title: STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression.
abstract: Inflammation and loss of cell polarity play pivotal roles in neurodegeneration and cancer. A central question in both diseases is how the loss of cell polarity is sensed by cell death machinery. Here, we identify apoptosis-stimulating protein of p53 with signature sequences of ankyrin repeat-, SH3 domain-, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, activator of p53, and regulator of cell polarity, as a transcriptional target of signal transducer and activator of transcription 1 (STAT1). LPS induces ASPP2 expression in murine macrophage and microglial cell lines, a human monocyte cell line, and primary human astrocytes in vitro. LPS and IFNs induce ASPP2 transcription through an NF-κB RELA/p65-independent but STAT1-dependent pathway. In an LPS-induced maternal inflammation mouse model, LPS induces nuclear ASPP2 in vivo at the blood-cerebral spinal fluid barrier (the brain's barrier to inflammation), and ASPP2 mediates LPS-induced apoptosis. Consistent with the role of ASPP2 as a gatekeeper to inflammation, ASPP2-deficient brains possess enhanced neuroinflammation. Elevated ASPP2 expression is also observed in mouse models and human neuroinflammatory disease tissue, where ASPP2 was detected in GFAP-expressing reactive astrocytes that coexpress STAT1. Because the ability of ASPP2 to maintain cellular polarity is vital to CNS development, our findings suggest that the identified STAT1/ASPP2 pathway may connect tumor suppression and cell polarity to neuroinflammation.
authors: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine and.
authors: Casmir
authors: C
authors: Turnquist
authors: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine and.
authors: Yihua
authors: Y
authors: Wang
authors: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine and.
authors: David T
authors: DT
authors: Severson
authors: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine and.
authors: Shan
authors: S
authors: Zhong
authors: Departments of Physiology, Anatomy and Genetics and.
authors: Bin
authors: B
authors: Sun
authors: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine and.
authors: Jingyi
authors: J
authors: Ma
authors: Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, 1200 Brussels, Belgium.
authors: Stefan N
authors: SN
authors: Constaninescu
authors: Neuropathology, University of Oxford, Oxford OX3 7DQ, United Kingdom; and.
authors: Olaf
authors: O
authors: Ansorge
authors: Departments of Physiology, Anatomy and Genetics and.
authors: Helen B
authors: HB
authors: Stolp
authors: Departments of Physiology, Anatomy and Genetics and.
authors: Zoltán
authors: Z
authors: Molnár
authors: Departments of Physiology, Anatomy and Genetics and.
authors: Francis G
authors: FG
authors: Szele
authors: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine and Xin.Lu@ludwig.ox.ac.uk.
authors: Xin
authors: X
authors: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D016764:Cell Polarity; D004660:Encephalitis / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000517:prevention & control*; D050794:STAT1 Transcription Factor / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C511437:Trp53bp2 protein, mouse; D025521:Tumor Suppressor Proteins
keywords: TLR4; TP53BP2; multiple sclerosis