Journal of Molecular Signaling最新文献

{"title":"Chronic Inflammation in Skin Malignancies.","authors":"Lihua Tang,&nbsp;Kepeng Wang","doi":"10.5334/1750-2187-11-2","DOIUrl":"https://doi.org/10.5334/1750-2187-11-2","url":null,"abstract":"<p><p>Chronic inflammation is linked to the development and progression of multiple cancers, including those of the lung, stomach, liver, colon, breast and skin. Inflammation not only drives the oncogenic transformation of epithelial cells under the stress of chronic infection and autoimmune diseases, but also promotes the growth, progression and metastatic spread of cancers. Tumor-infiltrating inflammatory cells are comprised of a diverse population of myeloid and immune cell types, including monocytes, macrophages, dendritic cells, T and B cells, and others. Different myeloid and lymphoid cells within tumor microenvironment exert diverse, often contradicting, effects during skin cancer development and progression. The nature of tumor-immune interaction determines the rate of cancer progression and the outcome of cancer treatment. Inflammatory environment within skin tumor also inhibits naturally occurring anti-tumor immunity and limits the efficacy of cancer immunotherapy. In this article we aim to give an overview on the mechanism by which inflammation interferes with the development and therapeutic intervention of cancers, especially those of the skin.</p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":"11 ","pages":"2"},"PeriodicalIF":0.0,"publicationDate":"2016-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.5334/1750-2187-11-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37206470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frizzled-4 C-terminus Distal to KTXXXW Motif is Essential for Normal Dishevelled Recruitment and Norrin-stimulated Activation of Lef/Tcf-dependent Transcriptional Activation.","authors":"Alexander C Bertalovitz,&nbsp;Milly S Pau,&nbsp;Shujuan Gao,&nbsp;Craig C Malbon,&nbsp;Hsien-Yu Wang","doi":"10.5334/1750-2187-11-1","DOIUrl":"https://doi.org/10.5334/1750-2187-11-1","url":null,"abstract":"<p><p>The carboxy (C)-termini of G protein coupled receptors (GPCR) dictate essential functions. The KTXXXW motif C-terminus of Frizzleds (FZD) has been implicated in recruitment of Dishevelled (DVL). Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. </p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":"11 ","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2016-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34329896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activator of G-protein Signaling 3 Controls Renal Epithelial Cell Survival and ERK5 Activation.","authors":"Shauna A Rasmussen,&nbsp;Michelle Kwon,&nbsp;Jeffrey D Pressly,&nbsp;Joe B Blumer,&nbsp;Kevin R Regner,&nbsp;Frank Park","doi":"10.5334/1750-2187-10-5","DOIUrl":"https://doi.org/10.5334/1750-2187-10-5","url":null,"abstract":"<p><p>Activator of G-protein signaling 3 (AGS3) is an accessory protein that functions to regulate the activation status of heterotrimeric G-protein subunits. To date, however, the downstream signaling pathways regulated by AGS3 remain to be fully elucidated, particularly in renal epithelial cells. In the present study, normal rat kidney (NRK-52E) proximal tubular epithelial cells were genetically modified to regulate the expression of AGS3 to investigate its role on MAPK and mTOR signaling to control epithelial cell number. Knockdown of endogenous AGS3 protein was associated with a reduced phosphorylated form of ERK5 and increased apoptosis as determined by elevated cleaved caspase-3. In the presence of the ERK5 inhibitor, BIX02189, a significant 2-fold change (P < 0.05) in G2/M transition state was detected compared to control conditions. Neither of the other MAPK, ERK1/2 or p38 MAPK, nor another pro-survival pathway, mTOR, was significantly altered by the changes in AGS3 protein levels in the renal epithelial cells. The selective ERK5 inhibitor, BIX02189, was found to dose-dependently reduce NRK cell number by up to 41% (P < 0.05) compared to control cells. In summary, these findings demonstrated that cell viability was regulated by AGS3 and