Alternative titles; symbols
HGNC Approved Gene Symbol: CABIN1
Cytogenetic location: 22q11.23 Genomic coordinates (GRCh38) : 22:24,011,304-24,178,628 (from NCBI)
Nagase et al. (1997) identified a cDNA for CABIN1, which they designated KIAA0330.
Calcineurin (see 114105) plays a pivotal role in the T-cell receptor-mediated signal transduction pathway and serves as a common target for the immunosuppressants FK506 and cyclosporin A. Sun et al. (1998) used the yeast 2-hybrid system to identify calcineurin-binding proteins. They initially isolated Cabin1, so named for 'calcineurin-binding protein-1,' from a mouse T-cell cDNA library. The open reading frame of human CABIN1 encodes 2,220 amino acids. The protein includes a leucine zipper, a putative SH3 binding site, and 3 putative nuclear localization sequences. In addition, CABIN1 contained several PEST sequences, which may target a wide variety of cellular proteins for degradation, and a number of consensus phosphorylation sites for various kinases, including protein kinase A (PKA), protein kinase C (PKC), and MAP kinases (see 601158). Immunoprecipitation from fractionated cell lysates confirmed that CABIN1 is a nuclear protein. Northern blot analysis indicated that CABIN1 is widely expressed in a variety of tissues, including the spleen and leukocytes.
Sun et al. (1998) showed that the interaction between CABIN1 and calcineurin is dependent on both PKC and calcium signals. PKC activation led to hyperphosphorylation of CABIN1. The expression of CABIN1 or its C-terminal fragments blocked IL2 (147680) promoter activation in response to PMA and ionomycin, and inhibited the dephosphorylation of NFAT (see 600489) by calcineurin in vivo.
Youn et al. (1999) used a yeast 2-hybrid system with a C-terminal 502-amino acid fragment of CABIN1 as bait to identify CABIN1-binding proteins. MEF2B (600661) was found to bind CABIN1 via the MADS/MEF2 box, a DNA binding domain that is highly conserved among isoforms of MEF2; thus, all the MEF2s were suspected to bind CABIN1. The minimal CABIN1 domain sufficient for mediating MEF2B interaction was contained in the C-terminal 64 amino acids of CABIN1. CABIN1 inhibited reporter gene expression driven by expressed MEF2B and MEF2D (600663) in a concentration-dependent manner. Youn et al. (1999) identified CABIN1 as a direct calmodulin (114180)-binding protein. Activated calmodulin could displace MEF2D from CABIN1 in vitro. The presence of calcium abrogated the binding of MEF2D to CABIN1. The antagonism by calcium was not sensitive to FK506, suggesting that the calcium effect was not mediated by calcineurin. Both calcineurin and CABIN1 were found to be involved in the regulation of MEF2 in an independent fashion. Overexpression of CABIN1 almost completely inhibited both Nur77 (see 139139) and T-cell receptor-mediated apoptosis. CABIN1 bound to MEF2 and sequestered MEF2 in a transcriptionally inactive state; therefore, it is a good candidate for an endogenous inhibitor that maintains the quiescence of MEF2 in unstimulated cells. Binding of CABIN1 to MEF2 exerts one level of control over MEF2 activity. Dissociation of MEF2 from CABIN1 via competition by activated calmodulin defines a novel signaling pathway involved in Nur77 expression and thymocyte apoptosis. Given that CABIN1 is ubiquitously expressed and that it interacted with all known isoforms of MEF2, this mode of regulation of MEF2 by CABIN1 and calmodulin may be operative in other physiologic processes involving MEF2.
Han et al. (2003) reported the crystal structure of the MADS-box/MEF2S domain of human MEF2B bound to a motif of the transcriptional corepressor CABIN1 and DNA at 2.2-angstrom resolution. The crystal structure reveals a stably folded MEF2S domain on the surface of the MADS box. CABIN1 adopts an amphipathic alpha-helix to bind a hydrophobic groove on the MEF2S domain, forming a triple-helical interaction. Han et al. (2003) concluded that their studies of the ternary CABIN1/MEF2/DNA complex show a general mechanism by which MEF2 recruits transcriptional corepressor CABIN1 and class II HDACs to specific DNA sites.
Youn and Liu (2000) reported that CABIN1 represses MEF2 by 2 distinct mechanisms. CABIN1 recruits mSIN3 and its associated histone deacetylases 1 (601241) and 2 (605164); CABIN1 also competes with p300 (602700) for binding to MEF2. Thus, Youn and Liu (2000) concluded that activation of MEF2 and the consequent transcription of NUR77 are controlled by the association of MEF2 with the histone deacetylases via the calcium-dependent repressor CABIN1.
Buckley et al. (2005) noted that the CABIN1 gene contains 29 exons spanning 167 kb.
The KIAA0330 sequence matches a genomic BAC from 22q11.2 (Scott, 1999).
Buckley, P. G., Mantripragada, K. K., de Stahl, T. D., Piotrowski, A., Hansson, C. M., Kiss, H., Vetrie, D., Ernberg, I. T., Nordenskjold, M., Bolund, L., Sainio, M., Rouleau, G. A., Niimura, M., Wallace, A. J., Evans, D. G. R., Grigelionis, G., Menzel, U., Dumanski, J. P. Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2. Hum. Mutat. 26: 540-549, 2005. [PubMed: 16287142] [Full Text: https://doi.org/10.1002/humu.20255]
Han, A., Pan, F., Stroud, J. C., Youn, H.-D., Liu, J. O., Chen, L. Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2. Nature 422: 730-734, 2003. [PubMed: 12700764] [Full Text: https://doi.org/10.1038/nature01555]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Scott, A. F. Personal Communication. Baltimore, Md. 11/11/1999.
Sun, L., Youn, H.-D., Loh, C., Stolow, M., He, W., Liu, J. O. Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity 8: 703-711, 1998. [PubMed: 9655484] [Full Text: https://doi.org/10.1016/s1074-7613(00)80575-0]
Youn, H.-D., Liu, J. O. Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2. Immunity 13: 85-94, 2000. [PubMed: 10933397] [Full Text: https://doi.org/10.1016/s1074-7613(00)00010-8]
Youn, H.-D., Sun, L., Prywes, R., Liu, J. O. Apoptosis of T cells mediated by Ca(2+)-induced release of the transcription factor MEF2. Science 286: 790-793, 1999. [PubMed: 10531067] [Full Text: https://doi.org/10.1126/science.286.5440.790]