Alternative titles; symbols
HGNC Approved Gene Symbol: CKB
Cytogenetic location: 14q32.33 Genomic coordinates (GRCh38): 14:103,519,667-103,522,830 (from NCBI)
Creatine kinase (EC 2.7.3.2) isoenzymes are crucial to energy metabolism, particularly in tissues with high energy requirements. Nuclear genes encode 4 CK subunits: cytoplasmic muscle (CKM; 123310), cytoplasmic brain (CKB), ubiquitous mitochondrial (CKMT1B; 123290), and sarcomeric mitochondrial (CKMTS; 123295) (summary by Klein et al., 1991).
Using a rabbit Ckb probe, Kaye et al. (1987) cloned CKB from a human NCI-H378 small cell lung cancer cell cDNA library. The deduced 381-amino acid protein shares over 98% homology with the rabbit enzyme. Northern blot analysis detected a 1.6-kb transcript in human psoas muscle and in all small cell lung cancer cell lines examined, but not in other tumor cell lines.
By screening a human brain cDNA library with a probe encoding the 5-prime end of human CKM, followed by screening a human placenta cDNA library, Villarreal-Levy et al. (1987) cloned CKB. Northern blot analysis detected CKB in normal human heart, hypertrophied human heart, embryonic rat cardiomyocytes, and human small cell carcinoma cell lines. Villarreal-Levy et al. (1987) stated that CKB is also expressed in smooth muscle and placenta, as well as other adult tissues and embryonic cells.
Mariman et al. (1989) reported the complete nucleotide sequence of the CKB gene.
From study of human-rodent cell hybrids, Povey et al. (1979) suggested that the BB form, which is expressed in human fibroblasts and in many human lymphoblastoid lines, is coded for by a structural locus on chromosome 14. Weil et al. (1980) confirmed the assignment of CKBB to chromosome 14. Although the heavy chain gene(s) of immunoglobulins are also on chromosome 14, 'linkage' to CKBB, referred to by Bohner et al. (1979), is chemical and probably unrelated to the synteny.
Kaye et al. (1987) mapped the CKB gene to chromosome 14q32 by somatic cell hybrid analysis. A second CKB sequence of unknown functional significance was identified by the same methods on chromosome 16, probably the short arm (16p13-q21). Villarreal-Levy et al. (1987) presented evidence indicating that the CKB gene is present in single copy in the human genome. Stallings et al. (1988) found that a probe for the 3-prime noncoding sequence of human CKB hybridized concordantly only to DNAs from somatic hybrids containing chromosome 14. Ma et al. (1991) demonstrated 3 Alu repeat sequences within the CKB pseudogene on chromosome 16p13.
Brubacher et al. (1989) demonstrated that CKB is closely linked to AKT1 (164730) and that both are distal to PI (107400) and AACT (107280). With an EcoRI restriction site polymorphism in the CKB gene, Benger et al. (1991) showed close linkage of CKB and IGH (147100).
Using Western blot analysis and confocal immunohistochemistry, Schlattner et al. (2002) investigated the localization of creatine kinases in mouse and human skin under healthy and pathologic conditions. In mouse skin, they found high amounts of Ckb coexpressed with lower amounts of Ckmt1b, both mainly localized in suprabasal layers of the dermis, different cell types of hair follicles, sebaceous glands, and the subcutaneous panniculus carnosus muscle. Except for sebaceous glands, these cells also expressed creatine transporter (CRT, or SLC6A8; 300036). Ckm and Ckmts were restricted to panniculus carnosus. Western blot analysis showed that Ckb and Crt were upregulated about 3-fold immediately after wounding of mouse skin, whereas the amount of Ckmt1b increased 10 to 15 days after wounding. Healthy and psoriatic human skin showed a similar coexpression pattern of CKB, CKMT1B, and CRT, with CRT upregulated in psoriasis.
