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Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer (2010)

D. Schramek ; A. Leibbrandt ; V. Sigl ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 468(7320): 98-102. doi: 10.1038/nature09387.

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Publication Date: 2010-10-01

Description: Breast cancer is one of the most common cancers in humans and will on average affect up to one in eight women in their lifetime in the United States and Europe. The Women's Health Initiative and the Million Women Study have shown that hormone replacement therapy is associated with an increased risk of incident and fatal breast cancer. In particular, synthetic progesterone derivatives (progestins) such as medroxyprogesterone acetate (MPA), used in millions of women for hormone replacement therapy and contraceptives, markedly increase the risk of developing breast cancer. Here we show that the in vivo administration of MPA triggers massive induction of the key osteoclast differentiation factor RANKL (receptor activator of NF-kappaB ligand) in mammary-gland epithelial cells. Genetic inactivation of the RANKL receptor RANK in mammary-gland epithelial cells prevents MPA-induced epithelial proliferation, impairs expansion of the CD49f(hi) stem-cell-enriched population, and sensitizes these cells to DNA-damage-induced cell death. Deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. These data show that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084017/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084017/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schramek, Daniel -- Leibbrandt, Andreas -- Sigl, Verena -- Kenner, Lukas -- Pospisilik, John A -- Lee, Heather J -- Hanada, Reiko -- Joshi, Purna A -- Aliprantis, Antonios -- Glimcher, Laurie -- Pasparakis, Manolis -- Khokha, Rama -- Ormandy, Christopher J -- Widschwendter, Martin -- Schett, Georg -- Penninger, Josef M -- HD055601/HD/NICHD NIH HHS/ -- R01 HD055601/HD/NICHD NIH HHS/ -- R01 HD055601-04/HD/NICHD NIH HHS/ -- England -- Nature. 2010 Nov 4;468(7320):98-102. doi: 10.1038/nature09387. Epub 2010 Sep 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20881962" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Apoptosis/radiation effects ; Cell Differentiation ; Cell Proliferation/drug effects ; DNA Damage ; Epithelial Cells/cytology/drug effects/metabolism/radiation effects ; Female ; Gamma Rays ; Integrin alpha6/metabolism ; Mammary Neoplasms, Experimental/*chemically ; induced/genetics/metabolism/*pathology ; Medroxyprogesterone Acetate/administration & dosage/adverse effects ; Mice ; NF-kappa B/metabolism ; Osteoclasts/cytology ; Phosphoproteins/analysis/immunology ; Progestins/administration & dosage/*adverse effects ; RANK Ligand/deficiency/genetics/*metabolism ; Receptor Activator of Nuclear Factor-kappa B/deficiency/genetics/metabolism ; Signal Transduction ; Stem Cells/cytology/drug effects/metabolism

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

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SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis (2011)

F. Ikeda ; Y. L. Deribe ; S. S. Skanland ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 471(7340): 637-41. doi: 10.1038/nature09814.

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Publication Date: 2011-04-02

Description: SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-kappaB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IkappaB kinases (IKKs) and subsequent activation of NF-kappaB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-kappaB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor alpha (TNF-alpha) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-kappaB and inhibits apoptosis via distinct pathways in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085511/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085511/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ikeda, Fumiyo -- Deribe, Yonathan Lissanu -- Skanland, Sigrid S -- Stieglitz, Benjamin -- Grabbe, Caroline -- Franz-Wachtel, Mirita -- van Wijk, Sjoerd J L -- Goswami, Panchali -- Nagy, Vanja -- Terzic, Janos -- Tokunaga, Fuminori -- Androulidaki, Ariadne -- Nakagawa, Tomoko -- Pasparakis, Manolis -- Iwai, Kazuhiro -- Sundberg, John P -- Schaefer, Liliana -- Rittinger, Katrin -- Macek, Boris -- Dikic, Ivan -- AR049288/AR/NIAMS NIH HHS/ -- MC_U117565398/Medical Research Council/United Kingdom -- R01 AR049288/AR/NIAMS NIH HHS/ -- R01 AR049288-07/AR/NIAMS NIH HHS/ -- England -- Nature. 2011 Mar 31;471(7340):637-41. doi: 10.1038/nature09814.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Frankfurt Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt, Main, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21455181" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; *Apoptosis/drug effects ; B-Lymphocytes/metabolism ; Carrier Proteins/metabolism ; Caspase 8/metabolism ; Cells, Cultured ; Dermatitis/genetics/metabolism/pathology ; Fas-Associated Death Domain Protein/metabolism ; Fibroblasts/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; I-kappa B Kinase/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Macrophages/metabolism ; Mice ; NF-kappa B/*metabolism ; Nerve Tissue Proteins/deficiency/genetics/*metabolism ; Tumor Necrosis Factor-alpha/metabolism/pharmacology ; Ubiquitin/*metabolism ; Ubiquitin-Protein Ligase Complexes/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination

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Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

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FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation (2011)

P. S. Welz ; A. Wullaert ; K. Vlantis ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 477(7364): 330-4. doi: 10.1038/nature10273.

