Abstract
Capicua (CIC) is an evolutionarily conserved transcription factor. CIC contains a high-mobility group (HMG) box that recognizes specific DNA sequences to regulate the expression of various target genes. CIC was originally identified in Drosophila melanogaster as a transcriptional repressor that suppresses the receptor tyrosine kinase signaling pathway. This molecule controls normal organ growth and tissue patterning as well as embryogenesis in Drosophila. Recent studies have also demonstrated its extensive functions in mammals. For example, CIC regulates several developmental and physiological processes, including lung development, abdominal wall closure during embryogenesis, brain development and function, neural stem cell homeostasis, T cell differentiation, and enterohepatic circulation of bile acids. CIC is also associated with the progression of various types of cancer and neurodegeneration in spinocerebellar ataxia type-1, systemic autoimmunity, and liver injury. In this review, I provide a broad overview of our current understanding of the regulation and functions of CIC in mammals and discuss future research directions.
Highlights
CIC functions in diseasesSpinocerebellar ataxia type-1 (SCA1) spinocerebellar ataxia type-1 (SCA1) is one of nine polyQ disorders[35,36]. Expansion of the CAG repeat in ATXN1 results in a long polyQ tractcontaining mutant ATXN1, which is associated with cerebellar neurodegeneration primarily due to Purkinje cell death[35]
In 2000, the capicua gene was first identified in Drosophila melanogaster as a transcriptional repressor involved in the regulation of embryogenesis[1]
The expression levels of some CIC target genes were downregulated in the cerebellum of the Atxn1154Q mice and were significantly rescued in the cerebellum of the Atxn1154Q; Cic-L+/− mice[15]. These findings suggest that the polyQ-expanded ATXN1 could enhance the transcriptional repressor activity of CIC for a subset of target genes, thereby contributing to the progression of spinocerebellar ataxia type-1 (SCA1)
Summary
Spinocerebellar ataxia type-1 (SCA1) SCA1 is one of nine polyQ disorders[35,36]. Expansion of the CAG repeat in ATXN1 results in a long polyQ tractcontaining mutant ATXN1, which is associated with cerebellar neurodegeneration primarily due to Purkinje cell death[35]. The expression levels of some CIC target genes were downregulated in the cerebellum of the Atxn1154Q mice and were significantly rescued in the cerebellum of the Atxn1154Q; Cic-L+/− mice[15] These findings suggest that the polyQ-expanded ATXN1 could enhance the transcriptional repressor activity of CIC for a subset of target genes, thereby contributing to the progression of SCA1. CIC deficiency promotes the self-renewal capacity and increases the expression of cancer stem cell markers, including EpCAM+/CD44hi/CD24lo and ALDH47,48, via derepression of ETV4, ETV5, and SOX2 in breast cancer cell lines[49] Consistent with this result, CIC levels were decreased in breast cancer patient samples with a CD44 high and CD24 low phenotype[49]. These data suggest that CIC suppresses breast cancer formation by restricting cancer stemness and identify CIC as a potential regulator of stem cell maintenance
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