cell proliferation, and reduced expression of Foxm1 target genes, including Cdc25b, Cyclin B1, Cyclin A2, Plk-1, AuroraB, CKS1 and Topo2alpha. Deletion of SPDEF in transgenic mice and cultures prostate tumor cells increased expression of Foxm1 and its target genes. Furthermore, an inverse correlation between SPDEF and Foxm1 levels was found in human prostate cancers. The two-gene signature of low SPDEF and high FoxM1 predicted poor survival in prostate cancer patients. Mechanistically, SPDEF bound to, and inhibited transcriptional activity of Foxm1 promoter by interfering with the ability of Foxm1 to activate its own promoter through auto-regulatory site located in the -745/-660 bp Foxm1 promoter region. Re-expression of Foxm1 restored cellular proliferation in the SPDEF-positive cancer cells and rescued progression of SPDEF-positive tumors in mouse prostates. Altogether, SPDEF inhibits prostate carcinogenesis by preventing Foxm1-regulated proliferation of prostate tumor cells. The present study identified novel crosstalk between SPDEF tumor suppressor and Foxm1 oncogene and demonstrated that this crosstalk is required for tumor cell proliferation during progression of prostate cancer in vivo.
-
SPDEF expression is inversely correlated with Foxm1 expression in human prostate cancer and of prognostic value for the prostate carcinoma patient survival.
2014Co-Authors: Xin-hua Cheng, Anusha Sridharan, Jeffrey A Whitsett, Markaisa Black, Vladimir Ustiyan, Logan Fulford, Mario Medvedovic, Vladimir V. Kalinichenko, Tanya V. KalinAbstract:The data from two human prostate cancer microarray datasets, GSE21034 [30] and GSE16560 [31] were downloaded from the GEO archive. Expression levels were compared between Indolent and Lethal prostate cancers (A), and High-risk and Low-risk sample groups (B). High-risk samples were derived from patients with surviving less than 12 months and low-risk samples from patients surviving more than 192 months. C. Two-gene expression signature predicts poor patient survival. Kaplan-Meier survival analysis of prostate cancer patients using dataset GSE16560 [31]. Patients were stratified by the expression level of FOXM1 or SPEDF, or both together. The group with “high” FOXM1 and “low” SPDEF expression had the worst outcome (median survival time of 55.5 months).
Hans Clevers - One of the best experts on this subject based on the ideXlab platform.
-
goblet cells contribute to ocular surface immune tolerance implications for dry eye disease
International Journal of Molecular Sciences, 2017Co-Authors: Flavia L Barbosa, Yangyan Xiao, Fang Bian, Terry G Coursey, Byung Yi Ko, Hans Clevers, Cintia S De Paiva, Stephen C PflugfelderAbstract:Conjunctival goblet cell (GC) loss in dry eye is associated with ocular surface inflammation. This study investigated if conjunctival GCs contribute to ocular surface immune tolerance. Antigens applied to the ocular surface, imaged by confocal microscopy, passed into the conjunctival stroma through goblet cell associated passages (GAPs) in wild type C57BL/6 (WT), while ovalbumin (OVA) was retained in the epithelium of SAM pointed domain containing ETS transcription factor (SPDEF) knockout mice (SPDEF−/−) that lack GCs and are a novel model of dry eye. Stimulated GC degranulation increased antigen binding to GC mucins. Induction of tolerance to topically applied OVA measured by cutaneous delayed type hypersensitivity (DTH) was observed in WT, but not SPDEF−/−. OTII CD4+ T cells primed by dendritic cells (DCs) from the conjunctival draining lymph nodes of SPDEF−/− had greater IFN-γ production and lower Foxp3 positivity than those primed by WT DCs. These findings indicate that conjunctival GCs contribute to ocular surface immune tolerance by modulating antigen distribution and antigen specific immune response. GC loss may contribute to the abrogation of ocular surface immune tolerance that is observed in dry eye.
