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Effects of MAPK signaling on 1,25-dihydroxyvitamin D-mediated CYP24 gene expression in the enterocyte-like cell line, Caco-2
We examined the role of the extracellular signal regulated kinases (ERK) in 1,25‐dihydroxyvitamin D (1,25(OH)2D3)‐induced gene expression in the differentiated Caco‐2 cells. 1,25(OH)2D3‐regulated expression of the 25‐hydroxyvitamin D, 24‐hydroxylase (CYP24) gene (both natural gene and promoter const...
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| Published in: | Journal of cellular physiology 2009-04, Vol.219 (1), p.132-142 |
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| creator | Cui, Min Zhao, Yan Hance, Kenneth W. Shao, Andrew Wood, Richard J. Fleet, James C. |
| description | We examined the role of the extracellular signal regulated kinases (ERK) in 1,25‐dihydroxyvitamin D (1,25(OH)2D3)‐induced gene expression in the differentiated Caco‐2 cells. 1,25(OH)2D3‐regulated expression of the 25‐hydroxyvitamin D, 24‐hydroxylase (CYP24) gene (both natural gene and promoter construct) was strongly modulated by altering ERK activity (i.e., reduced by MEK inhibitors and dominant negative (dn) ERK1 and ERK2, activated by epidermal growth factor) but ERK inhibition had no effect on 1,25(OH)2D3‐regulated expression of the transient receptor potential cation channel, subfamily V, member 6 (TRPV6). ERK5‐mediated phosphorylation of the transcription factor Ets‐1 enhanced 1,25(OH)2D3‐mediated CYP24 gene transcription in proliferating but not differentiated Caco‐2 cells due to reduced levels of ERK5 and Ets‐1 (total and phosphoprotein levels) in differentiated cells. MEK inhibition reduced 1,25(OH)2D3‐induced 3X‐VDRE promoter activity but had no impact on the association of vitamin D receptor (VDR) with chromatin suggesting a role for co‐activator recruitment in ERK‐modulation of vitamin D‐regulated CYP24 gene activation. Chromatin immunoprecipitation assays revealed that the ERK1/2 target, mediator 1 (MED1), is recruited to the CYP24, but not the TRPV6, promoter following 1,25(OH)2D3 treatment. MED1 phosphorylation was sensitive to activators and inhibitors of the ERK1/2 signaling and MED1 siRNA reduced 1,25(OH)2D3‐regulated human CYP24 promoter activity. This suggests ERK1/2 signaling enhances 1,25(OH)2D3 effects on the CYP24 promoter by MED1‐mediated events. Our data show that there are both promoter‐specific and cell stage‐specific roles for the ERK signaling pathway on 1,25(OH)2D3‐mediated gene induction in enterocyte‐like Caco‐2 cells. J. Cell. Physiol. 219: 132–142, 2009. © 2008 Wiley‐Liss, Inc. |
| doi_str_mv | 10.1002/jcp.21657 |
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ERK5‐mediated phosphorylation of the transcription factor Ets‐1 enhanced 1,25(OH)2D3‐mediated CYP24 gene transcription in proliferating but not differentiated Caco‐2 cells due to reduced levels of ERK5 and Ets‐1 (total and phosphoprotein levels) in differentiated cells. MEK inhibition reduced 1,25(OH)2D3‐induced 3X‐VDRE promoter activity but had no impact on the association of vitamin D receptor (VDR) with chromatin suggesting a role for co‐activator recruitment in ERK‐modulation of vitamin D‐regulated CYP24 gene activation. Chromatin immunoprecipitation assays revealed that the ERK1/2 target, mediator 1 (MED1), is recruited to the CYP24, but not the TRPV6, promoter following 1,25(OH)2D3 treatment. MED1 phosphorylation was sensitive to activators and inhibitors of the ERK1/2 signaling and MED1 siRNA reduced 1,25(OH)2D3‐regulated human CYP24 promoter activity. This suggests ERK1/2 signaling enhances 1,25(OH)2D3 effects on the CYP24 promoter by MED1‐mediated events. Our data show that there are both promoter‐specific and cell stage‐specific roles for the ERK signaling pathway on 1,25(OH)2D3‐mediated gene induction in enterocyte‐like Caco‐2 cells. J. Cell. Physiol. 