Knockdown of TrkA in cumulus oocyte complexes (COCs) inhibits EGF-induced cumulus expansion by down-regulation of IL-6
•TrkA participated in EGF-induced COC expansion.•Inhibition of TrkA has no effect on COC expansion-related transcripts induced by EGF.•Knockdown of TrkA did not inhibit EGF-induced phosphorylation of ERK1/2 and SMAD2.•The effect of TrkA on EGF-induced cumulus expansion is mediated through IL-6.•IL-6...
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| Veröffentlicht in: | Molecular and cellular endocrinology 2014-02, Vol.382 (2), p.804-813 |
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| creator | Wang, Yong Liang, Ning Yao, Guidong Tian, Hui Zhai, Yiwen Yin, Yimeng Sun, Fei |
| description | •TrkA participated in EGF-induced COC expansion.•Inhibition of TrkA has no effect on COC expansion-related transcripts induced by EGF.•Knockdown of TrkA did not inhibit EGF-induced phosphorylation of ERK1/2 and SMAD2.•The effect of TrkA on EGF-induced cumulus expansion is mediated through IL-6.•IL-6 may act as a new potential cumulus expansion-related transcript.
Tyrosine kinase receptor A (TrkA), the high-affinity receptor of nerve growth factor (NGF), is known to play key roles in ovarian follicular development, such as assembly of early follicles and follicular ovulation. However, little is known about the roles of TrkA in cumulus oocyte complex (COC) expansion. In this study, we found that TrkA was abundant in large antral follicles and knockdown of TrkA in COCs attenuated epidermal growth factor (EGF)-induced COC expansion and further decreased the ovulation rate. The effect of TrkA on COC expansion was not mediated through downstream EGF effectors, phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) or drosophila mothers against decapentaplegic protein (SMAD), or through up-regulation of COC expansion-related transcripts such as prostaglandin-endoperoxide synthase 2 (Ptgs2), hyaluronan synthase 2 (Has2), TNF-induced protein 6 (Tnfaip6) or pentraxin 3 (Ptx3). However, pharmacological blockade of TrkA transducing activity (K252α) in COCs decreased the mRNA expression and protein secretion of interleukin-6 (IL-6), identified from mRNA microarray of K252α-treated COCs. Meanwhile, knockdown of IL-6 attenuated EGF-induced COC expansion. In addition, IL-6 rescued the inhibitory effect of K252α on EGF-induced cumulus expansion. Therefore, IL-6 may act as a new potential cumulus expansion-related transcript, which may be involved in the integration of TrkA and EGF signaling in affecting COC expansion. Here, we provide mechanistic insights into the roles of TrkA in EGF-induced cumulus expansion. Understanding potential cross-points between TrkA and EGF affecting cumulus expansion will help in the discovery of new therapeutic targets in ovulation-related diseases. |
| doi_str_mv | 10.1016/j.mce.2013.10.031 |
| format | Article |
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Tyrosine kinase receptor A (TrkA), the high-affinity receptor of nerve growth factor (NGF), is known to play key roles in ovarian follicular development, such as assembly of early follicles and follicular ovulation. However, little is known about the roles of TrkA in cumulus oocyte complex (COC) expansion. In this study, we found that TrkA was abundant in large antral follicles and knockdown of TrkA in COCs attenuated epidermal growth factor (EGF)-induced COC expansion and further decreased the ovulation rate. The effect of TrkA on COC expansion was not mediated through downstream EGF effectors, phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) or drosophila mothers against decapentaplegic protein (SMAD), or through up-regulation of COC expansion-related transcripts such as prostaglandin-endoperoxide synthase 2 (Ptgs2), hyaluronan synthase 2 (Has2), TNF-induced protein 6 (Tnfaip6) or pentraxin 3 (Ptx3). However, pharmacological blockade of TrkA transducing activity (K252α) in COCs decreased the