HGNC Approved Gene Symbol: CCNC
Cytogenetic location: 6q16.2 Genomic coordinates (GRCh38): 6:99,542,387-99,568,814 (from NCBI)
Lew et al. (1991) isolated a number of cDNAs derived from human mRNAs that could substitute for G1 cyclin genes in S. cerevisiae. Three novel genes were identified, which they called cyclins C, D (CCND1; 168461), and E (CCNE1; 123837). The 3 novel proteins were sufficiently distantly related to the other members of the cyclin family and to each other as to constitute 3 new classes of cyclins. Cyclin C and E mRNAs accumulated periodically during the cell cycle, peaking at different times in G1.
Li et al. (1996) showed that the CCNC gene was deleted in a subset of acute lymphoblastic leukemias, suggesting its involvement in tumorigenesis.
Mammalian CDK8 (603184) and cyclin C are components of the RNA polymerase II holoenzyme complex, where they function as a protein kinase that phosphorylates the C-terminal domain of the largest subunit of RNA polymerase II. The CDK8/cyclin C protein complex is also found in a number of mammalian Mediator-like protein complexes, which repress activated transcription independently of the C-terminal domain in vitro. Akoulitchev et al. (2000) demonstrated that CDK8/cyclin C can regulate transcription by targeting the CDK7 (601955)/cyclin H (601953) subunits of the general transcription initiation factor IIH (189972). CDK8 phosphorylates mammalian cyclin H at serine 5 and serine 304 both in vitro and in vivo, in the vicinity of its functionally unique N- and C-terminal alpha-helical domains. This phosphorylation represses both the ability of TFIIH to activate transcription and its C-terminal kinase activity. In addition, mimicking CDK8 phosphorylation of cyclin H in vivo has a dominant-negative effect on cell growth. Akoulitchev et al. (2000) concluded that their results linked the Mediator complex and the basal transcription machinery by a regulatory pathway involving 2 cyclin-dependent kinases. This pathway appears to be unique to higher organisms.
p21 (CDKN1A; 116899) is a key mediator of p53 (TP53; 191170)-dependent cell cycle arrest. Donner et al. (2007) found that transcriptional activity of the p21 promoter in human cell lines varied in response to distinct p53-activating stimuli. Core Mediator subunits MED1 (PPARBP; 604311) and MED17 (603810) were recruited to the p21 gene regardless of the p53-activating stimuli used. In contrast, 3 subunits of the CDK module of Mediator, CDK8, MED12 (300188), and cyclin C, were recruited following treatment with nutlin-3, a nongenotoxic drug that activates p53, but not in response to DNA damage induced by ultraviolet light C.
CCNC was mapped to chromosome 6q21 by Demetrick et al. (1995) using fluorescence in situ hybridization. By fluorescence in situ hybridization, Li et al. (1996) confirmed the localization of CCNC to chromosome 6q21.
Akoulitchev, S., Chuikov, S., Reinberg, D. TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407: 102-106, 2000. [PubMed: 10993082] [Full Text: https://doi.org/10.1038/35024111]
Demetrick, D. J., Matsumoto, S., Hannon, G. J., Okamoto, K., Xiong, Y., Zhang, H., Beach, D. H. Chromosomal mapping of the genes for the human cell cycle proteins cyclin C (CCNC), cyclin E (CCNE), p21 (CDKN1) and KAP (CDKN3). Cytogenet. Cell Genet. 69: 190-192, 1995. [PubMed: 7698009] [Full Text: https://doi.org/10.1159/000133960]
Donner, A. J., Szostek, S., Hoover, J. M., Espinosa, J. M. CDK8 is a stimulus-specific positive coregulator of p53 target genes. Molec. Cell 27: 121-133, 2007. [PubMed: 17612495] [Full Text: https://doi.org/10.1016/j.molcel.2007.05.026]
Lew, D. J., Dulic, V., Reed, S. I. Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast. Cell 66: 1197-1206, 1991. [PubMed: 1833066] [Full Text: https://doi.org/10.1016/0092-8674(91)90042-w]
Li, H., Lahti, J. M., Valentine, M., Saito, M., Reed, S. I., Look, A. T., Kidd, V. J. Molecular cloning and chromosomal localization of the human cyclin C (CCNC) and cyclin E (CCNE) genes: deletion of the CCNC gene in human tumors. Genomics 32: 253-259, 1996. [PubMed: 8833152] [Full Text: https://doi.org/10.1006/geno.1996.0112]