219: 132–142, 2009. © 2008 Wiley‐Liss, Inc.</description><identifier>ISSN: 0021-9541</identifier><identifier>EISSN: 1097-4652</identifier><identifier>DOI: 10.1002/jcp.21657</identifier><identifier>PMID: 19097033</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Caco-2 Cells - physiology ; Calcitriol - metabolism ; Calcium - metabolism ; Calcium Channels - genetics ; Calcium Channels - metabolism ; Enzyme Inhibitors - metabolism ; Epidermal Growth Factor - metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Imidazoles - metabolism ; MAP Kinase Kinase 1 - antagonists & inhibitors ; MAP Kinase Kinase 1 - genetics ; MAP Kinase Kinase 1 - metabolism ; MAP Kinase Kinase 2 - antagonists & inhibitors ; MAP Kinase Kinase 2 - genetics ; MAP Kinase Kinase 2 - metabolism ; MAP Kinase Signaling System - physiology ; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors ; Mitogen-Activated Protein Kinase 1 - genetics ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors ; Mitogen-Activated Protein Kinase 3 - genetics ; Mitogen-Activated Protein Kinase 3 - metabolism ; Promoter Regions, Genetic ; Proto-Oncogene Protein c-ets-1 - genetics ; Proto-Oncogene Protein c-ets-1 - metabolism ; Receptors, Calcitriol - genetics ; Receptors, Calcitriol - metabolism ; Retinoid X Receptor alpha - genetics ; Retinoid X Receptor alpha - metabolism ; RNA Interference ; Steroid Hydroxylases - antagonists & inhibitors ; Steroid Hydroxylases - genetics ; Steroid Hydroxylases - metabolism ; TRPV Cation Channels - genetics ; TRPV Cation Channels - metabolism ; Two-Hybrid System Techniques ; Vitamin D3 24-Hydroxylase ; Vitamins - metabolism</subject><ispartof>Journal of cellular physiology, 2009-04, Vol.219 (1), p.132-142</ispartof><rights>Copyright © 2008 Wiley‐Liss, Inc.</rights><rights>(c) 2008 Wiley-Liss, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5177-67f60df3be827acf5f670439de9aeab658c7b1bbe6ee5cf5fdb8d7406819fad33</citedby><cites>FETCH-LOGICAL-c5177-67f60df3be827acf5f670439de9aeab658c7b1bbe6ee5cf5fdb8d7406819fad33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcp.21657$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcp.21657$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,315,786,790,891,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19097033$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cui, Min</creatorcontrib><creatorcontrib>Zhao, Yan</creatorcontrib><creatorcontrib>Hance, Kenneth W.</creatorcontrib><creatorcontrib>Shao, Andrew</creatorcontrib><creatorcontrib>Wood, Richard J.</creatorcontrib><creatorcontrib>Fleet, James C.</creatorcontrib><title>Effects of MAPK signaling on 1,25-dihydroxyvitamin D-mediated CYP24 gene expression in the enterocyte-like cell line, Caco-2</title><title>Journal of cellular physiology</title><addtitle>J. Cell. Physiol</addtitle><description>We examined the role of the extracellular signal regulated kinases (ERK) in 1,25‐dihydroxyvitamin D (1,25(OH)2D3)‐induced gene expression in the differentiated Caco‐2 cells. 1,25(OH)2D3‐regulated expression of the 25‐hydroxyvitamin D, 24‐hydroxylase (CYP24) gene (both natural gene and promoter construct) was strongly modulated by altering ERK activity (i.e., reduced by MEK inhibitors and dominant negative (dn) ERK1 and ERK2, activated by epidermal growth factor) but ERK inhibition had no effect on 1,25(OH)2D3‐regulated expression of the transient receptor potential cation channel, subfamily V, member 6 (TRPV6). ERK5‐mediated phosphorylation of the transcription factor Ets‐1 enhanced 1,25(OH)2D3‐mediated CYP24 gene transcription in proliferating but not differentiated Caco‐2 