IGF-1 Inhibits Apoptosis of Porcine Primary Granulosa Cell by Targeting Degradation of BimEL
Identifieur interne : 000B51 ( Ncbi/Merge ); précédent : 000B50; suivant : 000B52IGF-1 Inhibits Apoptosis of Porcine Primary Granulosa Cell by Targeting Degradation of BimEL
Auteurs : Ying Han ; Shumin Wang ; Yingzheng Wang ; Shenming ZengSource :
- International Journal of Molecular Sciences [ 1422-0067 ] ; 2019.
Abstract
Insulin-like growth factor-1 (IGF-1) is an intra-ovarian growth factor that plays important endocrine or paracrine roles during ovarian development. IGF-1 affects ovarian function and female fertility through reducing apoptosis of granulosa cells, yet the underlying mechanism remains poorly characterized. Here, we aimed to address these knowledge gaps using porcine primary granulosa cells and examining the anti-apoptotic mechanisms of IGF-1. IGF-1 prevented the granulosa cell from apoptosis, as shown by TUNEL and Annexin V/PI detection, and gained the anti-apoptotic index, the ratio of Bcl-2/Bax. This process was partly mediated by reducing the pro-apoptotic BimEL (Bcl-2 Interacting Mediator of Cell Death-Extra Long) protein level. Western blotting showed that IGF-1 promoted BimEL phosphorylation through activating p-ERK1/2, and that the proteasome system was responsible for degradation of phosphorylated BimEL. Meanwhile, IGF-1 enhanced the Beclin1 level and the rate of LC3 II/LC3 I, indicating that autophagy was induced by IGF-1. By blocking the proteolysis processes of both proteasome and autophagy flux with MG132 and chloroquine, respectively, the BimEL did not reduce and the phosphorylated BimEL protein accumulated, thereby indicating that both proteasome and autophagy pathways were involved in the degradation of BimEL stimulated by IGF-1. In conclusion, IGF-1 inhibited porcine primary granulosa cell apoptosis via degradation of pro-apoptotic BimEL. This study is critical for us to further understand the mechanisms of follicular survival and atresia regulated by IGF-1. Moreover, it provides a direction for the treatment of infertility caused by ovarian dysplasia, such as polycystic ovary syndrome and the improvement of assisted reproductive technology.
Url:
DOI: 10.3390/ijms20215356
PubMed: 31661816
PubMed Central: 6861984
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">IGF-1 Inhibits Apoptosis of Porcine Primary Granulosa Cell by Targeting Degradation of Bim<sub>EL</sub></title><author><name sortKey="Han, Ying" sort="Han, Ying" uniqKey="Han Y" first="Ying" last="Han">Ying Han</name></author><author><name sortKey="Wang, Shumin" sort="Wang, Shumin" uniqKey="Wang S" first="Shumin" last="Wang">Shumin Wang</name></author><author><name sortKey="Wang, Yingzheng" sort="Wang, Yingzheng" uniqKey="Wang Y" first="Yingzheng" last="Wang">Yingzheng Wang</name></author><author><name sortKey="Zeng, Shenming" sort="Zeng, Shenming" uniqKey="Zeng S" first="Shenming" last="Zeng">Shenming Zeng</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31661816</idno><idno type="pmc">6861984</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861984</idno><idno type="RBID">PMC:6861984</idno><idno type="doi">10.3390/ijms20215356</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000614</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000614</idno><idno type="wicri:Area/Pmc/Curation">000614</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000614</idno><idno type="wicri:Area/Pmc/Checkpoint">000708</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000708</idno><idno type="wicri:Area/Ncbi/Merge">000B51</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">IGF-1 Inhibits Apoptosis of Porcine Primary Granulosa Cell by Targeting Degradation of Bim<sub>EL</sub></title><author><name sortKey="Han, Ying" sort="Han, Ying" uniqKey="Han Y" first="Ying" last="Han">Ying Han</name></author><author><name sortKey="Wang, Shumin" sort="Wang, Shumin" uniqKey="Wang S" first="Shumin" last="Wang">Shumin Wang</name></author><author><name sortKey="Wang, Yingzheng" sort="Wang, Yingzheng" uniqKey="Wang Y" first="Yingzheng" last="Wang">Yingzheng Wang</name></author><author><name sortKey="Zeng, Shenming" sort="Zeng, Shenming" uniqKey="Zeng S" first="Shenming" last="Zeng">Shenming Zeng</name></author></analytic><series><title level="j">International Journal of Molecular Sciences</title><idno type="eISSN">1422-0067</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Insulin-like growth factor-1 (IGF-1) is an intra-ovarian growth factor that plays important endocrine or paracrine roles during ovarian development. IGF-1 affects ovarian function and female fertility through reducing apoptosis of granulosa cells, yet the underlying mechanism remains poorly characterized. Here, we aimed to address these knowledge gaps using porcine primary granulosa cells and examining the anti-apoptotic mechanisms of IGF-1. IGF-1 prevented the granulosa cell from apoptosis, as shown by TUNEL and Annexin V/PI detection, and gained the anti-apoptotic index, the