Nuclear receptor co-regulator Krüppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus
Estrogen, acting through its cognate receptor estrogen receptor-α (ESR1), is a critical regulator of uterine endometrial epithelial proliferation. Although the dynamic communication between endometrial stromal (ST) and epithelial cells is considered to be an important component in this process, key...
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description | Estrogen, acting through its cognate receptor estrogen receptor-α (ESR1), is a critical regulator of uterine endometrial epithelial proliferation. Although the dynamic communication between endometrial stromal (ST) and epithelial cells is considered to be an important component in this process, key molecular players in particular compartments remain poorly defined. Here, we used mice null for Krüppel-like factor 9 (KLF9) to evaluate the contribution of this nuclear protein in ST–epithelial interactions underlying proliferative effects of estrogen. We found that in ovariectomized mice administered estradiol-17β (E2) for 24 h, Klf9 null mutation resulted in lack of E2-induced proliferative response in all endometrial compartments. We demonstrated a negative association between Klf9 expression and nuclear levels of ESR1 transcriptional corepressor prohibitin (PHB) 2 in uterine ST and epithelial cells of E2-treated wild-type (WT) and Klf9 null mice. In early pregnancy uteri of WT mice, the temporal pattern of Klf9 transcript levels was inversely associated with that of Phb2. Deletion of Klf9 up-regulated uterine Phb2 expression and increased PHB2 nuclear localization in endometrial ST and epithelial cells, with no effects on the expression of the related Phb1. In the human endometrial ST cell line treated with E2 for 24 h, Klf9 siRNA targeting augmented PHB2 transcript and increased nuclear PHB2 protein levels, albeit this effect was not to the extent seen in vivo with Klf9 null mutants. Our findings suggest a novel mechanism for control of estrogen-induced luminal epithelial proliferation involving ST KLF9 regulation of paracrine factor(s) to repress epithelial expression of corepressor PHB2. |
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Although the dynamic communication between endometrial stromal (ST) and epithelial cells is considered to be an important component in this process, key molecular players in particular compartments remain poorly defined. Here, we used mice null for Krüppel-like factor 9 (KLF9) to evaluate the contribution of this nuclear protein in ST–epithelial interactions underlying proliferative effects of estrogen. We found that in ovariectomized mice administered estradiol-17β (E2) for 24 h, Klf9 null mutation resulted in lack of E2-induced proliferative response in all endometrial compartments. We demonstrated a negative association between Klf9 expression and nuclear levels of ESR1 transcriptional corepressor prohibitin (PHB) 2 in uterine ST and epithelial cells of E2-treated wild-type (WT) and Klf9 null mice. In early pregnancy uteri of WT mice, the temporal pattern of Klf9 transcript levels was inversely associated with that of Phb2. Deletion of Klf9 up-regulated uterine Phb2 expression and increased PHB2 nuclear localization in endometrial ST and epithelial cells, with no effects on the expression of the related Phb1. In the human endometrial ST cell line treated with E2 for 24 h, Klf9 siRNA targeting augmented PHB2 transcript and increased nuclear PHB2 protein levels, albeit this effect was not to the extent seen in vivo with Klf9 null mutants. Our findings suggest a novel mechanism for control of estrogen-induced luminal epithelial proliferation involving ST KLF9 regulation of paracrine factor(s) to repress epithelial expression of corepressor PHB2.</description><identifier>ISSN: 0022-0795</identifier><identifier>EISSN: 1479-6805</identifier><identifier>DOI: 10.1677/JOE-08-0383</identifier><identifier>PMID: 18835980</identifier><language>eng</language><publisher>England: BioScientifica</publisher><subject>Animals ; Cell Nucleus - metabolism ; Cell Proliferation ; Endometrium - cytology ; Endometrium - metabolism ; Epithelial Cells - cytology ; Epithelial Cells - metabolism ; Estradiol - metabolism ; Estrogen Receptor alpha - metabolism ; Estrogens - metabolism ; Female ; Gene Expression ; Kruppel-Like Transcription Factors - genetics ; Kruppel-Like Transcription Factors - metabolism ; Mice ; Protein Binding ; Regular