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

Publication ,  Journal Article
Turnquist, C; Wang, Y; Severson, DT; Zhong, S; Sun, B; Ma, J; Constaninescu, SN; Ansorge, O; Stolp, HB; Molnár, Z; Szele, FG; Lu, X
Published in: Proceedings of the National Academy of Sciences of the United States of America
July 2014

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.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

July 2014

Volume

111

Issue

27

Start / End Page

9834 / 9839

Related Subject Headings

  • Tumor Suppressor Proteins
  • Transcription, Genetic
  • STAT1 Transcription Factor
  • Neoplasms, Experimental
  • Mice
  • Humans
  • Gene Expression Regulation
  • Encephalitis
  • Cell Polarity
  • Astrocytes
 

Citation

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Turnquist, C., Wang, Y., Severson, D. T., Zhong, S., Sun, B., Ma, J., … Lu, X. (2014). STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression. Proceedings of the National Academy of Sciences of the United States of America, 111(27), 9834–9839. https://doi.org/10.1073/pnas.1407898111
Turnquist, Casmir, Yihua Wang, David T. Severson, Shan Zhong, Bin Sun, Jingyi Ma, Stefan N. Constaninescu, et al. “STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression.Proceedings of the National Academy of Sciences of the United States of America 111, no. 27 (July 2014): 9834–39. https://doi.org/10.1073/pnas.1407898111.
Turnquist C, Wang Y, Severson DT, Zhong S, Sun B, Ma J, et al. STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression. Proceedings of the National Academy of Sciences of the United States of America. 2014 Jul;111(27):9834–9.
Turnquist, Casmir, et al. “STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression.Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 27, July 2014, pp. 9834–39. Epmc, doi:10.1073/pnas.1407898111.
Turnquist C, Wang Y, Severson DT, Zhong S, Sun B, Ma J, Constaninescu SN, Ansorge O, Stolp HB, Molnár Z, Szele FG, Lu X. STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression. Proceedings of the National Academy of Sciences of the United States of America. 2014 Jul;111(27):9834–9839.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

July 2014

Volume

111

Issue

27

Start / End Page

9834 / 9839

Related Subject Headings

  • Tumor Suppressor Proteins
  • Transcription, Genetic
  • STAT1 Transcription Factor
  • Neoplasms, Experimental
  • Mice
  • Humans
  • Gene Expression Regulation
  • Encephalitis
  • Cell Polarity
  • Astrocytes