Alternative titles; symbols
HGNC Approved Gene Symbol: CDK11B
Cytogenetic location: 1p36.33 Genomic coordinates (GRCh38): 1:1,635,225-1,659,004 (from NCBI)
Bunnell et al. (1990) identified a human cell division control (CDC)-related protein kinase, p58, that is structurally and functionally related to p34(cdc2) (CDC2; 116940). Abnormal expression of the p58 protein kinase in eukaryotic cells had effects suggesting that it is a negative regulator of normal cell cycle progression. The gene is well conserved evolutionarily. Its expression is regulated during murine embryogenesis, and its activity is coordinately regulated with that of p34(cdc2) during the cell cycle.
Lahti et al. (1994) characterized the genomic region surrounding CDC2L1 and found that a related gene, CDC2L2 (116951), was located within 100 kb. They referred to CDC2L1 as PITSLRE B, based on the amino acid sequence of the region corresponding to the conserved CDC2 PSTAIRE box.
Xiang et al. (1994) isolated multiple, alternatively spliced CDC2L1 and CDC2L2 mRNAs. The CDC2L1 transcripts encode protein isoforms ranging in size from 58 to 110 kD. The isoforms vary in the length and sequence of their N-terminal regions; the protein kinase catalytic and C-terminal domains are identical. All contain a 30-residue acid blob domain comprised primarily of glutamic acid. The larger protein species contained a putative bipartite nuclear localization signal. Western blot analysis revealed that the 58-kD isoform was present only in cells undergoing apoptosis. Xiang et al. (1994) analyzed the expression pattern of the CDC2L1 mRNAs.
The CDC2L1 and CDC2L2 genes encode almost identical protein kinases of 110 kD that contain at their C termini the open reading frame of a smaller isoform of 58 kD. Cornelis et al. (2000) found that 2 PITSLRE protein kinase isoforms, p110 and p58, are translated from a single transcript by initiation at alternative in-frame AUG codons. p110 is produced by classic cap-dependent translation, whereas p58 results from internal initiation of translation controlled by an internal ribosome entry site (IRES) with unique properties. The IRES element is localized to the mRNA coding region, and its activity is cell cycle regulated, permitting translation of p58 in G2/M.
Loyer et al. (2008) stated that both CDC2L2 and CDC2L1 can produce a third isoform, p46, by caspase-dependent proteolysis of either the p110 or p58 isoforms. By immunofluorescence analysis of several human cell lines, they detected p110 in both nucleoplasm and nuclear speckles. Western blot analysis showed robust expression of p110 in several human cell lines and in activated human peripheral blood cells. Only activated blood cells expressed p58 and p46. Size exclusion chromatography of HeLa cells revealed that p110 fractionated with protein complexes of about 170 kD to over 1 MDa.
Lahti et al. (1994) demonstrated that 1 allele of the entire gene CDC2L complex was either deleted or translocated in 18 of 20 neuroblastoma (256700) cell lines investigated. They suggested that the CDC2L gene complex may harbor 1 or more tumor suppressor genes affected by chromosome 1p36 modifications in neuroblastoma.
By immunoprecipitation analysis and protein pull-down assays with human cell lines, Loyer et al. (2008) found that p110 CDK11 associated with the alpha and beta isoforms of cyclin L1 (CCNL1; 613384) and L2 (CCNL2; 613482) in a high molecular mass complex that showed splicing activity. The p58 and p46 CDK11 isoforms interacted more weakly with the cyclin L alpha isoforms. In vivo splicing assays showed that expression of cyclin L1-alpha, L1-beta, L2-alpha, or L2-beta and/or p110 CDK11 increased intron-splicing activity and altered alternative splice-site selection in a cyclin L1 and L2 isoform- and cell type-specific manner. In contrast with p110 CDK11, p58 and p46 CDK11 reduced splicing activity.
Eipers et al. (1992) detailed the complete structure of the CDC2L1 gene including its putative promoter region, transcriptional start sites, exonic sequences, and intron/exon boundary sequences. The gene spans 10 kb and contains 12 exons.
Gururajan et al. (1998) determined the structure of the 140-kb CDC2L genomic region. This region consists of 2 identical genomic segments arranged in a tail-to-tail configuration. Each segment contains a CDC2L gene linked to an MMP gene. See MMP21 (603320). In each case, the most widely expressed products of the CDC2L gene are derived from a genomic region that is composed of 20 exons and spans approximately 20 kb. The authors reported that only 15 amino acids of the 773-786 residues that encode the multiple CDC2L isoforms are unique to either CDC2L1 or CDC2L2.
