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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Available from: Robert J Rooney, Oct 07, 2015
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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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    ABSTRACT: The ANP32 family of proteins have been implicated in neuronal function through biochemical and cellular biology studies in neurons, as well as by recent behavioural studies of a gene-trapped loss-of-function mutation of Anp32e in mice, particularly with respect to fine motor function. A second targeted allele of the Anp32e, however, did not appear to demonstrate neurological phenotypes. Using a stringently controlled cohort of ten-generation backcrossed, co-caged, sex-matched, littermate pairs, we assayed for potential motor defects in the targeted ANP32E-deficient mice. We found no phenotypic difference in any assays. Since it is unlikely that the gene-trap is a more complete loss-of-function, our results suggest that ANP32E has no appreciable effect on motor functions and that genetic background differences most likely account for the gene-trap phenomena.
    PLoS ONE 05/2013; 8(5):e63815. DOI:10.1371/journal.pone.0063815 · 3.23 Impact Factor
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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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    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.
    EMBO Reports 05/2011; 12(5):428-35. DOI:10.1038/embor.2011.49 · 9.06 Impact Factor
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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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    ABSTRACT: The chemokine receptor CXCR4 and its endogenous ligand, CXCL12, are involved in development and homeostasis of the central nervous system and in the neuropathology of various neuroinflammatory/infectious disorders, including neuroAIDS. Our previous studies have shown that CXCR4 regulates cell cycle proteins that affect neuronal survival, such as the retinoblastoma protein, Rb. These studies also suggested that Rb-mediated gene repression might be involved in the neuronal protection against NMDA exitotoxicity conferred by stimulation of the CXCL12/CXCR4 axis. In order to further test this hypothesis, we focused on the potential interaction of Rb with another protein implicated in regulation of gene expression, leucine-rich acidic nuclear protein (Lanp), also known as ANP32A/pp32/PHAP1. Lanp is a critical member of the protein complex inhibitor of histone acetyl transferase (INHAT), which prevents histone tail's acetylation, thus leading to transcriptional repression. Our data show that, in primary rat cortical neurons cultured for up to 30 days, Lanp is predominantly localized into the nucleus throughout the culture period, in line with in vivo evidence. Moreover, co-immunoprecipitation experiments show that endogenous Lanp interacts with Rb in neurons. Stimulation of CXCR4 by its endogenous ligand, CXCL12, increased Lanp protein levels in these neurons. Importantly, the effect of CXCL12 was preserved after exposure of neurons to NMDA. Finally, overexpression of exogenous Lanp in the neurons protects them from excitotoxicity. Overall, these findings suggest that Lanp can interact with Rb in both young and mature neurons and is implicated in the regulation of neuronal survival by CXCL12/CXCR4. Electronic supplementary material The online version of this article (doi:10.1007/s11481-010-9228-5) contains supplementary material, which is available to authorized users.
    Journal of Neuroimmune Pharmacology 03/2011; 6(1):163-70. DOI:10.1007/s11481-010-9228-5 · 4.11 Impact Factor
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