cells due to reduced levels of ERK5 and Ets‐1 (total and phosphoprotein levels) in differentiated cells. MEK inhibition reduced 1,25(OH)2D3‐induced 3X‐VDRE promoter activity but had no impact on the association of vitamin D receptor (VDR) with chromatin suggesting a role for co‐activator recruitment in ERK‐modulation of vitamin D‐regulated CYP24 gene activation. Chromatin immunoprecipitation assays revealed that the ERK1/2 target, mediator 1 (MED1), is recruited to the CYP24, but not the TRPV6, promoter following 1,25(OH)2D3 treatment. MED1 phosphorylation was sensitive to activators and inhibitors of the ERK1/2 signaling and MED1 siRNA reduced 1,25(OH)2D3‐regulated human CYP24 promoter activity. This suggests ERK1/2 signaling enhances 1,25(OH)2D3 effects on the CYP24 promoter by MED1‐mediated events. Our data show that there are both promoter‐specific and cell stage‐specific roles for the ERK signaling pathway on 1,25(OH)2D3‐mediated gene induction in enterocyte‐like Caco‐2 cells. J. Cell. Physiol. 219: 132–142, 2009. © 2008 Wiley‐Liss, Inc.</description><subject>Caco-2 Cells - physiology</subject><subject>Calcitriol - metabolism</subject><subject>Calcium - metabolism</subject><subject>Calcium Channels - genetics</subject><subject>Calcium Channels - metabolism</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Epidermal Growth Factor - metabolism</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Humans</subject><subject>Imidazoles - metabolism</subject><subject>MAP Kinase Kinase 1 - antagonists & inhibitors</subject><subject>MAP Kinase Kinase 1 - genetics</subject><subject>MAP Kinase Kinase 1 - metabolism</subject><subject>MAP Kinase Kinase 2 - antagonists & inhibitors</subject><subject>MAP Kinase Kinase 2 - genetics</subject><subject>MAP Kinase Kinase 2 - metabolism</subject><subject>MAP Kinase Signaling System - physiology</subject><subject>Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinase 1 - genetics</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinase 3 - genetics</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Promoter Regions, Genetic</subject><subject>Proto-Oncogene Protein c-ets-1 - genetics</subject><subject>Proto-Oncogene Protein c-ets-1 - metabolism</subject><subject>Receptors, Calcitriol - genetics</subject><subject>Receptors, Calcitriol - metabolism</subject><subject>Retinoid X Receptor alpha - genetics</subject><subject>Retinoid X Receptor alpha - metabolism</subject><subject>RNA Interference</subject><subject>Steroid Hydroxylases - antagonists & inhibitors</subject><subject>Steroid Hydroxylases - genetics</subject><subject>Steroid Hydroxylases - metabolism</subject><subject>TRPV Cation Channels - genetics</subject><subject>TRPV Cation Channels - metabolism</subject><subject>Two-Hybrid System Techniques</subject><subject>Vitamin D3 24-Hydroxylase</subject><subject>Vitamins - metabolism</subject><issn>0021-9541</issn><issn>1097-4652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNp1kUtvEzEUhS0EoqGw4A8gr5Aq1a09HtuZDVI1tOFRIFKhPDaWZ-Y6cTsZp_akZCR-PA4JBRasLPl-5_hcH4SeMnrEKM2Or-rlUcakUPfQiNFCkVyK7D4apRkjhcjZHnoU4xWltCg4f4j2WJEoyvkI_Ti1Fuo-Ym_xu5PpWxzdrDOt62bYd5gdZoI0bj40wa-HW9ebhevwS7KAxpkeGlx-nWY5nkEHGNbLADG6JEtMP083XQ_B10MPpHXXgGtoW5ys4RCXpvYke4weWNNGeLI799Gns9OP5Sty_mHyujw5J7VgShGprKSN5RWMM2VqK6xUNOdFA4UBU0kxrlXFqgokgNiMm2rcqJzKMSusaTjfRy-2vstVlaLXKVgwrV4GtzBh0N44_e-kc3M987c6S_8klUwGz3cGwd-sIPZ64eJmHdOBX0Ut5VgoLvMEHmzBOvgYA9i7RxjVm6506kr_6iqxz_5O9YfclZOA4y3w3bUw_N9Jvymnvy3JVuFiD-s7hQnXWiquhP78fqIvJuzy4su3S035T3QxryY</recordid><startdate>200904</startdate><enddate>200904</enddate><creator>Cui, Min</creator><creator>Zhao, Yan</creator><creator>Hance, Kenneth W.</creator><creator>Shao, Andrew</creator><creator>Wood, Richard J.</creator><creator>Fleet, James C.