A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland.
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.
Kritikou
Ekaterini A
EA
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
Sharkey
Andrew
A
Abell
Kathrine
K
Came
Paul J
PJ
Anderson
Elizabeth
E
Clarkson
Richard W E
RW
Watson
Christine J
CJ
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*
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