title: A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland.
abstract: STAT3 is the key mediator of apoptosis in mammary gland. We demonstrate here that LIF is the physiological activator of STAT3, because in involuting mammary glands of Lif(-/-) mice, pSTAT3 is absent and the STAT3 target, C/EBPdelta, is not upregulated. Similar to Stat3 knockouts, Lif(-/-) mammary glands exhibit delayed involution, reduced apoptosis and elevated levels of p53. Significantly, Lif(-/-) glands display precocious development during pregnancy, when pSTAT3 is not normally detected. We show that pERK1/2 is significantly reduced in Lif(-/-) glands at this time, suggesting that at this stage LIF mediates its effects through pERK1/2. Inhibition of LIF-mediated ERK1/2 phosphorylation potentiates the proapoptotic effects of STAT3. LIF therefore signals alternately through ERK1/2, then STAT3, to regulate mammary growth and apoptosis.
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Ekaterini A
authors.initials: EA
authors.lastname: Kritikou
authors.forename: Andrew
authors.initials: A
authors.lastname: Sharkey
authors.forename: Kathrine
authors.initials: K
authors.lastname: Abell
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Came
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anderson
authors.forename: Richard W E
authors.initials: RW
authors.lastname: Clarkson
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Watson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002070:Butadienes / Q000494:pharmacology; D002364:Caseins / Q000096:biosynthesis / Q000235:genetics; D058966:Contactins; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048369:MAP Kinase Kinase 1; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D008894:Milk Proteins; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D019006:Neural Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000235:genetics; D053606:Receptors, OSM-LIF; D011980:Receptors, Progesterone / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D002070:Butadienes; D002364:Caseins; D058966:Contactins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D008222:Lymphokines; D008894:Milk Proteins; D019006:Neural Cell Adhesion Molecules; D009570:Nitriles; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D011980:Receptors, Progesterone; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C113580:U 0126; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases