Gene name - capicua
Cytological map position - 92D1-2
Function - transcription factor
Symbol - cic
FlyBase ID: FBgn0262582
Genetic map position -
Classification - HMG box protein
Cellular location - nuclear
|Recent literature||Futran, A. S., Kyin, S., Shvartsman, S. Y. and Link, A. J. (2015). Mapping the binding interface of ERK and transcriptional repressor Capicua using photocrosslinking. Proc Natl Acad Sci U S A 112: 8590-8595. PubMed ID: 26124095
Extracellular signal-regulated kinase (ERK; Rolled in Drosophila) coordinates cellular responses to a range of stimuli by phosphorylating its numerous substrates. One of these substrates, Capicua (Cic), is a transcriptional repressor that was first identified in Drosophila and has been implicated in a number of human diseases. This study used a chemical biology approach to map the binding interface of ERK and Cic. The noncanonical amino acid p-azidophenylalanine (AzF) was introduced into the ERK-binding region of Drosophila Cic, and photocrosslinking and tandem mass spectrometry were used to pinpoint its binding site on ERK. The ERK-binding region of human Cic was also identified, and it was shown to bind to the same site on ERK despite lacking conservation with the Drosophila Cic binding region. Finally, the amino acids involved in human Cic binding to ERK were mapped using AzF-labeled ERK. These results reveal the molecular details of the ERK-Cic interaction and demonstrate that the photocrosslinking approach is complementary to existing methods for mapping kinase-substrate binding interfaces.
|Jin, Y., Ha, N., Fores, M., Xiang, J., Glasser, C., Maldera, J., Jimenez, G. and Edgar, B. A. (2015). EGFR/Ras signaling controls Drosophila intestinal stem cell proliferation via Capicua-regulated genes. PLoS Genet 11: e1005634. PubMed ID: 26683696
Epithelial renewal in the Drosophila intestine is orchestrated by Intestinal Stem Cells (ISCs). Following damage or stress the intestinal epithelium produces ligands that activate the epidermal growth factor receptor (EGFR) in ISCs. This promotes their growth and division and, thereby, epithelial regeneration. This study demonstrates that the HMG-box transcriptional repressor, Capicua (Cic), mediates these functions of EGFR signaling. Depleting Cic in ISCs activated them for division, whereas overexpressed Cic inhibited ISC proliferation and midgut regeneration. Epistasis tests showed that Cic acted as an essential downstream effector of EGFR/Ras signaling, and immunofluorescence showed that Cic's nuclear localization was regulated by EGFR signaling. ISC-specific mRNA expression profiling and DNA binding mapping using DamID indicated that Cic represses cell proliferation via direct targets including string (Cdc25), Cyclin E, and the ETS domain transcription factors Ets21C and Pointed (pnt). pnt was required for ISC over-proliferation following Cic depletion, and ectopic pnt restored ISC proliferation even in the presence of overexpressed dominant-active Cic. These studies identify Cic, Pnt, and Ets21C as critical downstream effectors of EGFR signaling in Drosophila ISCs.
|Fores, M., Simon-Carrasco, L., Ajuria, L., Samper, N., Gonzalez-Crespo, S., Drosten, M., Barbacid, M. and Jimenez, G. (2017). A new mode of DNA binding distinguishes Capicua from other HMG-box factors and explains its mutation patterns in cancer. PLoS Genet 13(3): e1006622. PubMed ID: 28278156
HMG-box proteins, including Sox/SRY (Sox) and TCF/LEF1 (TCF) family members, bind DNA via their HMG-box. This study reports that Capicua (CIC), an HMG-box transcriptional repressor involved in Ras/MAPK signaling and cancer progression, employs an additional distinct mode of DNA binding that enables selective recognition of its targets. Contrary to previous assumptions, the HMG-box of CIC does not bind DNA alone but instead requires a distant motif (referred to as C1) present at the C-terminus of all CIC proteins. The HMG-box and C1 domains are both necessary for binding specific TGAATGAA-like sites, do not function via dimerization, and are active in the absence of cofactors, suggesting that they form a bipartite structure for sequence-specific binding to DNA. This binding mechanism operates throughout Drosophila development and in human cells, ensuring specific regulation of multiple CIC targets. It thus appears that HMG-box proteins generally depend on auxiliary DNA binding mechanisms for regulating their appropriate genomic targets, but that each sub-family has evolved unique strategies for this purpose. Finally, the key role of C1 in DNA binding also explains the fact that this domain is a hotspot for inactivating mutations in oligodendroglioma and other tumors.
|Goyal, Y., Levario, T. J., Mattingly, H. H., Holmes, S., Shvartsman, S. Y. and Lu, H. (2017). Parallel imaging of Drosophila embryos for quantitative analysis of genetic perturbations of the Ras pathway. Dis Model Mech [Epub ahead of print]. PubMed ID: 28495673
The Ras pathway patterns the poles of the Drosophila embryo by downregulating the levels and activity of a DNA-binding transcriptional repressor Capicua (Cic). This study demonstrates that the spatiotemporal pattern of Cic during this signaling event can be harnessed for functional studies of the Ras-pathway mutations from human diseases. The approach relies on a new microfluidic device that enables parallel imaging of Cic dynamics in dozens of live embryos. Although the pattern of Cic in early embryos is complex, it can be accurately approximated by a product of one spatial profile and one time-dependent amplitude. Analysis of these functions of space and time alone reveals the differential effects of mutations within the Ras pathway. Given the highly-conserved nature of Ras-dependent control of Cic, this approach opens a new way for functional analysis of multiple sequence variants from developmental abnormalities and cancers.
capicua (cic), meaning head-and-tail in Catalan, acts as a repressor of tailless (tll) and huckebein (hkb) in both the anterior and posterior domains of the early Drosophila embryo. Torso signaling acts to relieve repression of the tll and hkb Capicua-directed repression. In addition, cic mediates ventral repression of the dorsally expressed gene zerknullt (zen), a process that also requires Groucho and the transcripton factor Dorsal, and which is also inhibited by Torso signaling at the embryonic termini. cic encodes a putative transcription factor with a DNA-binding domain of the HMG box class. The Cic protein interacts with Gro in vitro, suggesting that both factors function in the same protein complex. Thus Gro and Cic form part of a repressor complex specifically inactivated by Tor signaling at the embryo poles (Jimenez, 2000).
Tor activation occurs exclusively at the embryonic poles via a ligand produced locally through the action of torso-like, fs(1)polehole (also known as fs(1)M3), fs(1)Nasrat and trunk genes. Trunk is likely to be the ligand for Tor, Torso-like is an accessory protein permitting Trunk to function, and both fs(1)Nasrat and fs(1)polehole have yet to be cloned. Tor signaling proceeds via the Ras/Raf/MAPK pathway to regulate expression of the zygotic genes tll and hkb, which are specifically expressed at each pole of the embryo. These genes encode transcription factors that initiate the developmental programs leading to differentiation of head and tail structures. Tor signaling does not activate terminal gene expression directly; rather, it functions by antagonizing at the poles a uniformly distributed repressor activity, allowing other maternal factors to activate transcription locally. Evidence for this view comes from the identification of regulatory elements in the tll promoter (called tor response elements, tor-REs) that confer terminal-specific expression and that, when mutated, cause severe derepression of tll transcription (Jimenez, 2000 and references therein).
Additional evidence for the regulation of tll and hkb by relief of repression derives from the role of the Groucho (Gro) corepressor in this process. Gro is a nuclear WD-repeat protein that does not bind DNA but interacts with a variety of DNA-bound transcriptional repressors. These associations recruit Gro to target promoters, bringing about transcriptional repression. Gro has been shown to participate in terminal development by restricting the expression of tll and hkb to the embryonic termini: embryos deprived of maternal Gro function show derepression of tll and hkb toward the middle of the embryo (Jimenez, 2000 and references therein).
What is the actual target of Tor signal inactivation at the embryonic poles? The Drosophila Yan Ets-like repressor factor is known to be degraded in response to RTK signaling during eye development. Thus, it is possible that the target of Tor signaling is similarly inactivated at the embryonic poles. The Gro protein is uniformly distributed in the blastoderm embryo and does not show down-regulation at the termini. Also, Gro corepressor activity during sex determination is not inhibited by Tor signaling, arguing that Gro is not the target of the Tor signal. To monitor the pattern of Cic distribution in embryos, a polyclonal antibody was raised against an HMG box-containing fragment of the protein. This antibody reveals a distinctive nuclear signal in wild-type but not cic1 blastoderm embryos, confirming both that Cic is a nuclear protein and that the cic1 allele is a strong loss-of-function mutation. Remarkably, Cic is distributed asymmetrically in blastoderm embryos, being present in nuclei from the presumptive trunk but absent at each embryonic pole. Because CIC mRNA is uniformly distributed in the embryo, the exclusion of the protein from the poles argues that Cic is under negative post-transcriptional regulation by the Tor signal transduction pathway (Jimenez, 2000).
To test this idea, the distribution of Cic was examined in tor mutant embryos. In such embryos, the Cic protein is detected not only in medial regions of the embryo but also at the termini, implying that Tor signaling inhibits accumulation of Cic protein at the embryo poles. These results suggest that Cic is the target inactivated by the Tor signal, possibly via MAPK phosphorylation and subsequent degradation of the protein, as in the case of Yan. Consistent with this idea, the Cic protein sequence includes 14 consensus MAPK phosphorylation sites. Future studies should define the mechanism by which Tor signaling regulates Cic accumulation and the functional domains of the protein involved in this control (Jimenez, 2000).
How does Cic mediate repression of terminal and dorsoventral genes? Because reporter constructs carrying the tor-RE of tll and zen ventral response element (VRE) are derepressed in cic mutant embryos, the simplest model suggests that Cic binds to these regulatory elements and recruits Gro for repression of these genes. Consistent with this idea, there are striking similarities between the consensus DNA-binding site for HMG box proteins and sequence elements within the tor-RE and VRE known to mediate transcriptional repression. However, although these elements are bound by control HMG box proteins, specific binding of Cic to them has not been detected. Perhaps Cic has a very low affinity for DNA and/or requires the presence of accessory factors for efficient DNA binding. Several HMG box proteins rely on interactions with partner proteins to increase their affinity for DNA. Clearly, identification of the precise molecular mechanism of Cic function will require further analyses of its ability to interact with target sequences in terminal and dorsal-specific genes (Jimenez, 2000).
That Cic functions in association with other factors is consistent with studies that have implicated several proteins in Gro-dependent repression of terminal and dorsal-specific genes. For example, it has been shown that Dri and Cut are two of the cofactors required for repression by Dorsal through the zen VRE (Valentine, 1998), and the current results indicate that Cic also contributes to switching Dorsal from an activator to a repressor of transcription. Similarly, the dramatic effects of Cic on terminal patterning indicate that both Cic and Gro are essential components in the repression of terminal genes. It is still not understood how the activity of all these factors is coordinated in vivo. Nevertheless, these results showing that Cic is under negative post-transcriptional control by the Tor RTK pathway, suggest that it functions as the regulatory element that links Tor signaling to the mechanism of repression (Jimenez, 2000).
Localized activation of the Ras/Raf pathway by epidermal growth factor receptor (Egfr) signalling specifies the formation of veins in the Drosophila wing. However, little is known about how the Egfr signal regulates transcriptional responses during the vein/intervein cell fate decision. Evidence is provided that Egfr signaling induces expression of vein-specific genes by inhibiting the Capicua (Cic) HMG-box repressor, a known regulator of embryonic body patterning. Lack of Cic function causes ectopic expression of Egfr targets such as argos, ventral veinless and decapentaplegic and leads to formation of extra vein tissue. In vein cells, Egfr signaling downregulates Cic protein levels in the nucleus and relieves repression of vein-specific genes, whereas intervein cells maintain high levels of Cic throughout larval and pupal development, repressing the expression of vein-specific genes and allowing intervein differentiation. However, regulation of some Egfr targets such as rhomboid appears not to be under direct control of Cic, suggesting that Egfr signaling branches out in the nucleus and controls different targets via distinct mediator factors. These results support the idea that localized inactivation of transcriptional repressors such as Cic is a rather general mechanism for regulation of target gene expression by the Ras/Raf pathway (Roch, 2002).
The expression pattern of cic in wild-type wing discs was examined. In situ hybridization of third instar discs shows uniform distribution of cic transcripts. By contrast, staining of similar discs with a specific Cic antibody reveals a complex pattern of protein accumulation: Cic accumulates at high levels in the wing pouch and in the primordial hinge region, but not in the notum region. At this stage, Cic levels begin to drop in the presumptive third longitudinal vein and in two rows of cells running along the D/V boundary that correspond to the future wing margin. Moreover, the remaining Cic protein in those cells is cytoplasmic, whereas in other regions of the wing pouch (and in the adjacent peripodial cells), Cic is clearly nuclear. During pupariation [from 6 to 34 hours after puparium formation (APF)], Cic levels also decline in all presumptive longitudinal wing veins and crossveins. This specific accumulation of Cic in intervein sectors is consistent with its role as a negative regulator of vein differentiation (Roch, 2002).
There are two key aspects of Cic function as a developmental regulator: its ability to repress specific target genes in defined territories, and its inhibition by the Ras/Raf pathway to allow expression of those targets in complementary positions. In the blastoderm embryo, Cic is required for development of trunk body regions and represses genes mediating differentiation of terminal structures. Torso RTK activation at each pole of the embryo alleviates Cic-dependent repression and initiates the terminal gene expression program. A similar model is proposed for cic function during specification of vein versus intervein fate in the wing. Loss of cic function in the wing causes formation of ectopic vein tissue, implying that Cic mediates intervein specification by restricting vein formation to appropriate regions. In intervein territories, Cic behaves as a repressor of vein-specific genes such as argos and vvl but does not seem to affect directly the expression of blistered, which is required for the specification of intervein fates. Finally, Egfr signaling leads to downregulation of Cic protein levels in vein nuclei, thus relieving Cic-mediated repression and promoting vein development (Roch, 2002).
Nevertheless, several data suggest a more complex regulation of vein specification compared to terminal patterning: (1) it has been shown that expression of rho, a positive target of Egfr signaling in the wing and other tissues, is not affected by cic during third larval instar and early pupariation. This suggests that Egfr signaling can mediate activation of some targets in the wing disc by mechanisms other than Cic inhibition. (2) Similarly, the Egfr pathway has been shown to repress bistered expression in presumptive vein cells, a process that is independent of Cic. These results imply that different transcription factors act downstream of the Egfr cascade to direct changes in gene expression during patterning of wing veins. Indeed, recent results indicate that Egfr signaling activates certain target genes via direct phosphorylation of Fos protein (Roch, 2002).
Moreover, vein differentiation is not a mere result of Egfr activation but depends on other signals such as Dpp and Notch, and on the distribution of additional transcription factors that contribute to wing patterning. For example, the Collier/Knot nuclear factor has been shown to induce high levels of Bs expression between veins L3 and L4, promoting intervein development in this region. All these inputs are linked in a complex circuit of intercellular signaling and gene regulation that progressively refines vein determination during late larval and pupal development. This signaling network could provide an explanation for the observed non-autonomy of cic phenotypes during vein specification. Thus, although cic represses aos expression in a cell-autonomous manner, this and other cic targets are likely to participate in signaling mechanisms that affect adjacent cells. Consistent with this idea, it has been found that cic mutant cells express ectopic Dpp product, a diffusible factor that promotes vein differentiation (Roch, 2002).
In cic mutant wings, many cells differentiate, acquiring morphological features that are intermediate between those observed in either vein and intervein cells. In these wings, most cells co-express Bs and Vvl proteins, which are normally restricted to vein and intervein cells, respectively, suggesting that vein/intervein fate specification may result from a balance of these factors rather than on a simple binary switch. In this context, the concerted activities of signaling cascades such as Dpp, Notch and Ras/Raf pathways may regulate cell differentiation by modulating the balance of nuclear factors that act in a dose-dependent way. This hypothesis provides a mechanism that could explain the enormous variability observed in the cell morphologies of different insect wings (Roch, 2002).
Cic acts in wing development in a way similar to that previously described in the early embryo. Moreover, the fact that mutant clones for the Groucho repressor display extraveins, similarly to cic clones, indicates that these two proteins could interact as partners during wing development, as is the case during embryonic development. Indeed, weak genetic interactions have been observed between different cic and gro alleles during wing development. Thus, Cic and Gro could be part of a conserved repressor complex downregulated by the Ras/Raf molecular cassette in different cellular contexts. In this regard, the phenotype of bullwinkle mutations (bullwinkle is allelic to cic) suggests that Cic may also function as a target of other RTK signals during patterning of the eggshell in the ovary. However, it should be noted that cic does not seem to act in all developmental processes mediated by Ras/Raf signaling in Drosophila. For example, the eyes of cic mutant flies appear normal, even though the Ras/Raf pathway controls several aspects of cell fate specification and patterning in this tissue. These observations support the idea that the Ras/Raf pathway can regulate cell specification in a cic-independent way depending on the cell context (Roch, 2002).
Previous work has shown that during patterning of ovary follicle cells, the expression of rho is controlled by the Ras/Raf pathway via another transcriptional repressor, the CF2 protein. CF2 is tagged for cytoplasmic retention and degradation after direct phosphorylation by MAPK. The Cic protein also has consensus sites for phosphorylation by MAPK, suggesting that Cic levels could be regulated post-transcriptionally in a way similar to CF2. This indicates that localized downregulation of specific repressors is a common mechanism for the activation of target genes by the Ras/Raf pathway. The identification of highly conserved cic homologs in mice and humans suggests that regulation of gene expression by RTK signaling in vertebrates may also involve relief of Cic-dependent repression (Roch, 2002).
The cic gene has been identified by positional cloning. cic is mapped to chromosomal position 92D1-2 using standard recombination and deficiency tests. DNA polymorphisms in this region specific to the cic1 chromosome were sought and the cic1 allele was found to be associated with the insertion of a 1.5-kb hobo transposon. This transposon maps ~300 bp away from a previously described P element, P(PZ) bwk8482, which causes the female sterile mutation bullwinkle (bwk; Rittenhouse, 1995). P(PZ) bwk8482 produces a phenotype different from cic1 and complements cic1, indicating that the two mutations affect different genetic functions. The cic1-specific hobo element is inserted in the 5' untranslated region of a novel gene, which corresponds to EST clone LD05430 from the Berkeley Drosophila Genome Project. Several lines of evidence confirm that this gene is cic. (1) Molecular analyses show that the hobo insertion disrupts the cic transcript. (2) The cic1 mutation is not complemented by small deficiencies (<500 bp) that span the hobo insertion site. (3) The cic phenotype is rescued by P-element transformation with a genomic fragment containing the cic gene. This fragment does not rescue the bwk phenotype, again showing that bwk and cic represent separate gene functions. Elucidation of the relationship between cic and bwk at the molecular level will require the cloning of bwk (Jimenez, 2000).
Sequencing of cic cDNA clones shows that they encode a putative transcription factor with a DNA-binding domain of the HMG box class. HMG box proteins are thought to function as architectural factors that induce bending of the target DNA and facilitate the assembly of multiprotein regulatory complexes at promoters. The Cic HMG box domain contains several amino acid residues shared by a group of HMG box factors that bind sequence specifically to DNA, such as the LEF-1/TCF-1 factors, SRY, and the SRY-related Sox proteins. Similarity searches against protein databases reveal that Cic defines a new subfamily within this group, which includes two related HMG box proteins from humans and Caenorhabditis elegans. The similarity between Cic and these proteins is particularly strong in the HMG box domain (75% and 67% identity with the human and C. elegans sequences, respectively), but also extends to other regions of the proteins, suggesting that they represent true orthologs (Jimenez, 2000).
In children, the majority of brain tumors arise in the cerebellum. Medulloblastomas, the most common of these, are believed to originate from the granule cell lineage. A mammalian gene, capicua (Cic), the ortholog of a Drosophila gene implicated in c-erbB (Egfr) signaling, is predominantly expressed during mouse granule cell development. Its expression in medulloblastoma is therefore of particular interest. This study anayzes the expression of human CIC in medulloblastoma. In silico SAGE analysis demonstrated that medulloblastomas exhibits the highest level of CIC expression and expression is most common in tumors of the CNS in general. The expression of CIC does not correlate with other markers, such as neurofilament, GFAP and Mib-1. In postnatally developing cerebellum a strong correlation was found between Cic expression and the maturation profile of cerebellar granule cell precursors. Expression of CIC is therefore a feature shared between immature granule cells and the tumors derived from them. Cic has been implicated as a mediator of ErbB signaling and this pathway has been associated with a poor prognosis for medulloblastomas. Therefore, further analysis of the role of Cic is likely to provide valuable insight into the biology of these tumors. Additionally, study of genes such as CIC should provide criteria by which to categorize these tumors into subgroups that might allow better allocation into specific treatment regimes (Lee, 2005).
Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative diseases caused by expansion of a polyglutamine tract in the disease protein, in this case, ATAXIN-1 (ATXN1). A key question in the field is whether neurotoxicity is mediated by aberrant, novel interactions with the expanded protein or whether its wild-type functions are augmented to a deleterious degree. Soluble protein complexes were examined from mouse cerebellum and it was found that the majority of wild-type and expanded ATXN1 assembles into large stable complexes containing the transcriptional repressor Capicua. ATXN1 directly binds Capicua and modulates Capicua repressor activity in Drosophila and mammalian cells, and its loss decreases the steady-state level of Capicua. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded ATXN1, substantially reduces the association of mutant ATXN1 with Capicua in vivo. These data provide insight into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protein interactions (Lam, 2006).
