Alternative titles; symbols
HGNC Approved Gene Symbol: ZBTB17
Cytogenetic location: 1p36.13 Genomic coordinates (GRCh38): 1:15,941,869-15,976,101 (from NCBI)
See ZNF91 (603971) for general information on zinc finger proteins.
Transcriptional regulatory proteins containing tandemly repeated zinc finger domains are thought to be involved in both normal and abnormal cellular proliferation and differentiation. One abundant class of such transcriptional regulators resembles the Drosophila Kruppel segmentation gene product due to the presence of repeated cys2-his2 (C2H2) zinc finger domains that are connected by conserved sequences, called H/C links. By screening a human insulinoma cDNA library with a degenerate oligonucleotide corresponding to the H/C linker sequence, Tommerup et al. (1993) isolated cDNAs potentially encoding zinc finger proteins. Tommerup and Vissing (1995) performed sequence analysis on a number of these cDNAs and identified several novel zinc finger protein genes, including ZNF151. The ZNF151 cDNA predicts a protein belonging to the Kruppel family of zinc finger proteins.
The MYC (190080) protein activates transcription as part of a heteromeric complex with MAX (154950). However, cells transformed by MYC are characterized by the loss of expression of numerous genes, suggesting that MYC may also repress gene expression. To search for proteins that may mediate gene repression by MYC, Peukert et al. (1997) used the yeast 2-hybrid system with the basic region and helix-loop-helix (HLH)/leucine zipper domain of MYC as bait. They identified a HeLa cell cDNA encoding ZNF151, which they called MIZ1 for 'MYC-interacting zinc finger protein-1.' The full-length MIZ1 cDNA sequence predicts an 803-amino acid protein containing an N-terminal POZ (poxvirus and zinc finger) domain and 13 zinc finger domains, 12 of which are clustered. The deduced human MIZ1 protein shares 92% sequence identity with the closely related mouse protein Z13. Peukert et al. (1997) noted that high MIZ1 expression was observed in brain and muscle.
Peukert et al. (1997) found that human MIZ1 had a potent growth arrest function; HeLa cells expressing recombinant MIZ1 progressed into S phase but not into mitosis. MIZ1 could bind to and transactivate the adenovirus major late and cyclin D1 (CCND1; 168461) promoters. The authors suggested that growth arrest by MIZ1 occurs via the transcriptional activation of a set of growth inhibitory genes. The POZ domain of several transcription factors has been shown to target the proteins to discrete subnuclear foci, to render the proteins insoluble upon extraction, and to inhibit both DNA binding of the attached zinc fingers and transcriptional activation in vivo. Thus, the POZ domain appears to act as a negative regulatory domain for transcription factor function. In contrast to other POZ domain proteins, MIZ1 was soluble and was predominantly located in the cytosol. MIZ1 interacted specifically with MYC and NMYC (164840). Interaction with MYC inhibited MIZ1 transactivation, overcame MIZ1-induced growth arrest, induced MIZ1 nuclear sequestration, and rendered MIZ1 insoluble in vivo. These effects depended on the integrity of the POZ domain of MIZ1. Peukert et al. (1997) suggested that MYC inhibits gene transcription by activating the latent inhibitory functions of the MIZ1 POZ domain.
Ziegelbauer et al. (2001) found that MIZ1 associates with microtubules, can bind directly to the low density lipoprotein receptor (LDLR; 606945) promoter, and can activate LDLR transcription. MIZ1 also binds to the promoter and activates transcription of other T113242 (a synthetic drug)-induced genes such as alpha-2 integrin (192974). Soft x-ray, indirect immunofluorescence, and green fluorescent protein time-lapse microscopy revealed that MIZ1 is largely cytoplasmic but accumulates in the nuclei of HepG2 cells upon treatment with T113242. Thus, MIZ1 appears to be regulated by association with microtubules and may activate gene transcription in response to changes in the cytoskeleton.
Herold et al. (2002) showed that transactivation by MIZ1 is negatively regulated by association with topoisomerase II-binding protein (TOPBP1; 607760). Ultraviolet (UV) irradiation downregulated expression of TOPBP1 and released MIZ1. MIZ1 bound to the p21CIP1 (116899) core promoter in vivo and was required for upregulation of p21CIP1 upon UV irradiation. Using both Myc -/- cells and a point mutant of MYC that is deficient in MIZ1-dependent repression, Herold et al. (2002) showed that MYC negatively regulates transcription of p21CIP1 upon UV irradiation and facilitates recovery from UV-induced cell cycle arrest through binding to MIZ1.
By FISH, Tommerup and Vissing (1995) mapped the ZNF151 gene to chromosome 1p36.2-p36.1.
Adhikary et al. (2003) found that Miz1-null mouse embryos were not viable. They did not undergo normal gastrulation and succumbed to massive apoptosis of ectodermal cells around embryonic day 7.5. Expression of p57(Kip2) (CDKN1C; 600856), a Miz1 target gene, was absent in Miz1-null embryos.
Adhikary, S., Peukert, K., Karsunky, H., Beuger, V., Lutz, W., Elsasser, H.-P., Moroy, T., Eilers, M. Miz1 is required for early embryonic development during gastrulation. Molec. Cell. Biol. 23: 7648-7657, 2003. [PubMed: 14560010] [Full Text: https://doi.org/10.1128/MCB.23.21.7648-7657.2003]
Herold, S., Wanzel, M., Beuger, V., Frohme, C., Beul, D., Hillukkala, T., Syvaoja, J., Saluz, H.-P., Haenel, F., Eilers, M. Negative regulation of the mammalian UV response by Myc through association with Miz-1. Molec. Cell 10: 509-521, 2002. [PubMed: 12408820] [Full Text: https://doi.org/10.1016/s1097-2765(02)00633-0]
Peukert, K., Staller, P., Schneider, A., Carmichael, G., Hanel, F., Eilers, M. An alternative pathway for gene regulation by Myc. EMBO J. 16: 5672-5686, 1997. [PubMed: 9312026] [Full Text: https://doi.org/10.1093/emboj/16.18.5672]
Tommerup, N., Aagaard, L., Lund, C. L., Boel, E., Baxendale, S., Bates, G. P., Lehrach, H., Vissing, H. A zinc-finger gene ZNF141 mapping at 4p16.3/D4S90 is a candidate gene for the Wolf-Hirschhorn (4p-) syndrome. Hum. Molec. Genet. 2: 1571-1575, 1993. [PubMed: 8268908] [Full Text: https://doi.org/10.1093/hmg/2.10.1571]
Tommerup, N., Vissing, H. Isolation and fine mapping of 16 novel human zinc finger-encoding cDNAs identify putative candidate genes for developmental and malignant disorders. Genomics 27: 259-264, 1995. [PubMed: 7557990] [Full Text: https://doi.org/10.1006/geno.1995.1040]
Ziegelbauer, J., Shan, B., Yager, D., Larabell, C., Hoffmann, B., Tjian, R. Transcription factor MIZ-1 is regulated via microtubule association. Molec. Cell 8: 339-349, 2001. [PubMed: 11545736] [Full Text: https://doi.org/10.1016/s1097-2765(01)00313-6]