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><scope>BSCLL</scope><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>200904</creationdate><title>Effects of MAPK signaling on 1,25-dihydroxyvitamin D-mediated CYP24 gene expression in the enterocyte-like cell line, Caco-2</title><author>Cui, Min ; Zhao, Yan ; Hance, Kenneth W. ; Shao, Andrew ; Wood, Richard J. ; Fleet, James C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5177-67f60df3be827acf5f670439de9aeab658c7b1bbe6ee5cf5fdb8d7406819fad33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Caco-2 Cells - physiology</topic><topic>Calcitriol - metabolism</topic><topic>Calcium - metabolism</topic><topic>Calcium Channels - genetics</topic><topic>Calcium Channels - metabolism</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Epidermal Growth Factor - metabolism</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Humans</topic><topic>Imidazoles - metabolism</topic><topic>MAP Kinase Kinase 1 - antagonists & inhibitors</topic><topic>MAP Kinase Kinase 1 - genetics</topic><topic>MAP Kinase Kinase 1 - metabolism</topic><topic>MAP Kinase Kinase 2 - antagonists & inhibitors</topic><topic>MAP Kinase Kinase 2 - genetics</topic><topic>MAP Kinase Kinase 2 - metabolism</topic><topic>MAP Kinase Signaling System - physiology</topic><topic>Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinase 1 - genetics</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinase 3 - genetics</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Promoter Regions, Genetic</topic><topic>Proto-Oncogene Protein c-ets-1 - genetics</topic><topic>Proto-Oncogene Protein c-ets-1 - metabolism</topic><topic>Receptors, Calcitriol - genetics</topic><topic>Receptors, Calcitriol - metabolism</topic><topic>Retinoid X Receptor alpha - genetics</topic><topic>Retinoid X Receptor alpha - metabolism</topic><topic>RNA Interference</topic><topic>Steroid Hydroxylases - antagonists & inhibitors</topic><topic>Steroid Hydroxylases - genetics</topic><topic>Steroid Hydroxylases - metabolism</topic><topic>TRPV Cation Channels - genetics</topic><topic>TRPV Cation Channels - metabolism</topic><topic>Two-Hybrid System Techniques</topic><topic>Vitamin D3 24-Hydroxylase</topic><topic>Vitamins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cui, Min</creatorcontrib><creatorcontrib>Zhao, Yan</creatorcontrib><creatorcontrib>Hance, Kenneth W.</creatorcontrib><creatorcontrib>Shao, Andrew</creatorcontrib><creatorcontrib>Wood, Richard J.</creatorcontrib><creatorcontrib>Fleet, James C.</creatorcontrib><collection>Istex</collection><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 cellular physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cui, Min</au><au>Zhao, Yan</au><au>Hance, Kenneth W.</au><au>Shao, Andrew</au><au>Wood, Richard J.</au><au>Fleet, James C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of MAPK signaling on 1,25-dihydroxyvitamin D-mediated CYP24 gene expression in the enterocyte-like cell line, Caco-2</atitle><jtitle>Journal of cellular physiology</jtitle><addtitle>J. Cell. Physiol</addtitle><date>2009-04</date><risdate>2009</risdate><volume>219</volume><issue>1</issue><spage>132</spage><epage>142</epage><pages>132-142</pages><issn>0021-9541</issn><eissn>1097-4652</eissn><notes>istex:D8225C577A72C59B8B95080815DE6B073682431F</notes><notes>United States Department of Agriculture, Agricultural Research Service - No. 58-1950-4-401</notes><notes>National Institutes of Health - No. DK054111</notes><notes>ArticleID:JCP21657</notes><notes>ark:/67375/WNG-SG1VSXZV-0</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Current address for Yan Zhao: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey PA 17033, USA</notes><notes>Current address for Andrew Shao: Council for Responsible Nutrition, Science and Regulatory, 1828 L Street, NW, Suite 900, Washington, DC 20036, USA.