Alternative titles; symbols
HGNC Approved Gene Symbol: MKI67
Cytogenetic location: 10q26.2 Genomic coordinates (GRCh38): 10:128,096,659-128,126,423 (from NCBI)
MKI67 is a 359-kD nuclear protein commonly used to detect and quantify proliferating cells, with increased expression associated with cell growth. MKI67 expression reflects the cellular proliferation rate, and MKI67 is broadly used as a diagnostic marker in various cancers (summary by Hou et al., 2011).
By immunoscreening a cDNA expression library, followed by RT-PCR and 5-prime and 3-prime RACE, Schluter et al. (1993) isolated 2 cDNAs encoding isoforms of Ki-67. The shorter isoform lacks exon 7. Northern blot analysis revealed multiple transcripts ranging from approximately 8.9 to 12.5 kb in proliferating but not quiescent cells. Immunoblot analysis showed expression of 320- and 359-kD proteins. Sequence analysis predicted that the short-lived 2,896- and 3,256-amino acid protein isoforms contain potential nuclear targeting signals, over 200 potential phosphorylation sites, 19 N-myristoylation sites, 3 amidation sites, and numerous PEST sites.
Schluter et al. (1993) found that antisense oligonucleotides to Ki-67 inhibited cellular proliferation in a dose-dependent manner, suggesting that Ki-67 protein expression may be an absolute requirement for cell proliferation.
Hou et al. (2011) showed that microRNA-519D (MIR519D; 614247) was downregulated in human hepatocellular carcinomas (HCCs) and that expression of MIR519D could suppress growth in the QGY-7703 human HCC cell line. Bioinformatic analysis revealed a potential MIR519D-binding site in the 3-prime UTR of MKI67. Overexpression of MIR519D significantly downregulated MKI67 and reduced colony formation by QGY-7703 cells. RT-PCR revealed an overall increase in MKI67 expression and a decrease in MIR519D expression in 10 HCCs compared with adjacent normal tissue.
In mice, Takeo et al. (2013) showed that nail stem cells (NSCs) reside in the proximal nail matrix and are defined by high expression of keratin-14 (148066), keratin-17 (148069), and KI67. The mechanisms governing NSC differentiation are coupled directly to their ability to orchestrate digit regeneration. Early nail progenitors undergo Wnt (see 164820)-dependent differentiation into the nail. After amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to the regeneration of the digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate the nail or digit. Nevertheless, beta-catenin (116806) stabilization in the NSC region induced their regeneration. Takeo et al. (2013) concluded that their results established a link between nail stem cell differentiation and digit regeneration, and suggested that NSCs may have the potential to contribute to the development of novel treatments for amputees.
Cuylen et al. (2016) reported that the proliferation marker protein KI67, encoded by the MKI67 gene, a component of the mitotic chromosome periphery, prevents chromosomes from collapsing into a single chromatin mass after nuclear envelope disassembly, thus enabling independent chromosome motility and efficient interactions with the mitotic spindle. The chromosome separation function of human KI67 was not confined within a specific protein domain, but correlated with size and net charge of truncation mutants that apparently lacked secondary structure. This suggested that KI67 forms a steric and electrostatic charge barrier, similar to surface-active agents (surfactants) that disperse particles or phase-separated liquid droplets in solvents. Fluorescence correlation spectroscopy showed a high surface density of KI67, and dual-color labeling of both protein termini revealed an extended molecular conformation, indicating brush-like arrangements that are characteristic of polymeric surfactants. Cuylen et al. (2016) concluded that their study elucidated a biomechanical role of the mitotic chromosome periphery in mammalian cells and suggested that natural proteins can function as surfactants in intracellular compartmentalization.
