NF2 regulates IP3R-mediated Ca 2+ signal and apoptosis in meningiomas
Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca ) channel in...
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| Veröffentlicht in: | The FASEB journal 2024-07, Vol.38 (13), p.e23737 |
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| creator | Lei, Zhaoying Niu, Jie Cai, Huajian Kong, Zhengyi Ding, Xue Dong, Yufei Zhang, Dong Li, Xu Shao, Jianzhong Lin, Aifu Zhou, Ruhong Yang, Shuxu Yan, Qingfeng |
| description | Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca
) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca
release by binding to IP3R1, which results in Ca
-dependent apoptosis. Knockout of NF2 decreased Ca
release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca
-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca
release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma. |
| doi_str_mv | 10.1096/fj.202400436R |
| format | Article |
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) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca
release by binding to IP3R1, which results in Ca
-dependent apoptosis. Knockout of NF2 decreased Ca
release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca
-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca
release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.202400436R</identifier><identifier>PMID: 38953724</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Apoptosis ; Calcium - metabolism ; Calcium Signaling ; Cell Line, Tumor ; Endoplasmic Reticulum - metabolism ; Humans ; Inositol 1,4,5-Trisphosphate Receptors - genetics ; Inositol 1,4,5-Trisphosphate Receptors - metabolism ; Male ; Meningeal Neoplasms - genetics ; Meningeal Neoplasms - metabolism ; Meningeal Neoplasms - pathology ; Meningioma - genetics ; Meningioma - metabolism ; Meningioma - pathology ; Mice ; Neurofibromin 2</subject><ispartof>The FASEB journal, 2024-07, Vol.38 (13), p.e23737</ispartof><rights>2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c614-ae7bae4de300c465de88c603608e4010af9e308ede036c7734091eecb27765c83</cites><orcidid>0000-0002-5381-8426</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38953724$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lei, Zhaoying</creatorcontrib><creatorcontrib>Niu, Jie</creatorcontrib><creatorcontrib>Cai, Huajian</creatorcontrib><creatorcontrib>Kong, Zhengyi</creatorcontrib><creatorcontrib>Ding, Xue</creatorcontrib><creatorcontrib>Dong, Yufei</creatorcontrib><creatorcontrib>Zhang, Dong</creatorcontrib><creatorcontrib>Li, Xu</creatorcontrib><creatorcontrib>Shao, Jianzhong</creatorcontrib><creatorcontrib>Lin, Aifu</creatorcontrib><creatorcontrib>Zhou, Ruhong</creatorcontrib><creatorcontrib>Yang, Shuxu</creatorcontrib><creatorcontrib>Yan, Qingfeng</creatorcontrib><title>NF2 regulates IP3R-mediated Ca 2+ signal and apoptosis in meningiomas</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca
) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca
release by binding to IP3R1, which results in Ca
-dependent apoptosis. Knockout of NF2 decreased Ca
release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca
-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca
release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Calcium - metabolism</subject><subject>Calcium Signaling</subject><subject>Cell Line, Tumor</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Humans</subject><subject>Inositol 1,4,5-Trisphosphate Receptors - genetics</subject><subject>Inositol 1,4,5-Trisphosphate Receptors - metabolism</subject><subject>Male</subject><subject>Meningeal Neoplasms - genetics</subject><subject>Meningeal Neoplasms - metabolism</subject><subject>Meningeal Neoplasms - pathology</subject><subject>Meningioma - genetics</subject><subject>Meningioma - metabolism</subject><subject>Meningioma - pathology</subject><subject>Mice</subject><subject>Neurofibromin 