-
SPDEF null mice lack conjunctival goblet cells and provide a model of dry eye
American Journal of Pathology, 2013Co-Authors: Christina K Marko, Gang Chen, Hans Clevers, Jeffrey A Whitsett, Balaraj B Menon, Ilene K GipsonAbstract:Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (SPDEF) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using SPDEF−/− mice, we determined that SPDEF is required for conjunctival goblet cell differentiation and that SPDEF−/− mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in SPDEF−/− mice revealed down-regulation of goblet cell–specific genes (Muc5ac, Tff1, Gcnt3). Up-regulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and proinflammatory genes (Il1-α, Il-1β, Tnf-α), all of which are up-regulated in dry eye. Interestingly, four Wnt pathway genes were down-regulated. SPDEF expression was significantly decreased in the conjunctival epithelium of Sjogren syndrome patients with dry eye and decreased goblet cell mucin expression. These data demonstrate that SPDEF is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. SPDEF−/− mice have an ocular surface phenotype similar to that in moderate dry eye, providing a new, more convenient model for the disease.
-
the ets domain transcription factor SPDEF promotes maturation of goblet and paneth cells in the intestinal epithelium
Gastroenterology, 2009Co-Authors: Alex Gregorieff, Daniel E Stange, Pekka Kujala, Harry Begthel, Maaike Van Den Born, Jeroen Korving, Peter J Peters, Hans CleversAbstract:Background & Aims Stem cells within the intestinal epithelium generate daughter cells that undergo lineage commitment and maturation through the combined action of the Wnt and Notch signaling cascades. Both pathways, in turn, regulate transcription factor networks that further define differentiation toward either enterocytes or 1 of 3 secretory cell lineages (Paneth, goblet, or enteroendocrine cells). In this study, we investigated the role of the Wnt-responsive, Ets-domain transcription factor SPDEF in the differentiation of goblet and Paneth cells. Methods The in vivo function of SPDEF was examined by disrupting the SPDEF gene in mice ( SPDEF −/− mice) and analyzing the intestinal phenotype using a range of histologic techniques and DNA microarray profiling. Results In accordance with expression data, we found that loss of SPDEF severely impaired the maturation of goblet and Paneth cells and, conversely, led to an accumulation of immature secretory progenitors. SPDEF appears to positively and negatively regulate a specific subset of goblet and Paneth cell genes, including Cryptdins , Mmp7 , Ang4 , Kallikreins , and Muc2 . Conclusions SPDEF acts downstream of Math1 to promote terminal differentiation of a secretory progenitor pool into Paneth and goblet cells.
-
SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production
Journal of Clinical Investigation, 2009Co-Authors: Gang Chen, Hans Clevers, Thomas R Korfhagen, Joseph A Kitzmiller, Alex Gregorieff, Yan Xu, Susan E Wert, Yutaka Maeda, Jeffrey A WhitsettAbstract:Various acute and chronic inflammatory stimuli increase the number and activity of pulmonary mucus-producing goblet cells, and goblet cell hyperplasia and excess mucus production are central to the pathogenesis of chronic pulmonary diseases. However, little is known about the transcriptional programs that regulate goblet cell differentiation. Here, we show that SAM-pointed domain-containing Ets-like factor (SPDEF) controls a transcriptional program critical for pulmonary goblet cell differentiation in mice. Initial cell-lineage-tracing analysis identified nonciliated secretory epithelial cells, known as Clara cells, as the progenitors of goblet cells induced by pulmonary allergen exposure in vivo. Furthermore, in vivo expression of SPDEF in Clara cells caused rapid and reversible goblet cell differentiation in the absence of cell proliferation. This was associated with enhanced expression of genes regulating goblet cell differentiation and protein glycosylation, including forkhead box A3 (Foxa3), anterior gradient 2 (Agr2), and glucosaminyl (N-acetyl) transferase 3, mucin type (Gcnt3). Consistent with these findings, levels of SPDEF and FOXA3 were increased in mouse goblet cells after sensitization with pulmonary allergen, and the proteins were colocalized in goblet cells lining the airways of patients with chronic lung diseases. Deletion of the mouse SPDEF gene resulted in the absence of goblet cells in tracheal/laryngeal submucosal glands and in the conducting airway epithelium after pulmonary allergen exposure in vivo. These data show that SPDEF plays a critical role in regulating a transcriptional network mediating the goblet cell differentiation and mucus hyperproduction associated with chronic pulmonary disorders.
