A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland

Kritikou, Ekaterini A.; Sharkey, Andrew; Abell, Kathrine; Came, Paul J.; Anderson, Elizabeth; Clarkson, Richard W. E.; Watson, Christine J.

doi:10.1242/dev.00578

Cited by 182 publications

(189 citation statements)

References 41 publications

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“…STAT3 activity was suppressed despite the induction of LIF expression in Nucling-KO glands. Previous studies reported that, LIF activated STAT3 via gp130, which is normally up-regulated after weaning to activate STAT3 (5,6,38). Our results indicated that the loss of Nucling inhibited the gene expression of gp130.…”

Section: Discussionsupporting

confidence: 55%

Nucling, a Novel Apoptosis-associated Protein, Controls Mammary Gland Involution by Regulating NF-κB and STAT3

Dang

Sakai²,

Pham

et al. 2015

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 55%

Nucling, a Novel Apoptosis-associated Protein, Controls Mammary Gland Involution by Regulating NF-κB and STAT3

Dang

Sakai²,

Pham

et al. 2015

Journal of Biological Chemistry

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“…LIF and OSM are two IL-6-class inflammatory cytokines that have been shown to control mammary gland remodeling through activation of STAT3 (8,9). These cytokines signal through specific ligand-receptor complexes that share the glycoprotein 130 (gp130) signal transduction subunit, which is essential for STAT3 activation in the involuting gland (41).…”

Section: Jak1mentioning

confidence: 99%

“…Following lactation and the weaning of the young, circulating levels of prolactin (PRL) decline and milk stasis induces the local production of interleukin-6 (IL-6)-class cytokines, in particular, IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM). These IL-6-class cytokines trigger a cascade of intracellular events that orchestrate a process known as mammary gland remodeling, which entails the death and selective removal of terminally differentiated alveolar cells (7)(8)(9).…”

mentioning

confidence: 99%

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Sakamoto

Wehde

Yoo

et al. 2016

Molecular and Cellular Biology

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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 acutephase 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/BIMdouble-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.T he postnatal growth, functional differentiation, and postlactational remodeling of the epithelial compartment of the mammary gland are controlled by hormones and locally synthesized cytokines (1). While estrogen is primarily required for the elongation of mammary ducts after the onset of puberty (2, 3), progesterone and prolactin orchestrate the specification, proliferation, and differentiation of secretory alveolar cells during pregnancy (4-6). Following lactation and the weaning of the young, circulating levels of prolactin (PRL) decline and milk stasis induces the local production of interleukin-6 (IL-6)-class cytokines, in particular, IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM). These IL-6-class cytokines trigger a cascade of intracellular events that orchestrate a process known as mammary gland remodeling, which entails the death and selective removal of terminally differentiated alveolar cells (7-9).PRL and IL-6-class cytokines signal through their corresponding receptors and utilize Janus kinases (JAKs) to activate downstream signal transducers and activators of transcription (STATs) that subsequently alter the transcriptional profile, growth, and homeostasis of mammary epithelial cells. Five of the seven STAT proteins that are known in mammals (i.e., STAT1, STAT3, STAT5a, STAT5b, and STAT6) have been found to be sequentially activated at defined stages of mammary gland development (10, 11). The levels of phosphorylated STAT1 have been reported to be elevated in nulliparous females, but this particular transcription factor seems to be largely dispensable for normal ma...

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“…interferon-␤ in primary murine pro-B cells (22), and that deletion of Stat3 in mammary gland epithelial cells led to the delay of involution due to the reduction of apoptosis (23) suggest that Stat3 plays a more complicated role in the regulation of cell survival and proliferation. Previously, we generated mutant mice in which Stat3 was ablated specifically in the hematopoietic cell lineage using btie2-cre mice (Stat3 f/f /btie2-cre) (24,25).…”

mentioning

confidence: 99%

Negative Regulation of Stat3 by Activating PTPN11 Mutants Contributes to the Pathogenesis of Noonan Syndrome and Juvenile Myelomonocytic Leukemia

Zhang

Chan²,

Chen³

et al. 2009

Journal of Biological Chemistry

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Noonan syndrome (NS) is an autosomal dominant congenital disorder characterized by multiple birth defects including heart defects and myeloproliferative disease (MPD). Approximately 50% of NS patients have germline gain-of-function mutations in PTPN11, which encodes the protein-tyrosine phosphatase, Shp2. We provide evidence that conditional ablation of Stat3 in hematopoietic cells and cardiac valvular tissues leads to myeloid progenitor hyperplasia and pulmonary stenosis due to the leaflet thickening, respectively. Consistently, STAT3 activation is significantly compromised in peripheral blood cells from NS patients bearing Shp2-activating mutations. Biochemical and functional analyses demonstrate that activated Shp2 is able to down-regulate Tyr(P)-Stat3 and that constitutively active Stat3 rescues activating mutant Shp2-induced granulocyte-macrophage colony-stimulating factor hypersensitivity in bone marrow cells. Collectively, our work demonstrates that Stat3 is an essential signaling component potentially contributing to the pathogenesis of NS and juvenile myelomonocytic leukemia caused by PTPN11 gain-of-function mutations.

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A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland

Cited by 182 publications

References 41 publications

Nucling, a Novel Apoptosis-associated Protein, Controls Mammary Gland Involution by Regulating NF-κB and STAT3

Nucling, a Novel Apoptosis-associated Protein, Controls Mammary Gland Involution by Regulating NF-κB and STAT3

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Negative Regulation of Stat3 by Activating PTPN11 Mutants Contributes to the Pathogenesis of Noonan Syndrome and Juvenile Myelomonocytic Leukemia

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