title: Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling.
abstract: Despite a wealth of knowledge about the significance of individual signal transducers and activators of transcription (STATs), essential functions of their upstream Janus kinases (JAKs) during postnatal development are less well defined. Using a novel mammary gland-specific JAK1 knockout model, we demonstrate here that this tyrosine kinase is essential for the activation of STAT1, STAT3, and STAT6 in the mammary epithelium. The loss of JAK1 uncouples interleukin-6-class ligands from their downstream effector, STAT3, which leads to the decreased expression of STAT3 target genes that are associated with the acute-phase response, inflammation, and wound healing. Consequently, JAK1-deficient mice exhibit impaired apoptosis and a significant delay in mammary gland remodeling. Using RNA sequencing, we identified several new JAK1 target genes that are upregulated during involution. These include Bmf and Bim, which are known regulators of programmed cell death. Using a BMF/BIM-double-knockout epithelial transplant model, we further validated that the synergistic action of these proapoptotic JAK1 targets is obligatory for the remodeling of the mammary epithelium. The collective results of this study suggest that JAK1 has nonredundant roles in the activation of particular STAT proteins and this tyrosine kinase is essential for coupling inflammatory cytokine signals to the cell death machinery in the differentiated mammary epithelium.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Wehde
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kyung Hyun
authors.initials: KH
authors.lastname: Yoo
authors.affiliation: Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Republic of Korea.
authors.forename: Taemook
authors.initials: T
authors.lastname: Kim
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Nirakar
authors.initials: N
authors.lastname: Rajbhandari
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ha Youn
authors.initials: HY
authors.lastname: Shin
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Aleata A
authors.initials: AA
authors.lastname: Triplett
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Rädler
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, and Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: Fabian
authors.initials: F
authors.lastname: Schuler
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, and Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.affiliation: Department of Microbiology, Dankook University, Cheonan, Republic of Korea.
authors.forename: Keunsoo
authors.initials: K
authors.lastname: Kang
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA kuwagner@unmc.edu.
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D053613:Janus Kinase 1 / Q000235:genetics* / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000276:immunology / Q000473:pathology*; D051379:Mice; D050791:STAT Transcription Factors / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000235:genetics; D017423:Sequence Analysis, RNA / Q000379:methods*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D016207:Cytokines; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1