Ataxin‐1 and Brother of ataxin‐1 are components of the Notch signalling pathway

Abstract

Ataxin-1 (ATXN1), a causative factor for spinocerebellar ataxia type 1 (SCA1), and the related Brother of ATXN1 (BOAT1) are human proteins involved in transcriptional repression. So far, little is known about which transcriptional pathways mediate the effects of ATXN1 and BOAT1. From our analyses of the properties of BOAT1 in Drosophila and of both proteins in mammalian cells, we report here that BOAT1 and ATXN1 are components of the Notch signalling pathway. In Drosophila, BOAT1 compromises the activities of Notch. In mammalian cells, both ATXN1 and BOAT1 bind to the promoter region of Hey1 and inhibit the transcriptional output of Notch through direct interactions with CBF1, a transcription factor that is crucial for the Notch pathway. Our results suggest that, in addition to their involvement in SCA1, ATXN1 and BOAT1 might participate in several Notch-controlled developmental and pathological processes.

An Out-of-frame Overlapping Reading Frame in the Ataxin-1 Coding Sequence Encodes a Novel Ataxin-1 Interacting Protein

“…From such studies, it is clear that ATXN1 associates with large protein complexes and interacts with a vast network of proteins (12,14,30). Current knowledge indicates that ATXN1 may be involved in transcriptional repression and regulate Notch-and Capicua-controlled developmental processes (12,(31)(32)(33). Here we add Alt-ATXN1 as a novel ATXN1 protein interactor in the nucleus.…”

“…ATXN1 also stimulates ␤-secretase processing of ␤-amyloid precursor protein (11). ATXN1 binds RNA and several transcription factors, and there is evidence that ATXN1 is involved in transcriptional regulation (7,12,13). ATXN1 genetically and physically interacts with many proteins, and further studies are required to use these data to elucidate the biological function of ATXN1 (14).…”

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

“…Such findings underscore the importance of regulation of the expression and accumulation level of these proteins. Many other important studies have been performed on the Ataxin-1 protein, integrating fly with mammalian studies to gain important functional insight (Tsuda et al 2005;Lam et al 2006;Tong et al 2011).…”

The transcriptional corepressor SMRTER influences both Notch and ecdysone signaling during Drosophila development

“…In addition, our lab has recently identified ATXN1 and the related BOAT1 as a new class of CBF1 corepressors (Tong et al, 2011). Based on these findings, CBF1 likely requires inputs from multiple transcriptional corepressors in tandem to repress gene transcription.…”

“…Many of these factors are dedicated transcriptional repressors or corepressors implicated in various human disorders, including leukemia, lymphoma and neurodegeneration. Intriguingly, several of these SMRT/N-CoR associating factors are also functionally connected with the Notch pathway (Kao et al, 1998;Doroquez et al, 2007;Salat et al, 2008;Tong et al, 2011), raising the possibility that SMRT, N-CoR and some of their associating factors may converge in regulating the Notch pathway.…”