ratio of Bcl-2/Bax. This process was partly mediated by reducing the pro-apoptotic Bim<sub>EL</sub> (Bcl-2 Interacting Mediator of Cell Death-Extra Long) protein level. Western blotting showed that IGF-1 promoted Bim<sub>EL</sub> phosphorylation through activating p-ERK1/2, and that the proteasome system was responsible for degradation of phosphorylated Bim<sub>EL</sub>. Meanwhile, IGF-1 enhanced the Beclin1 level and the rate of LC3 II/LC3 I, indicating that autophagy was induced by IGF-1. By blocking the proteolysis processes of both proteasome and autophagy flux with MG132 and chloroquine, respectively, the Bim<sub>EL</sub> did not reduce and the phosphorylated Bim<sub>EL</sub> protein accumulated, thereby indicating that both proteasome and autophagy pathways were involved in the degradation of Bim<sub>EL</sub> stimulated by IGF-1. In conclusion, IGF-1 inhibited porcine primary granulosa cell apoptosis via degradation of pro-apoptotic Bim<sub>EL</sub>. This study is critical for us to further understand the mechanisms of follicular survival and atresia regulated by IGF-1. Moreover, it provides a direction for the treatment of infertility caused by ovarian dysplasia, such as polycystic ovary syndrome and the improvement of assisted reproductive technology.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Jones, J I" uniqKey="Jones J">J.I. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Mol Sci</journal-id><journal-id journal-id-type="iso-abbrev">Int J Mol Sci</journal-id><journal-id journal-id-type="publisher-id">ijms</journal-id><journal-title-group><journal-title>International Journal of Molecular Sciences</journal-title></journal-title-group><issn pub-type="epub">1422-0067</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31661816</article-id><article-id pub-id-type="pmc">6861984</article-id><article-id pub-id-type="doi">10.3390/ijms20215356</article-id><article-id pub-id-type="publisher-id">ijms-20-05356</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>IGF-1 Inhibits Apoptosis of Porcine Primary Granulosa Cell by Targeting Degradation of Bim<sub>EL</sub></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Han</surname><given-names>Ying</given-names></name></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Shumin</given-names></name></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Yingzheng</given-names></name></contrib><contrib contrib-type="author"><name><surname>Zeng</surname><given-names>Shenming</given-names></name><xref rid="c1-ijms-20-05356" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-ijms-20-05356">National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding, and Reproduction of the Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China</aff><author-notes><corresp id="c1-ijms-20-05356"><label>*</label>Correspondence: <email>zengshenming@gmail.com</email>; Tel.: +86-183-1010-6460</corresp></author-notes><pub-date pub-type="epub"><day>28</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>11</month><year>2019</year></pub-date><volume>20</volume><issue>21</issue><elocation-id>5356</elocation-id><history><date date-type="received"><day>29</day><month>7</month><year>2019</year></date><date date-type="accepted"><day>04</day><month>9</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Insulin-like growth factor-1 (IGF-1) is an intra-ovarian growth factor that plays important endocrine or paracrine roles during ovarian development. IGF-1 affects ovarian function and female fertility through reducing apoptosis of granulosa cells, yet the underlying mechanism remains poorly characterized. Here, we aimed to address these knowledge gaps using porcine primary granulosa cells and examining the anti-apoptotic mechanisms of IGF-1. IGF-1 prevented the granulosa cell from apoptosis, as shown by TUNEL and Annexin V/PI detection, and gained the anti-apoptotic index, the ratio of Bcl-2/Bax. This process was partly mediated by reducing the pro-apoptotic Bim<sub>EL</sub> (Bcl-2 Interacting Mediator of Cell Death-Extra Long) protein level. Western blotting showed that IGF-1 promoted Bim<sub>EL</sub> phosphorylation through activating p-ERK1/2, and that the proteasome system was responsible for degradation of phosphorylated Bim<sub>EL</sub>. Meanwhile, IGF-1 enhanced the Beclin1 level and the rate of LC3 II/LC3 I, indicating that autophagy was induced by IGF-1. By blocking the proteolysis processes of both proteasome and autophagy flux with MG132 and chloroquine, respectively, the Bim<sub>EL</sub> did not reduce and the phosphorylated Bim<sub>EL</sub> protein accumulated, thereby indicating that both proteasome and autophagy pathways were involved in the degradation of Bim<sub>EL</sub> stimulated by IGF-1. In conclusion, IGF-1 inhibited porcine primary granulosa cell apoptosis via degradation of pro-apoptotic Bim<sub>EL</sub>. This study is critical for us to further understand the mechanisms of follicular survival and atresia regulated by IGF-1. Moreover, it provides a direction for the treatment of infertility caused by ovarian dysplasia, such as polycystic ovary syndrome and the improvement of assisted reproductive technology.