2</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkM1Lw0AQxRdRbKwevcreZevsRzabo4RWC0Wl9B42m0nYkC-y7cH_3kj9OA0z8-Px3iPknsOKQ6qfqmYlQCgAJfX-gkQ8lsC00XBJIjCpYFpLsyA3ITQAwIHra7KQJo1lIlRE1m8bQSesT609YqDbD7lnHZZ-3kqaWSoeafB1b1tq-5LacRiPQ_CB-p522Pu-9kNnwy25qmwb8O5nLslhsz5kr2z3_rLNnnfMaa6YxaSwqEqUAE7puERjnAapwaCardkqnV8GS5xvLkmkgpQjukIkiY6dkUvCzrJuGkKYsMrHyXd2-sw55N9t5FWT_7cx8w9nfjwVc6g_-je-_AKfC1jg</recordid><startdate>20240715</startdate><enddate>20240715</enddate><creator>Lei, Zhaoying</creator><creator>Niu, Jie</creator><creator>Cai, Huajian</creator><creator>Kong, Zhengyi</creator><creator>Ding, Xue</creator><creator>Dong, Yufei</creator><creator>Zhang, Dong</creator><creator>Li, Xu</creator><creator>Shao, Jianzhong</creator><creator>Lin, Aifu</creator><creator>Zhou, Ruhong</creator><creator>Yang, Shuxu</creator><creator>Yan, Qingfeng</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0002-5381-8426</orcidid></search><sort><creationdate>20240715</creationdate><title>NF2 regulates IP3R-mediated Ca 2+ signal and apoptosis in meningiomas</title><author>Lei, Zhaoying ; Niu, Jie ; Cai, Huajian ; Kong, Zhengyi ; Ding, Xue ; Dong, Yufei ; Zhang, Dong ; Li, Xu ; Shao, Jianzhong ; Lin, Aifu ; Zhou, Ruhong ; Yang, Shuxu ; Yan, Qingfeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c614-ae7bae4de300c465de88c603608e4010af9e308ede036c7734091eecb27765c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Calcium - metabolism</topic><topic>Calcium Signaling</topic><topic>Cell Line, Tumor</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>Humans</topic><topic>Inositol 1,4,5-Trisphosphate Receptors - genetics</topic><topic>Inositol 1,4,5-Trisphosphate Receptors - metabolism</topic><topic>Male</topic><topic>Meningeal Neoplasms - genetics</topic><topic>Meningeal Neoplasms - metabolism</topic><topic>Meningeal Neoplasms - pathology</topic><topic>Meningioma - genetics</topic><topic>Meningioma - metabolism</topic><topic>Meningioma - pathology</topic><topic>Mice</topic><topic>Neurofibromin 2</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lei, Zhaoying</creatorcontrib><creatorcontrib>Niu, Jie</creatorcontrib><creatorcontrib>Cai, Huajian</creatorcontrib><creatorcontrib>Kong, Zhengyi</creatorcontrib><creatorcontrib>Ding, Xue</creatorcontrib><creatorcontrib>Dong, Yufei</creatorcontrib><creatorcontrib>Zhang, Dong</creatorcontrib><creatorcontrib>Li, Xu</creatorcontrib><creatorcontrib>Shao, Jianzhong</creatorcontrib><creatorcontrib>Lin, Aifu</creatorcontrib><creatorcontrib>Zhou, Ruhong</creatorcontrib><creatorcontrib>Yang, Shuxu</creatorcontrib><creatorcontrib>Yan, Qingfeng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lei, Zhaoying</au><au>Niu, Jie</au><au>Cai, Huajian</au><au>Kong, Zhengyi</au><au>Ding, Xue</au><au>Dong, Yufei</au><au>Zhang, Dong</au><au>Li, Xu</au><au>Shao, Jianzhong</au><au>Lin, Aifu</au><au>Zhou, Ruhong</au><au>Yang, Shuxu</au><au>Yan, Qingfeng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NF2 regulates IP3R-mediated Ca 2+ signal and apoptosis in meningiomas</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2024-07-15</date><risdate>2024</risdate><volume>38</volume><issue>13</issue><spage>e23737</spage><pages>e23737-</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca
) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca
release by binding to IP3R1, which results in Ca
-dependent apoptosis. Knockout of NF2 decreased Ca
release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca
-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca
release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.</abstract><cop>United States</cop><pmid>38953724</pmid><doi>10.1096/fj.202400436R</doi><orcidid>https://orcid.org/0000-0002-5381-8426</orcidid></addata></record> |
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| subjects | Animals Apoptosis Calcium - metabolism Calcium Signaling Cell Line, Tumor Endoplasmic Reticulum - metabolism Humans Inositol 1,4,5-Trisphosphate Receptors - genetics Inositol 1,4,5-Trisphosphate Receptors - metabolism Male Meningeal Neoplasms - genetics Meningeal Neoplasms - metabolism Meningeal Neoplasms - pathology Meningioma - genetics Meningioma - metabolism Meningioma - pathology Mice Neurofibromin 2 |
| title | NF2 regulates IP3R-mediated Ca 2+ signal and apoptosis in meningiomas |
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