Eipers et al. (1991) assigned the expressed p58 gene to chromosome 1p36 by somatic cell hybrid analysis, in situ hybridization, and nested PCR amplification of microdissected chromosomes. The authors stated that this gene, tentatively symbolized PK58, may be implicated in the pathogenesis of tumors that have deletion in the region of 1p36.
By fluorescence in situ hybridization, Lahti et al. (1994) mapped the CDC2L1 gene to 1p36.3.
White et al. (1995) showed that CDC2L1 is located outside the consensus region of allelic loss of heterozygosity (LOH) associated with neuroblastomas, namely 1p36.3-p36.2, and is therefore not the neuroblastoma suppressor gene.
Bunnell, B., Heath, L. S., Adams, D. E., Lahti, J. M., Kidd, V. J. Elevated expression of a p58 protein kinase leads to changes in the CHO cell cycle. Proc. Nat. Acad. Sci. 87: 7467-7471, 1990. Note: Erratum: Proc. Nat. Acad. Sci. 88: 2612 only, 1991. [PubMed: 2217177] [Full Text: https://doi.org/10.1073/pnas.87.19.7467]
Cornelis, S., Bruynooghe, Y., Denecker, G., Van Huffel, S., Tinton, S., Beyaert, R. Identification and characterization of a novel cell cycle-regulated internal ribosome entry site. Molec. Cell 5: 597-605, 2000. [PubMed: 10882096] [Full Text: https://doi.org/10.1016/s1097-2765(00)80239-7]
Eipers, P. G., Barnoski, B. L., Han, J., Carroll, A. J., Kidd, V. J. Localization of the expressed human p58 protein kinase chromosomal gene to chromosome 1p36 and a highly related sequence to chromosome 15. Genomics 11: 621-629, 1991. [PubMed: 1774066] [Full Text: https://doi.org/10.1016/0888-7543(91)90069-q]
Eipers, P. G., Lahti, J. M., Kidd, V. J. Structure and expression of the human p58(clk-1) protein kinase chromosomal gene. Genomics 13: 613-621, 1992. [PubMed: 1639388] [Full Text: https://doi.org/10.1016/0888-7543(92)90132-c]
Gururajan, R., Lahti, J. M., Grenet, J., Easton, J., Gruber, I., Ambros, P. F., Kidd, V. J. Duplication of a genomic region containing the Cdc2L1-2 and MMP21-22 genes on human chromosome 1p36.3 and their linkage to D1Z2. Genome Res. 8: 929-939, 1998. [PubMed: 9750192] [Full Text: https://doi.org/10.1101/gr.8.9.929]
Lahti, J. M., Valentine, M., Xiang, J., Jones, B., Amann, J., Grenet, J., Richmond, G., Look, A. T., Kidd, V. J. Alterations in the PITSLRE protein kinase gene complex on chromosome 1p36 in childhood neuroblastoma. Nature Genet. 7: 370-375, 1994. [PubMed: 7920654] [Full Text: https://doi.org/10.1038/ng0794-370]
Loyer, P., Trembley, J. H., Grenet, J. A., Busson, A., Corlu, A., Zhao, W., Kocak, M., Kidd, V. J., Lahti, J. M. Characterization of cyclin L1 and L2 interactions with CDK11 and splicing factors: influence of cyclin L isoforms on splice site selection. J. Biol. Chem. 283: 7721-7732, 2008. [PubMed: 18216018] [Full Text: https://doi.org/10.1074/jbc.M708188200]
White, P. S., Maris, J. M., Beltinger, C., Sulman, E., Marshall, H. N., Fujimori, M., Kaufman, B. A., Biegel, J. A., Allen, C., Hilliard, C., Valentine, M. B., Look, A. T., Enomoto, H., Sakiyama, S., Brodeur, G. M. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3. Proc. Nat. Acad. Sci. 92: 5520-5524, 1995. [PubMed: 7777541] [Full Text: https://doi.org/10.1073/pnas.92.12.5520]
Xiang, J., Lahti, J. M., Grenet, J., Easton, J., Kidd, V. J. Molecular cloning and expression of alternatively spliced PITSLRE protein kinase isoforms. J. Biol. Chem. 269: 15786-15794, 1994. [PubMed: 8195233]