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STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression

STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression
STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression
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-?B 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.
TP53BP2, TLR4, multiple sclerosis
0027-8424
9834-9839
Turnquist, Casmir
b186b838-ec0f-48f7-8ec3-ed9a56adb592
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Severson, David T.
794a2ca8-7ccd-43df-9847-e2cf2ab1254b
Zhong, Shan
6d0d5d48-c69b-444d-acae-fd7a3fd76e23
Sun, Bin
f6c4e5d2-7d87-4c0f-aa66-53112f7ed6da
Ma, Jingyi
9a053e9a-3903-4517-a363-f41f1814e6a6
Constantinescu, Stefan N.
78e5c0ac-ff4f-488b-a5f5-cf74e418184a
Ansorge, Olaf
041480a0-6ac5-4878-9dc3-f875e48db7c0
Stolp, Helen B.
dd5f6f1c-f6cd-4cf2-a3d3-3535dce5e55d
Molnár, Zoltán
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Szele, Francis G.
7551db5f-3ce9-408c-83a5-ab14647bba8d
Lu, Xin
a681bac0-d6d1-4e8e-a642-4ce42ae2cc9d
Turnquist, Casmir
b186b838-ec0f-48f7-8ec3-ed9a56adb592
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Severson, David T.
794a2ca8-7ccd-43df-9847-e2cf2ab1254b
Zhong, Shan
6d0d5d48-c69b-444d-acae-fd7a3fd76e23
Sun, Bin
f6c4e5d2-7d87-4c0f-aa66-53112f7ed6da
Ma, Jingyi
9a053e9a-3903-4517-a363-f41f1814e6a6
Constantinescu, Stefan N.
78e5c0ac-ff4f-488b-a5f5-cf74e418184a
Ansorge, Olaf
041480a0-6ac5-4878-9dc3-f875e48db7c0
Stolp, Helen B.
dd5f6f1c-f6cd-4cf2-a3d3-3535dce5e55d
Molnár, Zoltán
9b15b8da-6939-43c6-946f-6c7f213baaf7
Szele, Francis G.
7551db5f-3ce9-408c-83a5-ab14647bba8d
Lu, Xin
a681bac0-d6d1-4e8e-a642-4ce42ae2cc9d

Turnquist, Casmir, Wang, Yihua, Severson, David T., Zhong, Shan, Sun, Bin, Ma, Jingyi, Constantinescu, Stefan N., Ansorge, Olaf, Stolp, Helen B., Molnár, Zoltán, Szele, Francis G. and Lu, Xin (2014) STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression. Proceedings of the National Academy of Sciences, 111 (27), 9834-9839. (doi:10.1073/pnas.1407898111).

Record type: Article

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-?B 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.

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Accepted/In Press date: 27 May 2014
e-pub ahead of print date: 23 June 2014
Published date: 8 July 2014
Keywords: TP53BP2, TLR4, multiple sclerosis
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 385899
URI: http://eprints.soton.ac.uk/id/eprint/385899
ISSN: 0027-8424
PURE UUID: 7ad565e2-e6db-40f1-94ad-95a7ccadedfb
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

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Date deposited: 26 Jan 2016 09:04
Last modified: 26 Nov 2019 01:32

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Contributors

Author: Casmir Turnquist
Author: Yihua Wang ORCID iD
Author: David T. Severson
Author: Shan Zhong
Author: Bin Sun
Author: Jingyi Ma
Author: Stefan N. Constantinescu
Author: Olaf Ansorge
Author: Helen B. Stolp
Author: Zoltán Molnár
Author: Francis G. Szele
Author: Xin Lu

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