was associated with ERK5 activation in renal epithelial cells. </p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":" ","pages":"6"},"PeriodicalIF":0.0,"publicationDate":"2015-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34329895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Intracellular Loop 2 F328S Frizzled-4 Mutation Implicated in Familial Exudative Vitreoretinopathy Impairs Dishevelled Recruitment.","authors":"Milly S Pau,&nbsp;Shujuan Gao,&nbsp;Craig C Malbon,&nbsp;Hsien-Yu Wang,&nbsp;Alexander C Bertalovitz","doi":"10.5334/1750-2187-10-6","DOIUrl":"https://doi.org/10.5334/1750-2187-10-6","url":null,"abstract":"<p><p>Familial exudative vitreoretinopathy (FEVR) is a disease state characterized by aberrant retinal angiogenesis. Norrin-induced activation of Frizzled-4 (Fz4) has a major role in regulating beta-catenin levels in the eye that, in turn, modulate the blood retina barrier (BRB). Here we gain insight on the basis of the pathology of a FEVR implicated F328S Fz4 mutant by study. The receptor exhibits a substantially reduced ability to activate Lef/Tcf-dependent transcription. This impaired activation correlates with a decreased ability to stabilize and recruit Dishevelled-2 (Dvl2) to the cell surface. Aromaticity at position 328 of the intracellular loop 2 (iloop2) is revealed similarly as a prerequisite for Dvl2 recruitment to the Fz4. This aromaticity at 328 enables normal Norrin-induced canonical activation. The corresponding position in iloop2 of other Frizzleds likely functions in Dvl recruitment. </p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":" ","pages":"5"},"PeriodicalIF":0.0,"publicationDate":"2015-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.5334/1750-2187-10-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34329894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction with the Paxillin LD1 Motif Relieves MEKK2 Auto-inhibition.","authors":"Michael P Kahle,&nbsp;Bruce D Cuevas","doi":"10.5334/1750-2187-10-4","DOIUrl":"https://doi.org/10.5334/1750-2187-10-4","url":null,"abstract":"<p><p>The cell signaling molecule MEK kinase 2 (MEKK2) is a key upstream regulator of MAPK activity that regulates numerous cellular functions, but the mechanisms that control MEKK2 activity are not well understood. Recently, we reported that MEKK2 both binds and promotes ubiquitylation of the scaffold protein paxillin, and thereby modulates the composition of adhesion complexes. In this study, we have extended our examination of this interaction and report that recombinant paxillin is sufficient to induce MEKK2 auto-phosphorylation. Furthermore, we utilize siRNA-mediated paxillin expression knockdown to reveal that MEKK2 activity is reduced in paxillin-deficient cells. Finally, we show that the paxillin leucine-rich motif 1 (LD1) is sufficient to bind to the MEKK2 amino terminal region and activate MEKK2. Taken together, our results show for the first time that paxillin association promotes MEKK2 activation and reveal the existence of a novel bi-directional regulatory relationship between MEKK2 and paxillin. </p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":" ","pages":"4"},"PeriodicalIF":0.0,"publicationDate":"2015-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34329893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gα13 Stimulates the Tyrosine Phosphorylation of Ric-8A.","authors":"Mingda Yan,&nbsp;Ji Hee Ha,&nbsp;Danny N Dhanasekaran","doi":"10.5334/1750-2187-10-3","DOIUrl":"https://doi.org/10.5334/1750-2187-10-3","url":null,"abstract":"<p><p>The G12 family of heterotrimeric G proteins is defined by their α-subunits, Gα12 and Gα13. These α-subunits regulate cellular homeostasis, cell migration, and oncogenesis in a context-specific manner primarily through their interactions with distinct proteins partners that include diverse effector molecules and scaffold proteins. With a focus on identifying any other novel regulatory protein(s) that can directly interact with Gα13, we subjected Gα13 to tandem affinity purification-coupled mass spectrometric analysis. Our results from such analysis indicate that Gα13 potently interacts with mammalian Ric-8A. Our mass