Cuylen-Haering et al. (2020) showed in HeLa cells that large cytoplasmic components were displaced before nuclear envelope assembly by the movement of chromosomes to a dense cluster during mitosis. Clustering occurred when chromosomes approached the poles of anaphase spindles and was mediated by a microtubule-independent mechanism involving Ki67. Ki67 formed repulsive molecular brushes during the early stages of mitosis, but during mitotic exit the brushes collapsed and Ki67 promoted chromosome clustering. Exclusion of mature ribosomes from nucleus after mitosis depended on Ki67-regulated chromosome clustering.
Schluter et al. (1993) determined that the Ki-67 gene contains 15 exons. The Ki-67 repeat region, within which there is a 22-amino acid Ki-67 motif, is encoded by exon 13.
From study of a panel of human-rodent somatic cell hybrids, Schonk et al. (1989) demonstrated that a gene involved in the expression of the MKI67 antigen is located on chromosome 10. By in situ hybridization, Fonatsch et al. (1991) regionalized the MKI67 gene to chromosome 10q25-qter. By FISH, Traut et al. (1998) mapped the mouse Mki67 gene to chromosome 7F3-F5.
Cuylen, S., Blaukopf, C., Politi, A. Z., Muller-Reichert, T., Neumann, B., Poser, I., Ellenberg, J., Hyman, A. A., Gerlich, D. W. Ki-67 acts as a biological surfactant to disperse mitotic chromosomes. Nature 535: 308-312, 2016. [PubMed: 27362226] [Full Text: https://doi.org/10.1038/nature18610]
Cuylen-Haering, S., Petrovic, M., Hernandez-Armendariz, A., Schneider, M. W. G., Samwer, M., Blaukopf, C., Holt, L. J., Gerlich, D. W. Chromosome clustering by Ki-67 excludes cytoplasm during nuclear assembly. Nature 587: 285-290, 2020. [PubMed: 32879492] [Full Text: https://doi.org/10.1038/s41586-020-2672-3]
Fonatsch, C., Duchrow, M., Rieder, H., Schluter, C., Gerdes, J. Assignment of the human Ki-67 gene (MKI67) to 10q25-qter. Genomics 11: 476-477, 1991. [PubMed: 1769665] [Full Text: https://doi.org/10.1016/0888-7543(91)90163-9]
Hou, Y.-Y., Cao, W.-W., Li, L., Li, S.-P., Liu, T., Wan, H.-Y., Liu, M., Li, X., Tang, H. MicroRNA-519d targets MKi67 and suppresses cell growth in the hepatocellular carcinoma cell line QGY-7703. Cancer Lett. 307: 182-190, 2011. [PubMed: 21524841] [Full Text: https://doi.org/10.1016/j.canlet.2011.04.002]
Schluter, C., Duchrow, M., Wohlenberg, C., Becker, M. H. G, Key, G., Flad, H.-D., Gerdes, J. The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins. J. Cell. Biol. 123: 513-522, 1993. [PubMed: 8227122] [Full Text: https://doi.org/10.1083/jcb.123.3.513]
Schonk, D. M., Kuijpers, H. J. H., vanDrunen, E., vanDalen, C. H., Geurts van Kessel, A. H. M., Verheijen, R., Ramaekers, F. C. S. Assignment of the gene(s) involved in the expression of the proliferation-related Ki-67 antigen to human chromosome 10. Hum. Genet. 83: 297-299, 1989. [PubMed: 2571566] [Full Text: https://doi.org/10.1007/BF00285178]
Takeo, M., Chou, W. C., Sun, Q., Lee, W., Rabbani, P., Loomis, C., Taketo, M. M., Ito, M. Wnt activation in nail epithelium couples nail growth to digit regeneration. Nature 499: 228-232, 2013. [PubMed: 23760480] [Full Text: https://doi.org/10.1038/nature12214]
Traut, W., Scholzen, T., Winking, H., Kubbutat, M. H. G., Gerdes, J. Assignment of the murine Ki-67 gene (Mki67) to chromosome band 7F3-F5 by in situ hybridization. Cytogenet. Cell Genet. 83: 12-13, 1998. [PubMed: 9925911] [Full Text: https://doi.org/10.1159/000015153]