mRNA expression and protein secretion of interleukin-6 (IL-6), identified from mRNA microarray of K252α-treated COCs. Meanwhile, knockdown of IL-6 attenuated EGF-induced COC expansion. In addition, IL-6 rescued the inhibitory effect of K252α on EGF-induced cumulus expansion. Therefore, IL-6 may act as a new potential cumulus expansion-related transcript, which may be involved in the integration of TrkA and EGF signaling in affecting COC expansion. Here, we provide mechanistic insights into the roles of TrkA in EGF-induced cumulus expansion. Understanding potential cross-points between TrkA and EGF affecting cumulus expansion will help in the discovery of new therapeutic targets in ovulation-related diseases.</description><identifier>ISSN: 0303-7207</identifier><identifier>EISSN: 1872-8057</identifier><identifier>DOI: 10.1016/j.mce.2013.10.031</identifier><identifier>PMID: 24215827</identifier><language>eng</language><publisher>Ireland: Elsevier Ireland Ltd</publisher><subject>Animals ; Attenuation ; C-Reactive Protein - genetics ; C-Reactive Protein - metabolism ; Carbazoles - pharmacology ; Cell Adhesion Molecules - genetics ; Cell Adhesion Molecules - metabolism ; Cellular ; COC expansion ; Cumulus Cells - cytology ; Cumulus Cells - drug effects ; Cumulus Cells - metabolism ; Cumulus oocyte complexes (COCs) ; Cyclooxygenase 2 - genetics ; Cyclooxygenase 2 - metabolism ; Diseases ; Enzyme Inhibitors - pharmacology ; Epidermal Growth Factor - metabolism ; Epidermal Growth Factor - pharmacology ; Female ; Gene Expression Regulation, Developmental ; Glucuronosyltransferase - genetics ; Glucuronosyltransferase - metabolism ; Growth factors ; Hyaluronan Synthases ; Indole Alkaloids - pharmacology ; Interleukin-6 (IL-6) ; Interleukin-6 - antagonists & inhibitors ; Interleukin-6 - genetics ; Interleukin-6 - metabolism ; Kinases ; Mice ; Mitogen-Activated Protein Kinase 1 - genetics ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - genetics ; Mitogen-Activated Protein Kinase 3 - metabolism ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Neurotrophic tyrosine kinase receptor type 1 (TrkA) ; Oocytes - cytology ; Oocytes - drug effects ; Oocytes - metabolism ; Ovulation - drug effects ; Proteins ; Receptor, trkA - antagonists & inhibitors ; Receptor, trkA - genetics ; Receptor, trkA - metabolism ; Receptors ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Secretions ; Signal Transduction ; Smad Proteins - genetics ; Smad Proteins - metabolism</subject><ispartof>Molecular and cellular endocrinology, 2014-02, Vol.382 (2), p.804-813</ispartof><rights>2013 Elsevier Ireland Ltd</rights><rights>Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-479ddef0be7f787bc9e7fb3f1b40df2e3a4e89ad52146fe5878072932b7b68c63</citedby><cites>FETCH-LOGICAL-c386t-479ddef0be7f787bc9e7fb3f1b40df2e3a4e89ad52146fe5878072932b7b68c63</cites><orcidid>0000-0002-6149-1961</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0303720713004711$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24215827$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Yong</creatorcontrib><creatorcontrib>Liang, Ning</creatorcontrib><creatorcontrib>Yao, Guidong</creatorcontrib><creatorcontrib>Tian, Hui</creatorcontrib><creatorcontrib>Zhai, Yiwen</creatorcontrib><creatorcontrib>Yin, Yimeng</creatorcontrib><creatorcontrib>Sun, Fei</creatorcontrib><title>Knockdown of TrkA in cumulus oocyte complexes (COCs) inhibits EGF-induced cumulus expansion by down-regulation of IL-6</title><title>Molecular and cellular endocrinology</title><addtitle>Mol Cell Endocrinol</addtitle><description>•TrkA participated in EGF-induced COC expansion.•Inhibition of TrkA has no effect on COC expansion-related transcripts induced by EGF.•Knockdown of TrkA did not inhibit EGF-induced phosphorylation of ERK1/2 and SMAD2.•The effect of TrkA on EGF-induced cumulus expansion is mediated through IL-6.•IL-6 may act as a new potential cumulus expansion-related transcript.
