| First Author | Turnquist C | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 27 | Pages | 9834-9 |
| PubMed ID | 24958857 | Mgi Jnum | J:319036 |
| Mgi Id | MGI:6862434 | Doi | 10.1073/pnas.1407898111 |
| Citation | Turnquist C, et al. (2014) STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression. Proc Natl Acad Sci U S A 111(27):9834-9 |
| abstractText | 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-kappaB 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. |