By 2-dimensional PAGE, followed by tandem mass spectrometry, Chang et al. (2008) found that the CKB gene was highly upregulated during maturation of osteoclasts. Inhibition of CKB using small hairpin RNA (shRNA) or a creatine kinase inhibitor greatly impaired bone resorption ability of human osteoclasts in vitro through the combined effects on actin ring formation, RhoA GTPase (see, e.g., 165390) activity, and vacuolar ATPase function. Activity of osteoclasts derived from Ckb-null mice were similarly affected. In vivo studies showed that Ckb-null mice were better protected against bone loss induced by ovariectomy, lipopolysaccharide challenge, or interleukin-1 (see 147720) treatment compared to wildtype animals. Administration of a creatine kinase inhibitor or adenoviruses harboring Ckb shRNA attenuated bone loss in rat and mouse models. The findings establish an important role for CKB in the bone-resorbing function of osteoclasts.
Clonidine and imidazoline mediate effects independent of alpha-2 adrenoceptors, such as regulation of blood pressure, induction of feeding, stimulation of firing of locus ceruleus neurons, and stimulation of insulin release, as well as induction of the expression of glial fibrillary acidic protein. Escriba et al. (1995) stated that radioligand binding studies had identified 2 major types of imidazoline receptors: the I(1)IR type with a high affinity for clonidine, and the I(2)IR type with a high affinity for idazoxan. Escriba et al. (1995) characterized a 130- to 140-kD protein from rat brain with a high affinity for idazoxan (i.e., an I(2)IR type). Immunoblot analysis demonstrated the presence of a 45-kD protein, suggesting to the authors that the receptor was solubilized as an oligomeric protein complex.
By N-terminal sequencing, Kimura et al. (2009) identified Bck as an approximately 45-kD protein from rat and rabbit brain that bound an immobilized I(2) imidazoline receptor ligand. Purified rabbit Bck also bound the I(2) ligand with high affinity. Binding did not alter Bck activity, although molecular modeling suggested that the I(2) ligand bound to Bck in a cleft or pocket adjacent to the active site. Kimura et al. (2009) concluded that BCK is an imidazoline-binding protein.
It had been proposed that a locus on chromosome 17 involved with the synthesis of brain type CK may exist (Povey et al., 1979; Donald et al., 1982)
Benger, J. C., Teshima, I., Walter, M. A., Brubacher, M. G., Daouk, G. H., Cox, D. W. Localization and genetic linkage of the human immunoglobulin heavy chain genes and the creatine kinase brain (CKB) gene: identification of a hot spot for recombination. Genomics 9: 614-622, 1991. [PubMed: 1674725] [Full Text: https://doi.org/10.1016/0888-7543(91)90354-h]
Bohner, J., Stein, W., Kuhlmann, E., Eggstein, M. Serum creatine kinase BB linked to immunoglobulin G. Clin. Chim. Acta 97: 83-88, 1979. [PubMed: 115622] [Full Text: https://doi.org/10.1016/0009-8981(79)90027-5]
Brubacher, M. G., Benger, J. C., Billingsley, G. D., Hofker, M. H., Nakamura, Y., White, R., Cox, D. W. A genetic linkage map of the distal region of human chromosome 14. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A133 only, 1989.
Chang, E.-J., Ha, J., Oerlemans, F., Lee, Y. J., Lee, S. W., Ryu, J., Kim, H. J., Lee, Y., Kim, H.-M., Choi, J.-Y., Kim, J. Y., Shin, C. S., Pak, Y. K., Tanaka, S., Wieringa, B., Lee, Z. H., Kim, H.-H. Brain-type creatine kinase has a crucial role in osteoclast-mediated bone resorption. Nature Med. 14: 966-972, 2008. [PubMed: 18724377] [Full Text: https://doi.org/10.1038/nm.1860]
Donald, L. J., Wang, H. S., Hamerton, J. L. Are there additional CKBB loci? (Abstract) Cytogenet. Cell Genet. 32: 267-268, 1982.
