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

Turnquist, C; Wang, Y; Severson, D T; Zhong, S; Sun, B; Ma, J; Constaninescu, S N; Ansorge, O; Stolp, H B; Molnár, Z; Szele, F G; Lu, X

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.

Citation

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. https://doi.org/10.1073/pnas.1407898111

• Journal Article Type: Article
• Acceptance Date: May 27, 2014
• Publication Date: Jul 8, 2014
• Deposit Date: Jul 13, 2018
• Journal: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Peer Reviewed: Peer Reviewed
• Volume: 111
• Issue: 27
• Pages: 9834-9
• DOI: https://doi.org/10.1073/pnas.1407898111
• Public URL: https://rvc-repository.worktribe.com/output/1405279