Capicua (protein)
Protein found in humans
From Wikipedia, the free encyclopedia
Capicua transcriptional repressor is a protein that in humans is encoded by the CIC gene.[5][6][7] Capicua functions as a transcriptional repressor in a way that ensures its impact on the progression of cancer, and plays a significant role in the operation of the central nervous system through its interaction with ataxin 1. The name of the protein derives from the Catalan expression cap-i-cua which literally translates to "head-and-tail".[8]
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| Aliases | CIC, capicua transcriptional repressor, MRD45, CIC gene | |||||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 612082; MGI: 1918972; GeneCards: CIC | |||||||||||||||||||||||||||||||||||||||||||||||||||||
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Structure
Capicua is a highly conserved protein, with a lot of similarity between human and Drosophila melanogaster homologs.[9] In the human body, capicua exists in two isoforms, the short (CIC-S) and the long (CIC-L) one, which differ in their N-terminal section. The two evolutionarily conserved domains of the protein are HMG-box (high-mobility group box) and the C1 domain: they work together to recognize specific octameric DNA sequences.[9] Capicua also contains a nuclear localisation sequence that allows it to enter the nucleus of the cell.
Clinical significance
A new disorder called autosomal dominant intellectual developmental disorder 45 caused by mutations of the CIC gene was first described in 2017.[10]
Spinocerebellar ataxia
Capicua forms a complex with ataxin 1 (CIC-ATXN1 complex) and owing to this interaction it plays a crucial role in the development of spinocerebellar ataxia type 1. While in a healthy organism this complex serves to ensure correct cellular function, in patients with ATXN1 mutations a modified complex has a toxic effect on cerebellar cells, resulting in the motor symptoms typical for this disorder.[9] Blocking the formation of the complex in a murine model of ataxia reduces the symptoms.
Tumors
CIC has been shown to act as a tumor suppressor in numerous types of cancer,[9] and, vice versa, mutations of CIC have been found in some types of tumors. According to a review published in 2020, CIC mutations were most often discovered in oligodendroglioma.[9] A genomic translocation resulting in the formation of a hybrid CIC-DUX4 gene may cause an aggressive Ewing-like sarcoma.[11] Instead of acting as a suppressor, a hybrid protein produced by fusion of CIC and DUX4 has been shown to act as an activator of genes.[12]
According to a review published in 2017, the CIC gene is deleted in 46-53% of analyzed oligodendroglioma tumors as part of the 1p/19q codeletion, a mutation that may also affect the FUBP1 gene.[13]
Ongoing research
According to a study published in 2021, CIC mutations may be among the causes of cerebral folate deficiency.[15]
History
The CIC gene was first identified in Drosophila in 2000.[9] It was shown to encode a transcriptional repressor participating in the regulation of embryogenesis. In a mutated fly which at the embryonic stage had only the first and the last segments present, with the intermediate segments missing, scientists discovered a mutation of the CIC gene, and this prompted them to call the protein capicua ("head-and-tail" in Catalan).
Interactions
- FOLR1 — capicua has been shown to affect the expression of folate receptor alpha, and CIC mutations might result in cerebral folate deficiency.[15]
- ATXN1 — capicua and ataxin 1 form a complex (ATXN1-CIC) which is crucial for proper brain development.[10]
- DUX4 – chimeric CIC-DUX4 proteins are found in tumors.[10]
- FOXO4 – chimeric CIC-FOXO4 proteins are found in tumors.[12]
- NUTM1 – chimeric CIC-NUTM1 proteins are found in tumors.[12]
- LEUTX – chimeric CIC-LEUTX proteins are found in tumors.[12]