IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development
To identify functions of the IKKalpha subunit of IkappaB kinase that require catalytic activity, we generated an Ikkalpha(AA) knockin allele containing alanines instead of serines in the activation loop. Ikkalpha(AA/AA) mice are healthy and fertile, but females display a severe lactation defect due...
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| Veröffentlicht in: | Cell 2001-12, Vol.107 (6), p.763-775 |
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| creator | Cao, Y Bonizzi, G Seagroves, T N Greten, F R Johnson, R Schmidt, E V Karin, M |
| description | To identify functions of the IKKalpha subunit of IkappaB kinase that require catalytic activity, we generated an Ikkalpha(AA) knockin allele containing alanines instead of serines in the activation loop. Ikkalpha(AA/AA) mice are healthy and fertile, but females display a severe lactation defect due to impaired proliferation of mammary epithelial cells. IKKalpha activity is required for NF-kappaB activation in mammary epithelial cells during pregnancy and in response to RANK ligand but not TNFalpha. IKKalpha and NF-kappaB activation are also required for optimal cyclin D1 induction. Defective RANK signaling or cyclin D1 expression results in the same phenotypic effect as the Ikkalpha(AA) mutation, which is completely suppressed by a mammary specific cyclin D1 transgene. Thus, IKKalpha is a critical intermediate in a pathway that controls mammary epithelial proliferation in response to RANK signaling via cyclin D1. |
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Ikkalpha(AA/AA) mice are healthy and fertile, but females display a severe lactation defect due to impaired proliferation of mammary epithelial cells. IKKalpha activity is required for NF-kappaB activation in mammary epithelial cells during pregnancy and in response to RANK ligand but not TNFalpha. IKKalpha and NF-kappaB activation are also required for optimal cyclin D1 induction. Defective RANK signaling or cyclin D1 expression results in the same phenotypic effect as the Ikkalpha(AA) mutation, which is completely suppressed by a mammary specific cyclin D1 transgene. Thus, IKKalpha is a critical intermediate in a pathway that controls mammary epithelial proliferation in response to RANK signaling via cyclin D1.</description><identifier>ISSN: 0092-8674</identifier><identifier>PMID: 11747812</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Caseins - genetics ; Caseins - metabolism ; Cells, Cultured ; Cyclin D1 - genetics ; Cyclin D1 - metabolism ; Epithelial Cells - metabolism ; Female ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Gene Expression Regulation ; Glycoproteins - genetics ; Glycoproteins - metabolism ; Humans ; I-kappa B Kinase ; Lactation - physiology ; Mammary Glands, Animal - cytology ; Mammary Glands, Animal - growth & development ; Mammary Glands, Animal - metabolism ; Mammary Glands, Animal - transplantation ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - metabolism ; Mice ; Mice, Transgenic ; NF-kappa B - metabolism ; Osteoprotegerin ; Pregnancy ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; RANK Ligand ; Receptor Activator of Nuclear Factor-kappa B ; Receptors, Cytoplasmic and Nuclear - genetics ; Receptors, Cytoplasmic and Nuclear - metabolism ; Receptors, Tumor Necrosis Factor ; Signal Transduction ; Tissue Transplantation ; Transgenes ; Tumor Necrosis Factor-alpha - pharmacology</subject><ispartof>Cell, 2001-12, Vol.107 (6), p.763-775</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11747812$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cao, Y</creatorcontrib><creatorcontrib>Bonizzi, G</creatorcontrib><creatorcontrib>Seagroves, T N</creatorcontrib><creatorcontrib>Greten, F R</creatorcontrib><creatorcontrib>Johnson, R</creatorcontrib><creatorcontrib>Schmidt, E