Escriba, P. V., Ozaita, A., Miralles, A., Reis, D. J., Garcia-Sevilla, J. A. Molecular characterization and isolation of a 45-kilodalton imidazoline receptor protein from the rat brain. Molec. Brain Res. 32: 187-196, 1995. [PubMed: 7500830] [Full Text: https://doi.org/10.1016/0169-328x(95)00074-3]
Hoo, J. J., Goedde, H. W. Determination of brain type creatine kinase for diagnosis of perinatal asphyxia--choice of method. (Letter) Pediat. Res. 16: 806 only, 1982. [PubMed: 6752857] [Full Text: https://doi.org/10.1203/00006450-198209000-00019]
Kaye, F. J., McBride, O. W., Battey, J. F., Gazdar, A. F., Sausville, E. A. Human creatine kinase-B complementary DNA: nucleotide sequence, gene expression in lung cancer, and chromosomal assignment to two distinct loci. J. Clin. Invest. 79: 1412-1420, 1987. [PubMed: 2883200] [Full Text: https://doi.org/10.1172/JCI112969]
Kimura, A., Tyacke, R. J., Robinson, J. J., Husbands, S. M., Minchin, M. C. W., Nutt, D. J., Hudson, A. L. Identification of an imidazoline binding protein: creatine kinase and an imidazoline-2 binding site. Brain Res. 1279: 21-28, 2009. [PubMed: 19410564] [Full Text: https://doi.org/10.1016/j.brainres.2009.04.044]
Klein, S. C., Haas, R. C., Perryman, M. B., Billadello, J. J., Strauss, A. W. Regulatory element analysis and structural characterization of the human sarcomeric mitochondrial creatine kinase gene. J. Biol. Chem. 266: 18058-18065, 1991. [PubMed: 1917943] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(18)55236-4]
Ma, T. S., Ifegwu, J., Watts, L., Siciliano, M. J., Roberts, R., Perryman, M. B. Serial Alu sequence transposition interrupting a human B creatine kinase pseudogene. Genomics 10: 390-399, 1991. [PubMed: 1676982] [Full Text: https://doi.org/10.1016/0888-7543(91)90324-8]
Mariman, E. C. M., Schepens, J. T. G., Wieringa, B. Complete nucleotide sequence of the human creatine kinase B gene. Nucleic Acids Res. 17: 6385 only, 1989. [PubMed: 2771648] [Full Text: https://doi.org/10.1093/nar/17.15.6385]
Pfeiffer, F. E., Homburger, H. A., Yanagihara, T. Creatine kinase BB isoenzyme in CSF in neurologic diseases: measurement by radioimmunoassay. Arch. Neurol. 40: 169-172, 1983. [PubMed: 6830458] [Full Text: https://doi.org/10.1001/archneur.1983.04050030063012]
Povey, S., Inwood, M., Tanyar, A., Bobrow, M. The expression of creatine kinase isozymes in human cultured cells. Ann. Hum. Genet. 43: 15-26, 1979. [PubMed: 496392] [Full Text: https://doi.org/10.1111/j.1469-1809.1979.tb01545.x]
Povey, S., Inwood, M., Tanyar, A., Bobrow, M. The expression of the BB isozyme of creatine kinase. (Abstract) Cytogenet. Cell Genet. 25: 198 only, 1979.
Schlattner, U., Mockli, N., Speer, O., Werner, S., Wallimann, T. Creatine kinase and creatine transporter in normal, wounded, and diseased skin. J. Invest. Derm. 118: 416-423, 2002. [PubMed: 11874479] [Full Text: https://doi.org/10.1046/j.0022-202x.2001.01697.x]
Stallings, R. L., Olson, E., Strauss, A. W., Thompson, L. H., Bachinski, L. L., Siciliano, M. J. Human creatine kinase genes on chromosomes 15 and 19, and proximity of the gene for the muscle form to the genes for apolipoprotein C2 and excision repair. Am. J. Hum. Genet. 43: 144-151, 1988. [PubMed: 3400641]
Villarreal-Levy, G., Ma, T. S., Kerner, S. A., Roberts, R., Perryman, M. B. Human creatine kinase: isolation and sequence analysis of cDNA clones for the B subunit, development of subunit specific probes, and determination of gene copy number. Biochem. Biophys. Res. Commun. 144: 1116-1127, 1987. [PubMed: 3034271] [Full Text: https://doi.org/10.1016/0006-291x(87)91427-6]
Weil, D., Van Cong, N., Gross, M.-S., Foubert, C., Frezal, J. Localisation du gene de la creatine kinase BB sur le chromosome 14 par l'analyse des hybrides homme-rongeur. Ann. Genet. 23: 150-154, 1980. [PubMed: 6968531]