spectrometric analysis data also indicates that Ric-8A, which was tandem affinity purified along with Gα13, is phosphorylated at Ser-436, Thr-441, Thr-443 and Tyr-435. Using a serial deletion approach, we have defined that the C-terminus of Gα13 containing the guanine-ring interaction site is essential and sufficient for its interaction with Ric-8A. Evaluation of Gα13-specific signaling pathways in SKOV3 or HeyA8 ovarian cancer cell lines indicate that Ric-8A potentiates Gα13-mediated activation of RhoA, Cdc42, and the downstream p38MAPK. We also establish that the tyrosine phosphorylation of Ric-8A, thus far unidentified, is potently stimulated by Gα13. Our results also indicate that the stimulation of tyrosine-phosphorylation of Ric-8A by Gα13 is partially sensitive to inhibitors of Src-family of kinases, namely PP2 and SI. Furthermore, we demonstrate that Gα13 promotes the translocation of Ric-8A to plasma membrane and this translocation is attenuated by the Src-inhibitors, SI1 and PP2. Thus, our results demonstrate for the first time that Gα13 stimulates the tyrosine phosphorylation of Ric-8A and Gα13-mediated tyrosine-phosphorylation plays a critical role in the translocation of Ric-8A to plasma membrane. </p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":"10 ","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2015-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9887379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of G-Protein βγ Signaling Decreases Levels of Messenger RNAs Encoding Proinflammatory Cytokines in T Cell Receptor-Stimulated CD4(+) T Helper Cells.","authors":"Thomas R Hynes,&nbsp;Evan A Yost,&nbsp;Cassandra M Hartle,&nbsp;Braden J Ott,&nbsp;Catherine H Berlot","doi":"10.5334/1750-2187-10-1","DOIUrl":"https://doi.org/10.5334/1750-2187-10-1","url":null,"abstract":"<p><strong>Background: </strong>Inhibition of G-protein βγ (Gβγ) signaling was found previously to enhance T cell receptor (TCR)-stimulated increases in interleukin 2 (IL-2) mRNA in CD4(+) T helper cells, suggesting that Gβγ might be a useful drug target for treating autoimmune diseases, as low dose IL-2 therapy can suppress autoimmune responses. Because IL-2 may counteract autoimmunity in part by shifting CD4(+) T helper cells away from the Type 1 T helper cell (TH1) and TH17 subtypes towards the TH2 subtype, the purpose of this study was to determine if blocking Gβγ signaling affected the balance of TH1, TH17, and TH2 cytokine mRNAs produced by CD4(+) T helper cells.</p><p><strong>Methods: </strong>Gallein, a small molecule inhibitor of Gβγ, and siRNA-mediated silencing of the G-protein β1 subunit (Gβ1) were used to test the effect of blocking Gβγ on mRNA levels of cytokines in primary human TCR-stimulated CD4(+) T helper cells.</p><p><strong>Results: </strong>Gallein and Gβ1 siRNA decreased interferon-γ (IFN-γ) and IL-17A mRNA levels in TCR-stimulated CD4(+) T cells grown under TH1-promoting conditions. Inhibiting Gβγ also decreased mRNA levels of STAT4, which plays a positive role in TH1 differentiation and IL-17A production. Moreover, mRNA levels of the STAT4-regulated TH1-associated proteins, IL-18 receptor β chain (IL-18Rβ), mitogen-activated protein kinase kinase kinase 8 (MAP3K8), lymphocyte activation gene 3 (LAG-3), natural killer cell group 7 sequence (NKG7), and oncostatin M (OSM) were also decreased upon Gβγ inhibition. Gallein also increased IL-4, IL-5, IL-9, and IL-13 mRNA levels in TCR-stimulated memory CD4(+) T cells grown in TH2-promoting conditions.</p><p><strong>Conclusions: </strong>Inhibiting Gβγ to produce these shifts in cytokine mRNA production might be beneficial for patients with autoimmune diseases such as rheumatoid arthritis (RA), Crohn's disease (CD), psoriasis, multiple sclerosis (MS), and Hashimoto's thyroiditis (HT), in which both IFN-γ and IL-17A are elevated.