V</creatorcontrib><creatorcontrib>Karin, M</creatorcontrib><title>IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development</title><title>Cell</title><addtitle>Cell</addtitle><description>To identify functions of the IKKalpha subunit of IkappaB kinase that require catalytic activity, we generated an Ikkalpha(AA) knockin allele containing alanines instead of serines in the activation loop. Ikkalpha(AA/AA) mice are healthy and fertile, but females display a severe lactation defect due to impaired proliferation of mammary epithelial cells. IKKalpha activity is required for NF-kappaB activation in mammary epithelial cells during pregnancy and in response to RANK ligand but not TNFalpha. IKKalpha and NF-kappaB activation are also required for optimal cyclin D1 induction. Defective RANK signaling or cyclin D1 expression results in the same phenotypic effect as the Ikkalpha(AA) mutation, which is completely suppressed by a mammary specific cyclin D1 transgene. Thus, IKKalpha is a critical intermediate in a pathway that controls mammary epithelial proliferation in response to RANK signaling via cyclin D1.</description><subject>Animals</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Caseins - genetics</subject><subject>Caseins - metabolism</subject><subject>Cells, Cultured</subject><subject>Cyclin D1 - genetics</subject><subject>Cyclin D1 - metabolism</subject><subject>Epithelial Cells - metabolism</subject><subject>Female</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Gene Expression Regulation</subject><subject>Glycoproteins - genetics</subject><subject>Glycoproteins - metabolism</subject><subject>Humans</subject><subject>I-kappa B Kinase</subject><subject>Lactation - physiology</subject><subject>Mammary Glands, Animal - cytology</subject><subject>Mammary Glands, Animal - growth & development</subject><subject>Mammary Glands, Animal - metabolism</subject><subject>Mammary Glands, Animal - transplantation</subject><subject>Membrane Glycoproteins - genetics</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>NF-kappa B - metabolism</subject><subject>Osteoprotegerin</subject><subject>Pregnancy</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>RANK Ligand</subject><subject>Receptor Activator of Nuclear Factor-kappa B</subject><subject>Receptors, Cytoplasmic and Nuclear - genetics</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Receptors, Tumor Necrosis Factor</subject><subject>Signal Transduction</subject><subject>Tissue Transplantation</subject><subject>Transgenes</subject><subject>Tumor Necrosis Factor-alpha - pharmacology</subject><issn>0092-8674</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kMtOwzAQRb0A0VL4BeQVu0h2bNfOsiqvKhVIqPtoEk-LwXkQJ4X-fV1RVjOae-bqzlyQKWNZmpi5lhNyHcInY8wopa7IhHMtteHplAyrPAfffQDt-nbvLAYKDcUQsBkceOpd80VLHH4QG_q-eM1pcLsG4ngXQUurQxV7-sAp_nZ93HNtQ-3Yn_Qa6hr6A935E2lxj77t6mh8Qy634APenuuMbJ4eN8uXZP32vFou1kmnZJqILZOgUwPCWoMlGm3TzLBMSRQcbWZ1KaTQgGAEY1bximNlkSFUuOUKxYzc_9nG075HDENRu1Chj3GwHUOhUzFXwsgI3p3BsazRFl3vTsGL_zeJI7_IZRQ</recordid><startdate>20011214</startdate><enddate>20011214</enddate><creator>Cao, Y</creator><creator>Bonizzi, G</creator><creator>Seagroves, T N</creator><creator>Greten, F R</creator><creator>Johnson, R</creator><creator>Schmidt, E V</creator><creator>Karin, M</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20011214</creationdate><title>IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development</title><author>Cao, Y ; Bonizzi, G ; Seagroves, T N ; Greten, F R ; Johnson, R ; Schmidt, E V ; Karin, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p542-3f04a728a3dd8ebe87d2980954e31ed9d7b3437aea8300d51c1ecde0eacef15e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Caseins - genetics</topic><topic>Caseins - metabolism</topic><topic>Cells, Cultured</topic><topic>Cyclin D1 - genetics</topic><topic>Cyclin D1 - metabolism</topic><topic>Epithelial Cells - metabolism</topic><topic>Female</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Gene