</p></abstract><kwd-group><kwd>IGF-1</kwd><kwd>Bim<sub>EL</sub></kwd><kwd>phosphorylation</kwd><kwd>apoptosis</kwd><kwd>autophagy</kwd></kwd-group></article-meta></front><floats-group><fig id="ijms-20-05356-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Insulin-like growth factor-1 (IGF-1) inhibited apoptosis and reduced the Bim<sub>EL</sub> level. (<bold>A</bold>) TUNEL (TdT-mediated dUTP Nick-End Labeling) assay showed the apoptosis percentage of porcine granulosa cells. Cells were cultured in the presence of IGF-1 (50 ng/mL) or absence of IGF-1 (CON) for 24 h. The left panel demonstrates the fluorescence microscopy of DNA fragmentation in cells detected by TUNEL (green). Cell nuclei were stained with Hoechst 33342 (blue) (×400). The right panel is the mortality rate of granulosa cells. (<bold>B</bold>) The image-based analysis of intensity of annexin V-FITC/PI staining showed healthy (blue dots), early apoptotic (brown dots), late apoptotic (bottle-green dots) and dead (yellow dots) cells. Cells were treated with an uncomfortable concentration of hydrochloric acid (0.01 mol/L) 10 min after treatment with or without IGF-1 (50 ng/mL) for 24 h. (<bold>C</bold>) The regulation effect of IGF-1 on the Bcl-2 and Bax protein was demonstrated. (<bold>D</bold>) The expression of Bim<sub>EL</sub> was downregulated by IGF-1. (<bold>E</bold>) The phosphorylation of Bim<sub>EL</sub> was induced by IGF-1. The values are expressed as means ± S.D of at least three separate experiments. * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01.</p></caption><graphic xlink:href="ijms-20-05356-g001"></graphic></fig><fig id="ijms-20-05356-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Inhibition of the ERK1/2 pathway impaired the effect of IGF-1 on Bim<sub>EL</sub> and the proteasome system was related to Bim<sub>EL</sub> downregulation. (<bold>A</bold>) Granulosa cells were treated with U0126 for 1 h before incubation in the presence of IGF-1 for 24 h. (<bold>B</bold>) Cells were pre-cultured in MG132 for 1 h and treatment with IGF-1 24 h. Bim<sub>EL</sub>, p-ERK1/2, ERK and β-Actin were detected with immunoblotting. Blots were probed with β-Actin to control for loading. Data are shown as means ± SD of at least three separate experiments. * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01.</p></caption><graphic xlink:href="ijms-20-05356-g002"></graphic></fig><fig id="ijms-20-05356-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Autophagy was activated by IGF-1, and both blocking the autophagy flux turnover and inhibiting the proteasome system facilitated the accumulation of IGF-1-induced Bim<sub>EL</sub> phosphorylation. (<bold>A</bold>) Beclin1 and LC3 were evoked in granulosa cells with different amounts of IGF-1. (<bold>B</bold>) The blockage of autophagy circulation accumulated the phosphorylation of Bim<sub>EL</sub> in the presence of IGF-1. Cells were preconditioned with chloroquine (10 μM) for 1 h before the supply of IGF-1 in medium. (<bold>C</bold>) Both autophagy and proteasome processes were involved in the degradation of Bim<sub>EL</sub>. Cells were preconditioned with chloroquine (10 μM) and/or MG132 (5 μM) for 1 h before the addition of IGF-1. Normalized cell lysates were immunoblotted with antibodies for Beclin1, LC3, Bim<sub>EL</sub>, p-ERK1/2. β-Actin served as the loading control. The values are expressed as means ± SD of at least three separate experiments. * <italic>p</italic> < 0.05. a, b, c, d, e, different letters represent significant difference (<italic>p</italic> < 0.05) statistically, and same letters represent no change statistically.</p></caption><graphic xlink:href="ijms-20-05356-g003"></graphic></fig><fig id="ijms-20-05356-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>The schema diagram of IGF-1-induced Bim<sub>EL</sub> degradation. IGF-1, combined with its receptor, spurred a series of downstream cascade reactions in porcine primary granulosa cells. IGF-1 activated the ERK1/2 pathway, which caused posttranslational phosphorylation modification of Bim<sub>EL</sub>. Modified Bim<sub>EL</sub> was degraded by autophagy and the proteasome pathway, respectively.</p></caption><graphic xlink:href="ijms-20-05356-g004"></graphic></fig></floats-group></pmc><affiliations><list></list><tree><noCountry><name sortKey="Han, Ying" sort="Han, Ying" uniqKey="Han Y" first="Ying" last="Han">Ying Han</name><name sortKey="Wang, Shumin" sort="Wang, Shumin" uniqKey="Wang S" first="Shumin" last="Wang">Shumin Wang</name><name sortKey="Wang, Yingzheng" sort="Wang, Yingzheng" uniqKey="Wang Y" first="Yingzheng" last="Wang">Yingzheng Wang</name><name sortKey="Zeng, Shenming" sort="Zeng, Shenming" uniqKey="Zeng S" first="Shenming" last="Zeng">Shenming Zeng</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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