papers ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Uterus - cytology ; Uterus - metabolism</subject><ispartof>Journal of endocrinology, 2009-01, Vol.200 (1), p.63-73</ispartof><rights>2009 Society for Endocrinology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b464t-6b7745d696177e9c2692c95b8bda19f658a100e2d700754ff6832d7abc4953993</citedby><cites>FETCH-LOGICAL-b464t-6b7745d696177e9c2692c95b8bda19f658a100e2d700754ff6832d7abc4953993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18835980$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pabona, J M P</creatorcontrib><creatorcontrib>Velarde, M C</creatorcontrib><creatorcontrib>Zeng, Z</creatorcontrib><creatorcontrib>Simmen, F A</creatorcontrib><creatorcontrib>Simmen, R C M</creatorcontrib><title>Nuclear receptor co-regulator Krüppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus</title><title>Journal of endocrinology</title><addtitle>J Endocrinol</addtitle><description>Estrogen, acting through its cognate receptor estrogen receptor-α (ESR1), is a critical regulator of uterine endometrial epithelial proliferation. Although the dynamic communication between endometrial stromal (ST) and epithelial cells is considered to be an important component in this process, key molecular players in particular compartments remain poorly defined. Here, we used mice null for Krüppel-like factor 9 (KLF9) to evaluate the contribution of this nuclear protein in ST–epithelial interactions underlying proliferative effects of estrogen. We found that in ovariectomized mice administered estradiol-17β (E2) for 24 h, Klf9 null mutation resulted in lack of E2-induced proliferative response in all endometrial compartments. We demonstrated a negative association between Klf9 expression and nuclear levels of ESR1 transcriptional corepressor prohibitin (PHB) 2 in uterine ST and epithelial cells of E2-treated wild-type (WT) and Klf9 null mice. In early pregnancy uteri of WT mice, the temporal pattern of Klf9 transcript levels was inversely associated with that of Phb2. Deletion of Klf9 up-regulated uterine Phb2 expression and increased PHB2 nuclear localization in endometrial ST and epithelial cells, with no effects on the expression of the related Phb1. In the human endometrial ST cell line treated with E2 for 24 h, Klf9 siRNA targeting augmented PHB2 transcript and increased nuclear PHB2 protein levels, albeit this effect was not to the extent seen in vivo with Klf9 null mutants. Our findings suggest a novel mechanism for control of estrogen-induced luminal epithelial proliferation involving ST KLF9 regulation of paracrine factor(s) to repress epithelial expression of corepressor PHB2.</description><subject>Animals</subject><subject>Cell Nucleus - metabolism</subject><subject>Cell Proliferation</subject><subject>Endometrium - cytology</subject><subject>Endometrium - metabolism</subject><subject>Epithelial Cells - cytology</subject><subject>Epithelial Cells - metabolism</subject><subject>Estradiol - metabolism</subject><subject>Estrogen Receptor alpha - metabolism</subject><subject>Estrogens - metabolism</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Kruppel-Like Transcription Factors - genetics</subject><subject>Kruppel-Like Transcription Factors - metabolism</subject><subject>Mice</subject><subject>Protein Binding</subject><subject>Regular papers</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Uterus - cytology</subject><subject>Uterus - metabolism</subject><issn>0022-0795</issn><issn>1479-6805</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9ks1u1TAQhS0EopfCij3yig0y2E7inw0SqgqFVnQDa8txJjcG3zjYSYEX4Wm664vh6F6gsGBljec7xzM6Rugxo8-ZkPLFu8tTQhWhlaruoA2rpSZC0eYu2lDKOaFSN0foQc6fKGUNk9V9dMSUqhqt6Ab9eL-4ADbhBA6mOSbsIkmwXYJdi_N0cz1NEEjwnwH31q2XGtuxw1OKg2_97EfMMXybEuTs44hLDXlOcQsj8WO3OOgwTH4eIHgbsIMQVm3wPSQ7HxSli3dxyYCXGdKSH6J7vQ0ZHh3OY_Tx9emHkzNycfnm7cmrC9LWop6JaKWsm05owaQE7bjQ3OmmVW1nme5FoyyjFHgnKZVN3fdCVaWwrat1U2ldHaOXe99paXfQORjnZIOZkt_Z9N1E683fndEPZhuvDBeMy4oXg6cHgxS_LGVxs_N53dGOUPYxQkhFa0EL-GwPuhRzTtD_foRRs-ZoSo6GKrPmWOgnt-f6wx6CKwDfA4PfDl99AtP6mJ0vY_reO3vb9dfvKCK2F_3D_m-Sn1Iyvcs</recordid><startdate>20090101</startdate><enddate>20090101</enddate><creator>Pabona, J M P</creator><creator>Velarde, M C</creator><creator>Zeng, Z</creator><creator>Simmen, F A</creator><creator>Simmen, R C M</creator><general>BioScientifica</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>5PM</scope></search><sort><creationdate>20090101</creationdate><title>Nuclear