Gang Chen - One of the best experts on this subject based on the ideXlab platform.
-
Role of SPDEF in the Regulation of Muc5b Expression in the Airways of Naive and Mucoobstructed Mice
American journal of respiratory cell and molecular biology, 2018Co-Authors: Gang Chen, Barbara R Grubb, Allison S Volmer, Kristen J. Wilkinson, Yangmei Deng, Lisa C. Jones, Ximena M. Bustamante-marin, Kimberlie A. Burns, Wanda K. O'nealAbstract:Understanding how expression of airway secretory mucins MUC5B and MUC5AC is regulated in health and disease is important to elucidating the pathogenesis of mucoobstructive respiratory diseases. The transcription factor SPDEF (sterile α-motif pointed domain epithelial specific transcription factor) is a key regulator of MUC5AC, but its role in regulating MUC5B in health and in mucoobstructive lung diseases is unknown. Characterization of SPDEF-deficient mice upper and lower airways demonstrated region-specific, SPDEF-dependent regulation of basal Muc5b expression. Neonatal SPDEF-deficient mice exhibited reductions in BAL Muc5ac and Muc5b. Adult SPDEF-deficient mice partially phenocopied Muc5b-deficient mice as they exhibited reduced Muc5b in nasopharyngeal and airway epithelia but not in olfactory Bowman glands, 75% incidence of nasopharyngeal hair/mucus plugs, and mild bacterial otitis media, without defective mucociliary clearance in the nasopharynx. In contrast, tracheal mucociliary clearance was reduced in SPDEF-deficient mice in the absence of lung disease. To evaluate the role of SPDEF in the development and persistence of Muc5b-predominant mucoobstructive lung disease, SPDEF-deficient mice were crossed with Scnn1b-transgenic (Scnn1b-Tg) mice, which exhibit airway surface dehydration-induced airway mucus obstruction and inflammation. SPDEF-deficient Scnn1b-Tg mice exhibited reduced Muc5ac, but not Muc5b, expression and BAL content. Airway mucus obstruction was not decreased in SPDEF-deficient Scnn1b-Tg mice, consistent with Muc5b-dominant Scnn1b disease, but increased airway neutrophilia was observed compared with SPDEF-sufficient Scnn1b-Tg mice. Collectively, these results indicate that SPDEF regulates baseline Muc5b expression in respiratory epithelia but does not contribute to Muc5b regulation in a mouse model of Muc5b-predominant mucus obstruction caused by airway dehydration.
-
airway epithelial SPDEF integrates goblet cell differentiation and pulmonary th2 inflammation
Journal of Clinical Investigation, 2015Co-Authors: Priya Rajavelu, Gang Chen, Thomas R Korfhagen, Joseph A Kitzmiller, Jeffrey A WhitsettAbstract:Epithelial cells that line the conducting airways provide the initial barrier and innate immune responses to the abundant particles, microbes, and allergens that are inhaled throughout life. The transcription factors SPDEF and FOXA3 are both selectively expressed in epithelial cells lining the conducting airways, where they regulate goblet cell differentiation and mucus production. Moreover, these transcription factors are upregulated in chronic lung disorders, including asthma. Here, we show that expression of SPDEF or FOXA3 in airway epithelial cells in neonatal mice caused goblet cell differentiation, spontaneous eosinophilic inflammation, and airway hyperresponsiveness to methacholine. SPDEF expression promoted DC recruitment and activation in association with induction of Il33, Csf2, thymic stromal lymphopoietin (Tslp), and Ccl20 transcripts. Increased Il4, Il13, Ccl17, and Il25 expression was accompanied by recruitment of Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. SPDEF was required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM) extract, as both were decreased in neonatal and adult SPDEF(-/-) mice compared with control animals. Together, our results indicate that SPDEF causes goblet cell differentiation and Th2 inflammation during postnatal development and is required for goblet cell metaplasia and normal Th2 inflammatory responses to HDM aeroallergen.