Expression Regulation</topic><topic>Glycoproteins - genetics</topic><topic>Glycoproteins - metabolism</topic><topic>Humans</topic><topic>I-kappa B Kinase</topic><topic>Lactation - physiology</topic><topic>Mammary Glands, Animal - cytology</topic><topic>Mammary Glands, Animal - growth & development</topic><topic>Mammary Glands, Animal - metabolism</topic><topic>Mammary Glands, Animal - transplantation</topic><topic>Membrane Glycoproteins - genetics</topic><topic>Membrane Glycoproteins - metabolism</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>NF-kappa B - metabolism</topic><topic>Osteoprotegerin</topic><topic>Pregnancy</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>RANK Ligand</topic><topic>Receptor Activator of Nuclear Factor-kappa B</topic><topic>Receptors, Cytoplasmic and Nuclear - genetics</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Receptors, Tumor Necrosis Factor</topic><topic>Signal Transduction</topic><topic>Tissue Transplantation</topic><topic>Transgenes</topic><topic>Tumor Necrosis Factor-alpha - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cao, Y</creatorcontrib><creatorcontrib>Bonizzi, G</creatorcontrib><creatorcontrib>Seagroves, T N</creatorcontrib><creatorcontrib>Greten, F R</creatorcontrib><creatorcontrib>Johnson, R</creatorcontrib><creatorcontrib>Schmidt, E V</creatorcontrib><creatorcontrib>Karin, M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cao, Y</au><au>Bonizzi, G</au><au>Seagroves, T N</au><au>Greten, F R</au><au>Johnson, R</au><au>Schmidt, E V</au><au>Karin, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2001-12-14</date><risdate>2001</risdate><volume>107</volume><issue>6</issue><spage>763</spage><epage>775</epage><pages>763-775</pages><issn>0092-8674</issn><abstract>To identify functions of the IKKalpha subunit of IkappaB kinase that require catalytic activity, we generated an Ikkalpha(AA) knockin allele containing alanines instead of serines in the activation loop. Ikkalpha(AA/AA) mice are healthy and fertile, but females display a severe lactation defect due to impaired proliferation of mammary epithelial cells. IKKalpha activity is required for NF-kappaB activation in mammary epithelial cells during pregnancy and in response to RANK ligand but not TNFalpha. IKKalpha and NF-kappaB activation are also required for optimal cyclin D1 induction. Defective RANK signaling or cyclin D1 expression results in the same phenotypic effect as the Ikkalpha(AA) mutation, which is completely suppressed by a mammary specific cyclin D1 transgene. Thus, IKKalpha is a critical intermediate in a pathway that controls mammary epithelial proliferation in response to RANK signaling via cyclin D1.</abstract><cop>United States</cop><pmid>11747812</pmid><tpages>13</tpages></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Carrier Proteins - genetics Carrier Proteins - metabolism Caseins - genetics Caseins - metabolism Cells, Cultured Cyclin D1 - genetics Cyclin D1 - metabolism Epithelial Cells - metabolism Female Fibroblasts - drug effects Fibroblasts - metabolism Gene Expression Regulation Glycoproteins - genetics Glycoproteins - metabolism Humans I-kappa B Kinase Lactation - physiology Mammary Glands, Animal - cytology Mammary Glands, Animal - growth & development Mammary Glands, Animal - metabolism Mammary Glands, Animal - transplantation Membrane Glycoproteins - genetics Membrane Glycoproteins - metabolism Mice Mice, Transgenic NF-kappa B - metabolism Osteoprotegerin Pregnancy Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism RANK Ligand Receptor Activator of Nuclear Factor-kappa B Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - metabolism Receptors, Tumor Necrosis Factor Signal Transduction Tissue Transplantation Transgenes Tumor Necrosis Factor-alpha - pharmacology |
| title | IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development |
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