receptor co-regulator Krüppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus</title><author>Pabona, J M P ; Velarde, M C ; Zeng, Z ; Simmen, F A ; Simmen, R C M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b464t-6b7745d696177e9c2692c95b8bda19f658a100e2d700754ff6832d7abc4953993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Cell Nucleus - metabolism</topic><topic>Cell Proliferation</topic><topic>Endometrium - cytology</topic><topic>Endometrium - metabolism</topic><topic>Epithelial Cells - cytology</topic><topic>Epithelial Cells - metabolism</topic><topic>Estradiol - metabolism</topic><topic>Estrogen Receptor alpha - metabolism</topic><topic>Estrogens - metabolism</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Kruppel-Like Transcription Factors - genetics</topic><topic>Kruppel-Like Transcription Factors - metabolism</topic><topic>Mice</topic><topic>Protein Binding</topic><topic>Regular papers</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Uterus - cytology</topic><topic>Uterus - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pabona, J M P</creatorcontrib><creatorcontrib>Velarde, M C</creatorcontrib><creatorcontrib>Zeng, Z</creatorcontrib><creatorcontrib>Simmen, F A</creatorcontrib><creatorcontrib>Simmen, R C M</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>PubMed Central (Full Participant titles)</collection><jtitle>Journal of endocrinology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pabona, J M P</au><au>Velarde, M C</au><au>Zeng, Z</au><au>Simmen, F A</au><au>Simmen, R C M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nuclear receptor co-regulator Krüppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus</atitle><jtitle>Journal of endocrinology</jtitle><addtitle>J Endocrinol</addtitle><date>2009-01-01</date><risdate>2009</risdate><volume>200</volume><issue>1</issue><spage>63</spage><epage>73</epage><pages>63-73</pages><issn>0022-0795</issn><eissn>1479-6805</eissn><abstract>Estrogen, acting through its cognate receptor estrogen receptor-α (ESR1), is a critical regulator of uterine endometrial epithelial proliferation. Although the dynamic communication between endometrial stromal (ST) and epithelial cells is considered to be an important component in this process, key molecular players in particular compartments remain poorly defined. Here, we used mice null for Krüppel-like factor 9 (KLF9) to evaluate the contribution of this nuclear protein in ST–epithelial interactions underlying proliferative effects of estrogen. We found that in ovariectomized mice administered estradiol-17β (E2) for 24 h, Klf9 null mutation resulted in lack of E2-induced proliferative response in all endometrial compartments. We demonstrated a negative association between Klf9 expression and nuclear levels of ESR1 transcriptional corepressor prohibitin (PHB) 2 in uterine ST and epithelial cells of E2-treated wild-type (WT) and Klf9 null mice. In early pregnancy uteri of WT mice, the temporal pattern of Klf9 transcript levels was inversely associated with that of Phb2. Deletion of Klf9 up-regulated uterine Phb2 expression and increased PHB2 nuclear localization in endometrial ST and epithelial cells, with no effects on the expression of the related Phb1. In the human endometrial ST cell line treated with E2 for 24 h, Klf9 siRNA targeting augmented PHB2 transcript and increased nuclear PHB2 protein levels, albeit this effect was not to the extent seen in vivo with Klf9 null mutants. Our findings suggest a novel mechanism for control of estrogen-induced luminal epithelial proliferation involving ST KLF9 regulation of paracrine factor(s) to repress epithelial expression of corepressor PHB2.</abstract><cop>England</cop><pub>BioScientifica</pub><pmid>18835980</pmid><doi>10.1677/JOE-08-0383</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Cell Nucleus - metabolism Cell Proliferation Endometrium - cytology Endometrium - metabolism Epithelial Cells - cytology Epithelial Cells - metabolism Estradiol - metabolism Estrogen Receptor alpha - metabolism Estrogens - metabolism Female Gene Expression Kruppel-Like Transcription Factors - genetics Kruppel-Like Transcription Factors - metabolism Mice Protein Binding Regular papers Repressor Proteins - genetics Repressor Proteins - metabolism Uterus - cytology Uterus - metabolism |
title | Nuclear receptor co-regulator Krüppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus |
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