</notes><notes>Current address for Ken Hance: Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, National Institute of Health, Bethesda, MD 20892</notes><abstract>We examined the role of the extracellular signal regulated kinases (ERK) in 1,25‐dihydroxyvitamin D (1,25(OH)2D3)‐induced gene expression in the differentiated Caco‐2 cells. 1,25(OH)2D3‐regulated expression of the 25‐hydroxyvitamin D, 24‐hydroxylase (CYP24) gene (both natural gene and promoter construct) was strongly modulated by altering ERK activity (i.e., reduced by MEK inhibitors and dominant negative (dn) ERK1 and ERK2, activated by epidermal growth factor) but ERK inhibition had no effect on 1,25(OH)2D3‐regulated expression of the transient receptor potential cation channel, subfamily V, member 6 (TRPV6). ERK5‐mediated phosphorylation of the transcription factor Ets‐1 enhanced 1,25(OH)2D3‐mediated CYP24 gene transcription in proliferating but not differentiated Caco‐2 cells due to reduced levels of ERK5 and Ets‐1 (total and phosphoprotein levels) in differentiated cells. MEK inhibition reduced 1,25(OH)2D3‐induced 3X‐VDRE promoter activity but had no impact on the association of vitamin D receptor (VDR) with chromatin suggesting a role for co‐activator recruitment in ERK‐modulation of vitamin D‐regulated CYP24 gene activation. Chromatin immunoprecipitation assays revealed that the ERK1/2 target, mediator 1 (MED1), is recruited to the CYP24, but not the TRPV6, promoter following 1,25(OH)2D3 treatment. MED1 phosphorylation was sensitive to activators and inhibitors of the ERK1/2 signaling and MED1 siRNA reduced 1,25(OH)2D3‐regulated human CYP24 promoter activity. This suggests ERK1/2 signaling enhances 1,25(OH)2D3 effects on the CYP24 promoter by MED1‐mediated events. Our data show that there are both promoter‐specific and cell stage‐specific roles for the ERK signaling pathway on 1,25(OH)2D3‐mediated gene induction in enterocyte‐like Caco‐2 cells. J. Cell. Physiol. 219: 132–142, 2009. © 2008 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>19097033</pmid><doi>10.1002/jcp.21657</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Caco-2 Cells - physiology Calcitriol - metabolism Calcium - metabolism Calcium Channels - genetics Calcium Channels - metabolism Enzyme Inhibitors - metabolism Epidermal Growth Factor - metabolism Gene Expression Regulation, Enzymologic Humans Imidazoles - metabolism MAP Kinase Kinase 1 - antagonists & inhibitors MAP Kinase Kinase 1 - genetics MAP Kinase Kinase 1 - metabolism MAP Kinase Kinase 2 - antagonists & inhibitors MAP Kinase Kinase 2 - genetics MAP Kinase Kinase 2 - metabolism MAP Kinase Signaling System - physiology Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors Mitogen-Activated Protein Kinase 1 - genetics Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors Mitogen-Activated Protein Kinase 3 - genetics Mitogen-Activated Protein Kinase 3 - metabolism Promoter Regions, Genetic Proto-Oncogene Protein c-ets-1 - genetics Proto-Oncogene Protein c-ets-1 - metabolism Receptors, Calcitriol - genetics Receptors, Calcitriol - metabolism Retinoid X Receptor alpha - genetics Retinoid X Receptor alpha - metabolism RNA Interference Steroid Hydroxylases - antagonists & inhibitors Steroid Hydroxylases - genetics Steroid Hydroxylases - metabolism TRPV Cation Channels - genetics TRPV Cation Channels - metabolism Two-Hybrid System Techniques Vitamin D3 24-Hydroxylase Vitamins - metabolism |
| title | Effects of MAPK signaling on 1,25-dihydroxyvitamin D-mediated CYP24 gene expression in the enterocyte-like cell line, Caco-2 |
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