To establish whether CIC also interacts with mutant forms of ATXN1, immunoprecipitation was performed on lysates from HeLa cells transiently transfected with variants of FLAG-tagged ATXN1 containing 2Q, 82Q, or 82Q with a S776A mutation (which abolishes the interaction of ATXN1 with 14-3-3) or 2Q with a deletion of the AXH domain. Both endogenous CIC isoforms coimmunoprecipitated with each of these ATXN1 variants, except the one lacking the AXH domain. It is concluded that the ATXN1-CIC interaction requires the AXH domain and is independent of 14-3-3 binding (Lam, 2006).
To identify the domains responsible for interaction between the two proteins, yeast two-hybrid interaction assays were performed using a series of ATXN1 and CIC deletion constructs. Two N-terminal fragments of CIC-S (amino acids 1-300 and 1-205) interact with the C-terminal half of ATXN1, and the AXH domain of ATXN1 is sufficient for its interaction with CIC. To further map the ATXN1 binding domain of CIC, serial deletions were generated at the N terminus of mouse CIC-S for pull-down assays with GST-tagged full-length wild-type ATXN1. The interaction region was narrowed to 31 amino acids (amino acids 16-46) of CIC-S. Comparison of this 31-amino acid sequence across species revealed a conserved stretch of eight amino acids present in both CIC-S and CIC-L isoforms with the consensus sequence WXX(L/I)(V/L)PX(L/M). It was then confirmed in vitro that human ATXN1 binds to Drosophila Cic through the consensus eight amino acids. ATXN1 and CIC thus appear to be in vivo binding partners that interact directly through evolutionarily conserved domains (Lam, 2006).
CIC contains a Sox-like high mobility group (HMG) box and likely acts as a transcriptional repressor. Given that ATXN1 lacks sequence-specific DNA binding activity, CIC could be involved in directing ATXN1 to gene targets for repression. These studies clearly show that ATXN1 has a synergistic effect on the transcriptional repressor activity of CIC that is partially compromised by the polyglutamine expansion. One possible explanation is that polyglutamine expansion alters the conformational state of the ATXN1 protein, which in turn alters the conformational or functional state of the ATXN1-CIC complex. Identifying transcriptional targets of the ATXN1-CIC complexes, particularly in the selectively vulnerable Purkinje cells, will likely reveal specific pathways that are critical for disease pathogenesis (Lam, 2006).
Ewing's family tumors (EFTs) are highly malignant tumors arising from bone and soft tissues that exhibit EWS-FLI1 or variant EWS-ETS gene fusions in more than 85% of the cases. CIC, a human homolog of Drosophila capicua which encodes a high mobility group box transcription factor, is fused to a double homeodomain gene DUX4 as a result of a recurrent chromosomal translocation t(4;19)(q35;q13). This translocation was seen in two cases of soft tissue sarcoma diagnosed as Ewing-like sarcoma. CIC-DUX4 exhibits a transforming potential for NIH 3T3 fibroblasts, and as a consequence of fusion with a C-terminal fragment of DUX4, CIC acquires an enhanced transcriptional activity, suggesting that expression of its downstream targets might be deregulated. Gene expression analysis identified the ETS family genes, ERM/ETV5 and ETV1, as potential targets for the gene product of CIC-DUX4. Indeed, CIC-DUX4 directly binds the ERM promoter by recognizing a novel target sequence and significantly up-regulates its expression. This study clarifies the function of CIC and its role in tumorigenesis, as well as the importance of the PEA3 subclass of ETS family proteins in the development of EFTs arising through mechanisms different from those involving EWS-ETS chimeras. Moreover, the study identifies the role of DUX4 that is closely linked to facioscapulohumeral muscular dystrophy in transcriptional regulation (Kawamura-Saito, 2006).
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine tract in ataxin-1 (ATXN1). SCA1 pathogenesis studies support a model in which the expanded glutamine tract causes toxicity by modulating the normal activities of ATXN1. To explore native interactions that modify the toxicity of ATXN1, a targeted duplication of the mouse ataxin-1-like (Atxn1l, also known as Boat) locus, a highly conserved paralog of SCA1, was generated, and the role of this protein in SCA1 pathology was tested. Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals, it was found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua (CIC). These results provide genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1, and they underscore the importance of studying the paralogs of genes mutated in neurodegenerative diseases to gain insight into mechanisms of pathogenesis (Bowman, 2007).
date revised: 11 March 2000
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