The role of LANP and ataxin 1 in E4F-mediated transcriptional repression

Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
EMBO Reports (Impact Factor: 9.06). 08/2007; 8(7):671-7. DOI: 10.1038/sj.embor.7400983
Source: PubMed


The leucine-rich acidic nuclear protein (LANP) belongs to the INHAT family of corepressors that inhibits histone acetyltransferases. The mechanism by which LANP restricts its repression to specific genes is unknown. Here, we report that LANP forms a complex with transcriptional repressor E4F and modulates its activity. As LANP interacts with ataxin 1--a protein mutated in the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1)--we tested whether ataxin 1 can alter the E4F-LANP interaction. We show that ataxin 1 relieves the transcriptional repression induced by the LANP-E4F complex by competing with E4F for LANP. These results provide the first functional link, to our knowledge, between LANP and ataxin 1, and indicate a potential mechanism for the transcriptional aberrations observed in SCA1.

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    • "These proteins have been ascribed a surprisingly diverse number of biochemical activities including inhibition of PP2A [8], [9], association with microtubules [3], [10], [11], apoptotic caspase inhibition [12]–[15], regulation of mRNA transport and stability [16]–[18], and control of gene transcription [19]–[24]. Whereas PP2A inhibition is most frequently reported as critical in ANP32-mediated neuronal regulation [2], [5], the regulation of transcriptional activity, potentially through E4F1, has also been suggested to mediate ANP32 neuronal effects [25], [26]. "
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    • "It also selectively forms protein complexes with histone deacetylase (HDAC) 3 and 4 (Tsai et al, 2004; Bolger et al, 2007). Additionally, ATXN1 interacts with various transcription factors, including Capicua, and cofactors such as LANP that are implicated in transcriptional repression (Lam et al, 2006; Riley & Orr, 2006; Cvetanovic et al, 2007). Our characterization of a protein related to ATXN1, Brother of ATXN1 (BOAT1; Mizutani et al, 2005), supports the idea that these proteins are involved in transcriptional repression. "
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    • "Recent studies in neuronal cells indicate that Lanp interacts with a transcriptional repressor, E4F, and enhances its activity, further supporting the nuclear role for Lanp in neurons (Cvetanovic et al. 2007). Moreover, in the context of neurodegenerative disorders, the mutated ataxin-1, which has been implicated in spinocerebellar ataxia type 1 (SCA1), is able to relieve Lanp-E4F gene repression by competing with Lanp for binding to E4F; these interactions might lead to SCA1 neuropatholgy in cerebellum (Cvetanovic et al. 2007). "
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