</p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":" ","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2015-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.5334/1750-2187-10-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34318732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Gαs/cAMP Signaling Decreases TCR-Stimulated IL-2 transcription in CD4(+) T Helper Cells.","authors":"Thomas R Hynes,&nbsp;Evan A Yost,&nbsp;Stacy M Yost,&nbsp;Cassandra M Hartle,&nbsp;Braden J Ott,&nbsp;Catherine H Berlot","doi":"10.5334/1750-2187-10-2","DOIUrl":"https://doi.org/10.5334/1750-2187-10-2","url":null,"abstract":"<p><strong>Background: </strong>The role of cAMP in regulating T cell activation and function has been controversial. cAMP is generally known as an immunosuppressant, but it is also required for generating optimal immune responses. As the effect of cAMP is likely to depend on its cellular context, the current study investigated whether the mechanism of activation of Gαs and adenylyl cyclase influences their effect on T cell receptor (TCR)-stimulated interleukin-2 (IL-2) mRNA levels.</p><p><strong>Methods: </strong>The effect of blocking Gs-coupled receptor (GsPCR)-mediated Gs activation on TCR-stimulated IL-2 mRNA levels in CD4(+) T cells was compared with that of knocking down Gαs expression or inhibiting adenylyl cyclase activity. The effect of knocking down Gαs expression on TCR-stimulated cAMP accumulation was compared with that of blocking GsPCR signaling.</p><p><strong>Results: </strong>ZM-241385, an antagonist to the Gs-coupled A2A adenosine receptor (A2AR), enhanced TCR-stimulated IL-2 mRNA levels in primary human CD4(+) T helper cells and in Jurkat T cells. A dominant negative Gαs construct, GαsDN3, also enhanced TCR-stimulated IL-2 mRNA levels. Similar to GsPCR antagonists, GαsDN3 blocked GsPCR-dependent activation of both Gαs and Gβγ. In contrast, Gαs siRNA and 2',5'-dideoxyadenosine (ddA), an adenylyl cyclase inhibitor, decreased TCR-stimulated IL-2 mRNA levels. Gαs siRNA, but not GαsDN3, decreased TCR-stimulated cAMP synthesis. Potentiation of IL-2 mRNA levels by ZM-241385 required at least two days of TCR stimulation, and addition of ddA after three days of TCR stimulation enhanced IL-2 mRNA levels.</p><p><strong>Conclusions: </strong>GsPCRs play an inhibitory role in the regulation of TCR-stimulated IL-2 mRNA levels whereas Gαs and cAMP can play a stimulatory one. Additionally, TCR-dependent activation of Gαs does not appear to involve GsPCRs. These results suggest that the context of Gαs/cAMP activation and the stage of T cell activation and differentiation determine the effect on TCR-stimulated IL-2 mRNA levels.</p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":" ","pages":"2"},"PeriodicalIF":0.0,"publicationDate":"2015-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34329891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Forkhead box O1 and muscle RING finger 1 protein expression in atrophic and hypertrophic denervated mouse skeletal muscle.","authors":"Ann-Kristin Fjällström,&nbsp;Kim Evertsson,&nbsp;Marlene Norrby,&nbsp;Sven Tågerud","doi":"10.1186/1750-2187-9-9","DOIUrl":"https://doi.org/10.1186/1750-2187-9-9","url":null,"abstract":"<p><strong>Background: </strong>Forkhead box O (FoxO) transcription factors and E3 ubiquitin ligases such as Muscle RING finger 1 (MuRF1) are believed to participate in the regulation of skeletal muscle mass. The function of FoxO transcription factors is regulated by post-translational modifications such as phosphorylation and acetylation. In the present study FoxO1 protein expression, phosphorylation and acetylation as well as MuRF1 protein expression, were examined in atrophic and hypertrophic denervated skeletal muscle.</p><p><strong>Methods: </strong>Protein expression, phosphorylation and acetylation were studied semi-quantitatively using Western blots. Muscles studied were 6-days denervated mouse hind-limb muscles (anterior tibial as well as pooled gastrocnemius and soleus muscles, all atrophic), 6-days denervated mouse hemidiaphragm muscles (hypertrophic) and innervated control muscles. Total muscle homogenates were used as well as separated nuclear and cytosolic fractions of innervated and 6-days denervated anterior tibial and hemidiaphragm muscles.