-
SPDEF null mice lack conjunctival goblet cells and provide a model of dry eye
American Journal of Pathology, 2013Co-Authors: Christina K Marko, Gang Chen, Hans Clevers, Jeffrey A Whitsett, Balaraj B Menon, Ilene K GipsonAbstract:Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (SPDEF) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using SPDEF−/− mice, we determined that SPDEF is required for conjunctival goblet cell differentiation and that SPDEF−/− mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in SPDEF−/− mice revealed down-regulation of goblet cell–specific genes (Muc5ac, Tff1, Gcnt3). Up-regulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and proinflammatory genes (Il1-α, Il-1β, Tnf-α), all of which are up-regulated in dry eye. Interestingly, four Wnt pathway genes were down-regulated. SPDEF expression was significantly decreased in the conjunctival epithelium of Sjogren syndrome patients with dry eye and decreased goblet cell mucin expression. These data demonstrate that SPDEF is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. SPDEF−/− mice have an ocular surface phenotype similar to that in moderate dry eye, providing a new, more convenient model for the disease.
-
SPDEF functions as a colorectal tumor suppressor by inhibiting β catenin activity
Gastroenterology, 2013Co-Authors: Taeko K Noah, Gang Chen, Noah F Shroyer, Allison Price, Eileen King, Mary Kay Washington, Bruce J AronowAbstract:Background & Aims Expression of the SAM pointed domain containing ETS transcription factor (SPDEF or prostate-derived ETS factor) is regulated by Atoh1 and is required for the differentiation of goblet and Paneth cells. SPDEF has been reported to suppress the development of breast, prostate, and colon tumors. We analyzed levels of SPDEF in colorectal tumor samples from patients and its tumor-suppressive functions in mouse models of colorectal cancer (CRC). Methods We analyzed levels of SPDEF messenger RNA and protein in more than 500 human CRC samples and more than 80 nontumor controls. SPDEF −/− and wild-type mice (controls) were either bred with Apc Min/+ mice, or given azoxymethane (AOM) and dextran sodium sulfate (DSS), or 1,2-dimethylhydrazine and DSS, to induce colorectal tumors. Expression of SPDEF also was induced transiently by administration of tetracycline to SPDEF dox-intestine mice with established tumors, induced by the combination of AOM and DSS or by breeding with Apc Min/+ mice. Colon tissues were collected and analyzed for tumor number, size, grade, and for cell proliferation and apoptosis. We also analyzed the effects of SPDEF expression in HCT116 and SW480 human CRC cells. Results In colorectal tumors from patients, loss of SPDEF was observed in approximately 85% of tumors and correlated with progression from normal tissue, to adenoma, to adenocarcinoma. SPDEF −/− ; Apc Min/+ mice developed approximately 3-fold more colon tumors than SPDEF +/+ ; Apc Min/+ mice. Likewise, SPDEF −/− mice developed approximately 3-fold more colon tumors than SPDEF +/+ mice after administration of AOM and DSS. After administration of 1,2-dimethylhydrazine and DSS, invasive carcinomas were observed exclusively in SPDEF −/− mice. Conversely, expression of SPDEF was sufficient to promote cell-cycle exit in cells of established adenomas from SPDEF dox-intestine ; Apc Min/+ mice and in SPDEF dox-intestine mice after administration of AOM + DSS. SPDEF inhibited the expression of β-catenin−target genes in mouse colon tumors, and interacted with β-catenin to block its transcriptional activity in CRC cell lines, resulting in lower levels of cyclin D1 and c-MYC. Conclusions SPDEF is a colon tumor suppressor and a candidate therapeutic target for colon adenomas and adenocarcinoma.
