Receptor activator of NF-kappaB ligand regulates the proliferation of mammary epithelial cells via Id2.
Receptor activator of NF-kappaB ligand (RANKL) is a key regulator for mammary gland development during pregnancy. RANKL-deficient mice display impaired development of lobulo-alveolar mammary structures. Similar mammary gland defects have been reported in mice lacking Id2. Here we report that RANKL induces the proliferation of mammary epithelial cells via Id2. RANKL triggers marked nuclear translocation of Id2 in mammary epithelial cells. In vivo studies further demonstrated the defective nuclear translocation of Id2, but the normal expression of cyclin D1, in the mammary epithelial cells of rankl-/- mice. In vitro studies with nuclear localization sequence-tagged Id2 revealed that the nuclear localization of Id2 itself is critical for the downregulation of p21 promoter activity. Moreover, RANKL stimulation failed to induce cell growth and to downregulate p21 expression in Id2-/- mammary epithelial cells. Our results indicate that the inhibitor of helix-loop-helix protein, Id2, is critical to control the proliferation of mammary epithelial cells in response to RANKL stimulation.
Kim
Nam-Shik
NS
Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-783, Kyungbuk, South Korea.
Kim
Hyun-Ju
HJ
Koo
Bon-Kyoung
BK
Kwon
Min-Chul
MC
Kim
Young-Woong
YW
Cho
Yunje
Y
Yokota
Yoshifumi
Y
Penninger
Josef M
JM
Kong
Young-Yun
YY
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018257:Helix-Loop-Helix Motifs; D051797:Inhibitor of Differentiation Protein 2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008817:Mice, Mutant Strains; D011401:Promoter Regions, Genetic; D021381:Protein Transport / Q000187:drug effects; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry
D002352:Carrier Proteins; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D019938:Cyclin D1