</p><p><strong>Results: </strong>Expression of FoxO1 and MuRF1 proteins increased 0.3-3.7-fold in all 6-days denervated muscles studied, atrophic as well as hypertrophic. Phosphorylation of FoxO1 at S256 increased about 0.8-1-fold after denervation in pooled gastrocnemius and soleus muscles and in hemidiaphragm but not in unfractionated anterior tibial muscle. A small (0.2-fold) but statistically significant increase in FoxO1 phosphorylation was, however, observed in cytosolic fractions of denervated anterior tibial muscle. A statistically significant increase in FoxO1 acetylation (0.8-fold) was observed only in denervated anterior tibial muscle. Increases in total FoxO1 and in phosphorylated FoxO1 were only seen in cytosolic fractions of denervated atrophic anterior tibial muscle whereas in denervated hypertrophic hemidiaphragm both total FoxO1 and phosphorylated FoxO1 increased in cytosolic as well as in nuclear fractions. MuRF1 protein expression increased in cytosolic as well as in nuclear fractions of both denervated atrophic anterior tibial muscle and denervated hypertrophic hemidiaphragm muscle.</p><p><strong>Conclusions: </strong>Increased expression of FoxO1 and MuRF1 in denervated muscles (atrophic as well as hypertrophic) suggests that these proteins participate in the tissue remodelling occurring after denervation. The effect of denervation on the level of phosphorylated and acetylated FoxO1 differed in the muscles studied and may be related to differences in fiber type composition of the muscles.</p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":"9 ","pages":"9"},"PeriodicalIF":0.0,"publicationDate":"2014-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1750-2187-9-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32714515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seminal plasma induces the expression of IL-1α in normal and neoplastic cervical cells via EP2/EGFR/PI3K/AKT pathway.","authors":"Anthonio O Adefuye,&nbsp;Kurt J Sales,&nbsp;Arieh A Katz","doi":"10.1186/1750-2187-9-8","DOIUrl":"https://doi.org/10.1186/1750-2187-9-8","url":null,"abstract":"<p><strong>Background: </strong>Cervical cancer is a chronic inflammatory disease of multifactorial etiology usually presenting in sexually active women. Exposure of neoplastic cervical epithelial cells to seminal plasma (SP) has been shown to promote the growth of cancer cells in vitro and tumors in vivo by inducing the expression of inflammatory mediators including pro-inflammatory cytokines. IL-1α is a pleotropic pro-inflammatory cytokine induced in several human cancers and has been associated with virulent tumor phenotype and poorer prognosis. Here we investigated the expression of IL-1α in cervical cancer, the role of SP in the regulation of IL-1α in neoplastic cervical epithelial cells and the molecular mechanism underlying this regulation.</p><p><strong>Methods and results: </strong>Real-time quantitative RT-PCR confirmed the elevated expression of IL-1α mRNA in cervical squamous cell carcinoma and adenocarcinoma tissue explants, compared with normal cervix. Using immunohistochemistry, IL-1α was localized to the neoplastically transformed squamous, columnar and glandular epithelium in all cases of squamous cell carcinoma and adenocarcinomas explants studied. We found that SP induced the expression of IL-α in both normal and neoplastic cervical tissue explants. Employing HeLa (adenocarcinoma) cell line as a model system we identified PGE2 and EGF as possible ligands responsible for SP-mediated induction of IL-1α in these neoplastic cells. In addition, we showed that SP activates EP2/EGFR/PI3kinase-Akt signaling to induce IL-1α mRNA and protein expression. Furthermore, we demonstrate that in normal cervical tissue explants the induction of IL-1α by SP is via the activation of EP2/EGFR/PI3 kinase-Akt signaling.</p><p><strong>Conclusion: </strong>SP-mediated induction of IL-1α in normal and neoplastic cervical epithelial cells suggests that SP may promote cervical inflammation as well as progression of cervical cancer in sexually active women.</p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":"9 ","pages":"8"},"PeriodicalIF":0.0,"publicationDate":"2014-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1750-2187-9-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32681304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}