Alternative titles; symbols
HGNC Approved Gene Symbol: ZNF703
Cytogenetic location: 8p11.23 Genomic coordinates (GRCh38): 8:37,695,782-37,700,019 (from NCBI)
ZNF703, or NLZ1, belongs to the NET family of transcriptional regulators, which includes Drosophila Noca and Elb, C. elegans Tlp1, and the vertebrate NLZ proteins. ZNF703 is a transcriptional repressor of TCF (see 153245)/beta-catenin (CTNNB1; 116806)-mediated transcription (Pereira-Castro et al., 2013).
Slorach et al. (2011) cloned mouse Znf703, which they called Zeppo1. The deduced protein shares 96% amino acid identity with its human ortholog. It has an SP box in its N-terminal half, and a cysteine-rich domain, a C2H2-type zinc finger, and a proline- and tyrosine-rich domain, in its C-terminal half.
Pereira-Castro et al. (2013) stated that the deduced 590-amino acid ZNF703 protein, which they called NLZ1, contains 6 domains conserved in NLZ proteins: an N-terminal leucine- and proline-rich (LP) domain, followed by an SP domain, a proline- and tyrosine-rich (PY) domain, a BTD (SP8; 608306) box, a C2H2-type zinc finger, and a C-terminal tyrosine- and leucine-rich (YL) domain. RT-PCR detected NLZ1 in all human and mouse tissues examined and in all human tumor cell lines examined. Using 3-prime RACE, Pereira-Castro et al. (2013) found 3 NLZ1 transcripts that differed only in the lengths of their 3-prime UTRs. All 3 transcripts were detected in human placenta, muscle, liver, intestine, and brain. Only the longest transcript, which showed predominant expression, had a canonical polyadenylation signal (AATAAA). Epitope-tagged human NLZ1 localized to nucleus, and a small amount was found in nuclear dot-like structures.
Pereira-Castro et al. (2013) stated that the ZNF703 gene maps to chromosome 8p11.23.
Breast cancers (see 114480) often show amplification of chromosome 11q12-q14 and/or chromosome 8p12. Kwek et al. (2009) found that CCND1 (168461) on chromosome 11q13 induced expression of ZNF703 on chromosome 8p12. Moreover, CCND1 and ZNF703 cooperated with a dominant-negative TP53 (191170) mutant to induce colony formation in breast cancer cell lines.
Holland et al. (2011) found that ZNF703 expression was elevated in luminal B breast cancer subtype and that it functioned as a driver of breast tumor formation. Tumors with elevated ZNF703 levels were characterized by alterations in a lipid metabolism and detoxification pathway that included DHRS2 (615194) as a key signaling component.
Using a reporter gene assay, Slorach et al. (2011) found that mouse Zeppo1 functioned as a transcriptional repressor. Overexpression of Zeppo1 in mouse mammary epithelial cells reduced cell-cell adhesion, increased cell invasion and proliferation, and increased lung metastases in a mouse breast cancer model. Zeppo1 complexed with Grg4 (TLE4; 605132) and repressed E-cadherin (CDH1; 192090), Wnt (see 164820) and Tgf-beta (TGFB1; 190180) reporter expression. Zeppo1 promoted expression of a metastasis-associated isoform of p120 catenin (CTNND1; 601045) and altered p120 catenin localization upon cell contact with the extracellular matrix.
Using yeast 2-hybrid and coimmunoprecipitation analyses, Pereira-Castro et al. (2013) showed that human NLZ1 interacted with GRG5 (AES; 600188). Domain analysis revealed that the YL domain of NLZ1 was essential for NLZ1 nuclear localization and that the PY domain contributed to NLZ1 nuclear localization. NLZ1 functioned as a repressor in a reporter gene assay, and it reduced TCF/beta-catenin-mediated transcriptional activation in cotransfected HEK293 cells.
Using cells from embryonic day-7.75 mice, mouse embryonic stem cells, and transfected HEK293 cells, Kumar et al. (2016) showed that mouse Zfp703 was a Wnt target gene that inhibited Wnt/beta-catenin activity in Wnt reporter assays and in Wnt-dependent mesoderm differentiation. Zfp703 bound directly to Tcf1 to inhibit beta-catenin/Tcf1 complex formation, and it did so independently of the Groucho/Tle transcriptional corepressor. The authors proposed that Zfp703 is a feedback suppressor of Wnt/beta-catenin signaling that inhibits the association of beta-catenin with nuclear Tcf1 on Wnt response elements in target genes.
Pereira-Castro et al. (2013) stated that the NLZ1 and NLZ2 (ZNF503; 613902) genes originated from a duplication event that occurred more than 730 million years ago, after the separation of urochordate and vertebrate lineages.
Holland, D. G., Burleigh, A., Git, A., Goldgraben, M. A., Perez-Mancera, P. A., Chin, S.-F., Hurtado, A., Bruna, A., Ali, H. R., Greenwood, W., Dunning, M. J., Samarajiwa, S., and 10 others. ZNF703 is a common luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium. EMBO Molec. Med. 3: 167-180, 2011. [PubMed: 21337521] [Full Text: https://doi.org/10.1002/emmm.201100122]
Kumar, A., Chalamalasetty, R. B., Kennedy, M. W., Thomas, S., Inala, S. N., Garriock, R. J., Yamaguchi, T. P. Zfp703 is a Wnt/beta-catenin feedback suppressor targeting the beta-catenin/Tcf1 complex. Molec. Cell. Biol. 36: 1793-1802, 2016. [PubMed: 27090637] [Full Text: https://doi.org/10.1128/MCB.01010-15]
Kwek, S. S., Roy, R., Zhou, H., Climent, J., Martinez-Climent, J. A., Fridlyand, J., Albertson, D. G. Co-amplified genes at 8p12 and 11q13 in breast tumors cooperate with two major pathways in oncogenesis. Oncogene 28: 1892-1903, 2009. [PubMed: 19330026] [Full Text: https://doi.org/10.1038/onc.2009.34]
Pereira-Castro, I., Costa, A. M. S., Oliviera, M. J., Barbosa, I., Rocha, A. S., Azevedo, L., Teixeira de Costa, L. Characterization of human NLZ1/ZNF703 identifies conserved domains essential for proper subcellular localization and transcriptional repression. J. Cell. Biochem. 114: 120-133, 2013. [PubMed: 22886885] [Full Text: https://doi.org/10.1002/jcb.24309]
Slorach, E. M., Chou, J., Werb, Z. Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform expression and localization. Genes Dev. 25: 471-484, 2011. [PubMed: 21317240] [Full Text: https://doi.org/10.1101/gad.1998111]