Tyrosine kinase receptor A (TrkA), the high-affinity receptor of nerve growth factor (NGF), is known to play key roles in ovarian follicular development, such as assembly of early follicles and follicular ovulation. However, little is known about the roles of TrkA in cumulus oocyte complex (COC) expansion. In this study, we found that TrkA was abundant in large antral follicles and knockdown of TrkA in COCs attenuated epidermal growth factor (EGF)-induced COC expansion and further decreased the ovulation rate. The effect of TrkA on COC expansion was not mediated through downstream EGF effectors, phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) or drosophila mothers against decapentaplegic protein (SMAD), or through up-regulation of COC expansion-related transcripts such as prostaglandin-endoperoxide synthase 2 (Ptgs2), hyaluronan synthase 2 (Has2), TNF-induced protein 6 (Tnfaip6) or pentraxin 3 (Ptx3). However, pharmacological blockade of TrkA transducing activity (K252α) in COCs decreased the mRNA expression and protein secretion of interleukin-6 (IL-6), identified from mRNA microarray of K252α-treated COCs. Meanwhile, knockdown of IL-6 attenuated EGF-induced COC expansion. In addition, IL-6 rescued the inhibitory effect of K252α on EGF-induced cumulus expansion. Therefore, IL-6 may act as a new potential cumulus expansion-related transcript, which may be involved in the integration of TrkA and EGF signaling in affecting COC expansion. Here, we provide mechanistic insights into the roles of TrkA in EGF-induced cumulus expansion. Understanding potential cross-points between TrkA and EGF affecting cumulus expansion will help in the discovery of new therapeutic targets in ovulation-related diseases.</description><subject>Animals</subject><subject>Attenuation</subject><subject>C-Reactive Protein - genetics</subject><subject>C-Reactive Protein - metabolism</subject><subject>Carbazoles - pharmacology</subject><subject>Cell Adhesion Molecules - genetics</subject><subject>Cell Adhesion Molecules - metabolism</subject><subject>Cellular</subject><subject>COC expansion</subject><subject>Cumulus Cells - cytology</subject><subject>Cumulus Cells - drug effects</subject><subject>Cumulus Cells - metabolism</subject><subject>Cumulus oocyte complexes (COCs)</subject><subject>Cyclooxygenase 2 - genetics</subject><subject>Cyclooxygenase 2 - metabolism</subject><subject>Diseases</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epidermal Growth Factor - metabolism</subject><subject>Epidermal Growth Factor - pharmacology</subject><subject>Female</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Glucuronosyltransferase - genetics</subject><subject>Glucuronosyltransferase - metabolism</subject><subject>Growth factors</subject><subject>Hyaluronan Synthases</subject><subject>Indole Alkaloids - pharmacology</subject><subject>Interleukin-6 (IL-6)</subject><subject>Interleukin-6 - antagonists & inhibitors</subject><subject>Interleukin-6 - genetics</subject><subject>Interleukin-6 - metabolism</subject><subject>Kinases</subject><subject>Mice</subject><subject>Mitogen-Activated Protein Kinase 1 - genetics</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3 - genetics</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Neurotrophic tyrosine kinase receptor type 1 (TrkA)</subject><subject>Oocytes - cytology</subject><subject>Oocytes - drug effects</subject><subject>Oocytes - metabolism</subject><subject>Ovulation - drug effects</subject><subject>Proteins</subject><subject>Receptor, trkA - antagonists & inhibitors</subject><subject>Receptor, trkA - genetics</subject><subject>Receptor, trkA - metabolism</subject><subject>Receptors</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Secretions</subject><subject>Signal Transduction</subject><subject>Smad Proteins - genetics</subject><subject>Smad Proteins - metabolism</subject><issn>0303-7207</issn><issn>1872-8057</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUtv1DAURi0EotPCD2CDvCyLDH7Ej4hVNepLjNRNWVuxfQOeJvFgJ23n3-NoSpeIle2r832W7kHoEyVrSqj8ulsPDtaMUF7ea8LpG7SiWrFKE6HeohXhhFeKEXWCTnPeEUKUYPo9OmE1o0IztUKP38foHnx8GnHs8H16uMBhxG4e5n7OOEZ3mAC7OOx7eIaMzzd3m_ylIL-CDVPGl9dXVRj97MC_huB53445xBHbA16aqwQ_576dllH55HZbyQ_oXdf2GT6-nGfox9Xl_eam2t5d324utpXjWk5VrRrvoSMWVKe0sq4pF8s7amviOwa8rUE3rReM1rIDoZUmijWcWWWldpKfofNj7z7F3zPkyQwhO-j7doQ4Z0OlooJzqf8DrRuipBBKFJQeUZdizgk6s09haNPBUGIWM2ZnihmzmFlGxUzJfH6pn-0A_jXxV0UBvh0BKPt4DJBMdgHGstmQwE3Gx_CP-j_dMZ49</recordid><startdate>20140215</startdate><enddate>20140215</enddate><creator>Wang, Yong</creator><creator>Liang, Ning</creator><creator>Yao, Guidong</creator><creator>Tian, Hui</creator><creator>Zhai, Yiwen</creator><creator>Yin, Yimeng</creator><creator>Sun, Fei</creator><general>Elsevier