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Publication Date: 2011-08-02

Description: Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Welz, Patrick-Simon -- Wullaert, Andy -- Vlantis, Katerina -- Kondylis, Vangelis -- Fernandez-Majada, Vanesa -- Ermolaeva, Maria -- Kirsch, Petra -- Sterner-Kock, Anja -- van Loo, Geert -- Pasparakis, Manolis -- England -- Nature. 2011 Jul 31;477(7364):330-4. doi: 10.1038/nature10273.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Genetics, Centre for Molecular Medicine, University of Cologne, Zulpicher Str. 47a, 50674 Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21804564" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Apoptosis ; Chronic Disease ; Colitis/enzymology/metabolism/*pathology ; Colon/enzymology/metabolism/*pathology ; Cysteine Endopeptidases/metabolism ; Enteritis/enzymology/metabolism/*pathology ; Epithelial Cells/enzymology/metabolism/*pathology ; Fas-Associated Death Domain Protein/deficiency/*metabolism ; Inflammatory Bowel Diseases/enzymology/metabolism/pathology ; Intracellular Signaling Peptides and Proteins/deficiency/metabolism ; Metagenome/physiology ; Mice ; Myeloid Differentiation Factor 88/deficiency/metabolism ; Necrosis ; Paneth Cells/pathology ; Receptor-Interacting Protein Serine-Threonine Kinases/*antagonists & ; inhibitors/*metabolism ; Signal Transduction ; Tumor Necrosis Factors/deficiency

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Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

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RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis (2014)

M. Dannappel ; K. Vlantis ; S. Kumari ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 513(7516): 90-4. doi: 10.1038/nature13608.

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Publication Date: 2014-08-19

Description: Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206266/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dannappel, Marius -- Vlantis, Katerina -- Kumari, Snehlata -- Polykratis, Apostolos -- Kim, Chun -- Wachsmuth, Laurens -- Eftychi, Christina -- Lin, Juan -- Corona, Teresa -- Hermance, Nicole -- Zelic, Matija -- Kirsch, Petra -- Basic, Marijana -- Bleich, Andre -- Kelliher, Michelle -- Pasparakis, Manolis -- R01 AI075118/AI/NIAID NIH HHS/ -- R01AI075118/AI/NIAID NIH HHS/ -- T32 AI095213/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Sep 4;513(7516):90-4. doi: 10.1038/nature13608. Epub 2014 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany [2]. ; Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. ; Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; Tierforschungszentrum, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany. ; Institute for Laboratory Animal Science, Hannover Medical School, D-30625 Hannover, Germany. ; 1] Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25132550" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; *Apoptosis ; Caspase 8/metabolism ; Cell Survival ; Epithelial Cells/*cytology/metabolism/*pathology ; Fas-Associated Death Domain Protein/deficiency/metabolism ; Female ; *Homeostasis ; Inflammation/metabolism/pathology ; Intestines/cytology/metabolism/pathology ; Keratinocytes/metabolism/pathology ; Male ; Mice ; Mice, Knockout ; Myeloid Differentiation Factor 88/metabolism ; *Necrosis ; Paneth Cells/metabolism/pathology ; Receptor-Interacting Protein Serine-Threonine ; Kinases/deficiency/genetics/*metabolism ; Receptors, Tumor Necrosis Factor, Type I/deficiency/metabolism ; Skin/cytology/metabolism/pathology

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Necroptosis and its role in inflammation (2015)

M. Pasparakis ; P. Vandenabeele

Nature Publishing Group (NPG)

In: Nature. 517(7534): 311-20. doi: 10.1038/nature14191.

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Publication Date: 2015-01-17

Description: Regulated cell death has essential functions in development and in adult tissue homeostasis. Necroptosis is a newly discovered pathway of regulated necrosis that requires the proteins RIPK3 and MLKL and is induced by death receptors, interferons, toll-like receptors, intracellular RNA and DNA sensors, and probably other mediators. RIPK1 has important kinase-dependent and scaffolding functions that inhibit or trigger necroptosis and apoptosis. Mouse-model studies have revealed important functions for necroptosis in inflammation and suggested that it could be implicated in the pathogenesis of many human inflammatory diseases. We discuss the mechanisms regulating necroptosis and its potential role in inflammation and disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pasparakis, Manolis -- Vandenabeele, Peter -- England -- Nature. 2015 Jan 15;517(7534):311-20. doi: 10.1038/nature14191.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Genetics, Centre for Molecular Medicine and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany. ; 1] VIB Inflammation Research Center, Ghent University, UGhent-VIB Research Building FSVM, 9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium. [3] Methusalem program, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25592536" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Apoptosis ; Cell Survival ; Disease ; Humans ; Inflammation/genetics/metabolism/*pathology ; Necrosis/genetics/metabolism/*pathology ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism

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Electronic Resource

Erratum to “Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis” (1999)

Moore, R.J. ; Owens, D.M. ; Stamp, G. ; [et al.]

[s.l.] : Nature America Inc.

Nature medicine 5 (1999), S. 1087-1087

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ISSN: 1546-170X

Source: Nature Archives 1869 - 2009

Topics: Biology , Medicine

Notes: [Auszug] Nature Med. 5, 828– 831 (1999). On page 829, the legend for Fig 1 was incorrect. The corrected figure and legend are shown here. We regret this ...

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1038/12532

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