-
sam pointed domain ets factor mediates epithelial cell intrinsic innate immune signaling during airway mucous metaplasia
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Thomas R Korfhagen, Gang Chen, Joseph A Kitzmiller, Anusha Sridharan, Hans Michael Haitchi, Rashmi S Hegde, Senad Divanovic, Christopher L Karp, Jeffrey A WhitsettAbstract:Airway mucus plays a critical role in clearing inhaled toxins, particles, and pathogens. Diverse toxic, inflammatory, and infectious insults induce airway mucus secretion and goblet cell metaplasia to preserve airway sterility and homeostasis. However, goblet cell metaplasia, mucus hypersecretion, and airway obstruction are integral features of inflammatory lung diseases, including asthma, chronic obstructive lung disease, and cystic fibrosis, which cause an immense burden of morbidity and mortality. These chronic lung diseases are united by susceptibility to microbial colonization and recurrent airway infections. Whether these twinned phenomena (mucous metaplasia, compromised host defenses) are causally related has been unclear. Here, we demonstrate that SAM pointed domain ETS factor (SPDEF) was induced by rhinoviral infection of primary human airway cells and that cytoplasmic activities of SPDEF, a transcriptional regulator of airway goblet cell metaplasia, inhibited Toll-like receptor (TLR) activation of epithelial cells. SPDEF bound to and inhibited activities of TLR signaling adapters, MyD88 and TRIF, inhibiting MyD88-induced cytokine production and TRIF-induced interferon β production. Conditional expression of SPDEF in airway epithelial cells in vivo inhibited LPS-induced neutrophilic infiltration and bacterial clearance. SPDEF-mediated inhibition of both TLR and type I interferon signaling likely protects the lung against inflammatory damage when inciting stimuli are not eradicated. Present findings provide, at least in part, a molecular explanation for increased susceptibility to infection in lung diseases associated with mucous metaplasia and a mechanism by which patients with florid mucous metaplasia may tolerate microbial burdens that are usually associated with fulminant inflammatory disease in normal hosts.
Vladimirovich Petr Kolosov - One of the best experts on this subject based on the ideXlab platform.
-
interleukin 13 induces mucin 5ac production involving stat6 SPDEF in human airway epithelial cells
Cell Communication and Adhesion, 2010Co-Authors: Hongmei Yu, Vladimirovich Petr Kolosov, Juliy M Perelman, Xiangdong ZhouAbstract:AbstractMucus hypersecretion is commonly observed in many chronic airway inflammatory diseases. Mucin 5AC (MUC5AC) is a major airway mucin because of its high expression in goblet cells. Here, the authors identified a gene called SAM domain–containing prostate-derived Ets factor (SPDEF) that was induced by interleukin (IL)-13. Their results showed that specific knockdown of SPDEF reduced IL-13-induced MUC5AC expression in human airway epithelial cells. This finding was associated with decreased expression of anterior gradient 2 (AGR2) and Ca2+-activated Cl− channel (CLCA1), which regulate IL-13-mediated MUC5AC overproduction. Furthermore, transfection with SPDEF siRNA enhanced expression of forkhead box a2 (Foxa2), a key transcription factor that is known to prevent mucus production. The authors also demonstrated that the repression of STAT6 inhibited expression of SPDEF and MUC5AC induced by IL-13. These results show that SPDEF plays a critical role in regulating a transcriptional network mediating IL-13...
-
interleukin 13 induces mucin 5ac production involving stat6 SPDEF in human airway epithelial cells
Cell Communication and Adhesion, 2010Co-Authors: Vladimirovich Petr Kolosov, Juliy M Perelman, Xiangdong ZhouAbstract:Mucus hypersecretion is commonly observed in many chronic airway inflammatory diseases. Mucin 5AC (MUC5AC) is a major airway mucin because of its high expression in goblet cells. Here, the authors identified a gene called SAM domain-containing prostate-derived Ets factor (SPDEF) that was induced by interleukin (IL)-13. Their results showed that specific knockdown of SPDEF reduced IL-13-induced MUC5AC expression in human airway epithelial cells. This finding was associated with decreased expression of anterior gradient 2 (AGR2) and Ca(2+)-activated Cl(-) channel (CLCA1), which regulate IL-13-mediated MUC5AC overproduction. Furthermore, transfection with SPDEF siRNA enhanced expression of forkhead box a2 (Foxa2), a key transcription factor that is known to prevent mucus production. The authors also demonstrated that the repression of STAT6 inhibited expression of SPDEF and MUC5AC induced by IL-13. These results show that SPDEF plays a critical role in regulating a transcriptional network mediating IL-13-induced MUC5AC synthesis dependent on STAT6.