Ireland Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7U5</scope><scope>8FD</scope><scope>L7M</scope><orcidid>https://orcid.org/0000-0002-6149-1961</orcidid></search><sort><creationdate>20140215</creationdate><title>Knockdown of TrkA in cumulus oocyte complexes (COCs) inhibits EGF-induced cumulus expansion by down-regulation of IL-6</title><author>Wang, Yong ; Liang, Ning ; Yao, Guidong ; Tian, Hui ; Zhai, Yiwen ; Yin, Yimeng ; Sun, Fei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-479ddef0be7f787bc9e7fb3f1b40df2e3a4e89ad52146fe5878072932b7b68c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Attenuation</topic><topic>C-Reactive Protein - genetics</topic><topic>C-Reactive Protein - metabolism</topic><topic>Carbazoles - pharmacology</topic><topic>Cell Adhesion Molecules - genetics</topic><topic>Cell Adhesion Molecules - metabolism</topic><topic>Cellular</topic><topic>COC expansion</topic><topic>Cumulus Cells - cytology</topic><topic>Cumulus Cells - drug effects</topic><topic>Cumulus Cells - metabolism</topic><topic>Cumulus oocyte complexes (COCs)</topic><topic>Cyclooxygenase 2 - genetics</topic><topic>Cyclooxygenase 2 - metabolism</topic><topic>Diseases</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Epidermal Growth Factor - metabolism</topic><topic>Epidermal Growth Factor - pharmacology</topic><topic>Female</topic><topic>Gene Expression Regulation, Developmental</topic><topic>Glucuronosyltransferase - genetics</topic><topic>Glucuronosyltransferase - metabolism</topic><topic>Growth factors</topic><topic>Hyaluronan Synthases</topic><topic>Indole Alkaloids - pharmacology</topic><topic>Interleukin-6 (IL-6)</topic><topic>Interleukin-6 - antagonists & inhibitors</topic><topic>Interleukin-6 - genetics</topic><topic>Interleukin-6 - metabolism</topic><topic>Kinases</topic><topic>Mice</topic><topic>Mitogen-Activated Protein Kinase 1 - genetics</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Mitogen-Activated Protein Kinase 3 - genetics</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Neurotrophic tyrosine kinase receptor type 1 (TrkA)</topic><topic>Oocytes - cytology</topic><topic>Oocytes - drug effects</topic><topic>Oocytes - metabolism</topic><topic>Ovulation - drug effects</topic><topic>Proteins</topic><topic>Receptor, trkA - antagonists & inhibitors</topic><topic>Receptor, trkA - genetics</topic><topic>Receptor, trkA - metabolism</topic><topic>Receptors</topic><topic>RNA, Small Interfering - genetics</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Secretions</topic><topic>Signal Transduction</topic><topic>Smad Proteins - genetics</topic><topic>Smad Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Yong</creatorcontrib><creatorcontrib>Liang, Ning</creatorcontrib><creatorcontrib>Yao, Guidong</creatorcontrib><creatorcontrib>Tian, Hui</creatorcontrib><creatorcontrib>Zhai, Yiwen</creatorcontrib><creatorcontrib>Yin, Yimeng</creatorcontrib><creatorcontrib>Sun, Fei</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Technology Research Database</collection><collection>Advanced Technologies Database with Aerospace</collection><jtitle>Molecular and cellular endocrinology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Yong</au><au>Liang, Ning</au><au>Yao, Guidong</au><au>Tian, Hui</au><au>Zhai, Yiwen</au><au>Yin, Yimeng</au><au>Sun, Fei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Knockdown of TrkA in cumulus oocyte complexes (COCs) inhibits EGF-induced cumulus expansion by down-regulation of IL-6</atitle><jtitle>Molecular and cellular endocrinology</jtitle><addtitle>Mol Cell Endocrinol</addtitle><date>2014-02-15</date><risdate>2014</risdate><volume>382</volume><issue>2</issue><spage>804</spage><epage>813</epage><pages>804-813</pages><issn>0303-7207</issn><eissn>1872-8057</eissn><abstract>•TrkA participated in EGF-induced COC expansion.•Inhibition of TrkA has no effect on COC expansion-related transcripts induced by EGF.•Knockdown of TrkA did not inhibit EGF-induced phosphorylation of ERK1/2 and SMAD2.•The effect of TrkA on EGF-induced cumulus expansion is mediated through IL-6.•IL-6 may act as a new potential cumulus expansion-related transcript.
Tyrosine kinase receptor A (TrkA), the high-affinity receptor of nerve growth factor (NGF), is known to play key roles in ovarian follicular development, such as assembly of early follicles and follicular ovulation. However, little is known about the roles of TrkA in cumulus oocyte complex (COC) expansion. In this study, we found that TrkA was abundant in large antral follicles and knockdown of TrkA in COCs attenuated epidermal growth factor (EGF)-induced COC expansion and further decreased the ovulation rate. The effect of TrkA on COC expansion was not mediated through downstream EGF effectors, phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) or drosophila mothers against decapentaplegic protein (SMAD), or through up-regulation of COC expansion-related transcripts such as prostaglandin-endoperoxide synthase 2 (Ptgs2), hyaluronan synthase 2 (Has2), TNF-induced protein 6 (Tnfaip6) or pentraxin 3 (Ptx3). However, pharmacological blockade of TrkA transducing activity (K252α) in COCs decreased the mRNA expression and protein secretion of interleukin-6 (IL-6), identified from mRNA microarray of K252α-treated COCs. Meanwhile, knockdown of IL-6 attenuated EGF-induced COC expansion. In addition, IL-6 rescued the inhibitory effect of K252α on EGF-induced cumulus expansion. Therefore, IL-6 may act as a new potential cumulus expansion-related transcript, which may be involved in the integration of TrkA and EGF signaling in affecting COC expansion. Here, we provide mechanistic insights into the roles of TrkA in EGF-induced cumulus expansion. Understanding potential cross-points between TrkA and EGF affecting cumulus expansion will help in the discovery of new therapeutic targets in ovulation-related diseases.</abstract><cop>Ireland</cop><pub>Elsevier Ireland Ltd</pub><pmid>24215827</pmid><doi>10.1016/j.mce.2013.10.031</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-6149-1961</orcidid></addata></record> |
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| ispartof | Molecular and cellular endocrinology, 2014-02, Vol.382 (2), p.804-813 |
| issn | 0303-7207 1872-8057 |
| language | eng |
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| subjects | Animals Attenuation C-Reactive Protein - genetics C-Reactive Protein - metabolism Carbazoles - pharmacology Cell Adhesion Molecules - genetics Cell Adhesion Molecules - metabolism Cellular COC expansion Cumulus Cells - cytology Cumulus Cells - drug effects Cumulus Cells - metabolism Cumulus oocyte complexes (COCs) Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism Diseases Enzyme Inhibitors - pharmacology Epidermal Growth Factor - metabolism Epidermal Growth Factor - pharmacology Female Gene Expression Regulation, Developmental Glucuronosyltransferase - genetics Glucuronosyltransferase - metabolism Growth factors Hyaluronan Synthases Indole Alkaloids - pharmacology Interleukin-6 (IL-6) Interleukin-6 - antagonists & inhibitors Interleukin-6 - genetics Interleukin-6 - metabolism Kinases Mice Mitogen-Activated Protein Kinase 1 - genetics Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - genetics Mitogen-Activated Protein Kinase 3 - metabolism Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Neurotrophic tyrosine kinase receptor type 1 (TrkA) Oocytes - cytology Oocytes - drug effects Oocytes - metabolism Ovulation - drug effects Proteins Receptor, trkA - antagonists & inhibitors Receptor, trkA - genetics Receptor, trkA - metabolism Receptors RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Secretions Signal Transduction Smad Proteins - genetics Smad Proteins - metabolism |
| title | Knockdown of TrkA in cumulus oocyte complexes (COCs) inhibits EGF-induced cumulus expansion by down-regulation of IL-6 |
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