Alternative titles; symbols
HGNC Approved Gene Symbol: HIVEP3
Cytogenetic location: 1p34.2 Genomic coordinates (GRCh38) : 1:41,506,365-42,035,934 (from NCBI)
Members of the ZAS family, such as ZAS3 (HIVEP3), are large proteins that contain a ZAS domain, a modular protein structure consisting of a pair of C2H2 zinc fingers with an acidic-rich region and a serine/threonine -rich sequence. These proteins bind specific DNA sequences, including the kappa-B motif (GGGACTTTCC), in the promoters and enhancer regions of several genes and viruses, including human immunodeficiency virus (HIV). ZAS genes span more than 150 kb and contain at least 10 exons, one of which is longer than 5.5 kb (summary by Allen and Wu, 2005).
Hicar et al. (2001) cloned HIVEP3, a member of the HIVEP family (see HIVEP1; 194540). HIVEPs encode large zinc finger proteins and regulate transcription via the kappa-B enhancer motif. HIVEP3 is homologous to the mouse Krc (kappa-B-binding and recognition component of the V(D)J recombination signal sequence) protein. The largest open reading frame of HIVEP3 contains 2,406 amino acids and is 80% identical to Krc. RNA studies showed that multiple HIVEP3 transcripts are differentially expressed and regulated. Transcription termination occurs in the ultimate exon, exon 10, or in exon 6. Therefore, HIVEP3 may produce protein isoforms that contain or exclude the C-terminal DNA-binding domain and the leucine zipper by alternative RNA splicing and differential polyadenylation.
Oukka et al. (2002) described a function for the zinc finger transcription factor Krc in regulating patterns of gene activation in response to proinflammatory stimuli. Krc overexpression inhibited, while antisense or dominant-negative Krc enhanced, NF-kappa-B (NFKB; see 164011)-dependent transactivation and JNK (601158) phosphorylation and consequently inhibited apoptosis and cytokine gene expression. The effect of Krc was mediated through its interaction with the adaptor protein TRAF2 (601895). Oukka et al. (2002) concluded that Krc is a participant in the signal transduction pathway leading from the TNF receptor (see 602746) to gene activation and may play a critical role in inflammatory and apoptotic responses.
Hong et al. (2003) found an absence of non-Rel kappa-B protein and constitutive nuclear expression and activation of the NFKB p65 subunit (RELA; 164014) in immortalized pre-B-cell lines from a malignant mouse teratoma that spontaneously developed in a Zas3 -/- Rag2 (179616) -/- mouse. The results suggested that ZAS3 modulates NFKB transcriptional activation.
Using T-cell lines, Oukka et al. (2004) showed that KRC was induced by T-cell receptor (TCR; see 186880) signaling and enhanced IL2 (147680) production by binding to JUN (165160) and coactivating AP1 (165160), which bound the IL2 promoter.
Jones et al. (2006) showed that Schnurri-3 (Shn3), a mammalian homolog of the Drosophila zinc-finger adaptor protein Shn, is an essential regulator of adult bone formation. Mice lacking Shn3 display adult-onset osteosclerosis with increased bone mass due to augmented osteoblast activity. Shn3 was found to control protein levels of Runx2 (600211), the principal transcriptional regulator of osteoblast differentiation, by promoting its degradation through recruitment of the E3 ubiquitin ligase WWP1 (602037) to Runx2. By this means, Runx2-mediated extracellular matrix mineralization was antagonized, revealing an essential role for Shn3 as a central regulator of postnatal bone mass.
By genomic sequence analysis, Hicar et al. (2001) determined that the HIVEP3 gene spans at least 300 kb and has 10 exons.
By genomic sequence analysis, Hicar et al. (2001) mapped the HIVEP3 gene to chromosome 1p34.
By deleting exon 2 of the Krc gene, Oukka et al. (2004) generated mice lacking the Krc protein but retaining normal lymphoid development and CD4 T-cell numbers and CD4 T-cell maturation markers. CD4 T cells from Krc -/- mice produced significantly less IL2 after TCR stimulation, but were able to respond to exogenous IL2 with normal Ifng (147570) production.
Jones et al. (2010) stated that Shn2 (HIVEP2; 143054) -/- mice display a modest low-turnover osteopenia due to reduced osteoclast and osteoblast function, whereas Shn3 -/- mice show severe osteosclerosis due to increased osteoblast activity and elevated rate of bone formation. Jones et al. (2010) found that Shn2 -/- Shn3 -/- double-knockout mice displayed severe growth retardation resulting in dwarfism and did not survive beyond 3 weeks of age. Shn2 -/- Shn3 -/- skeletal defects were due to shortening of both axial and appendicular skeletons, incomplete formation of thoracic vertebrae, impaired sternum development, and shortening of proximal and distal limb bones. Increased bone mass in Shn2 -/- Shn3 -/- mice was similar to that observed in Shn3 -/- mice and was due to elevated osteoblast activity. Complete ablation of both Shn2 and Shn3 was necessary to perturb growth plate maturation, whereas deletion of a single Shn3 allele was sufficient to cause increased bone mass, which could be augmented by deletion of an Shn2 allele.
Allen, C. E., Wu, L.-C. ZAS zinc finger proteins: the other kappa-B-binding protein family.In: Iuchi, S; Kuldell, N. (eds.) : Zinc Finger Proteins: From Atomic Contact to Cellular Function. Georgetown, Tex.: Landes Bioscience 2005. Pp. 213-220.
Hicar, M. D., Liu, Y., Allen, C. E., Wu, L.-C. Structure of the human zinc finger protein HIVEP3: molecular cloning, expression, exon-intron structure, and comparison with paralogous genes HIVEP1 and HIVEP2. Genomics 71: 89-100, 2001. [PubMed: 11161801] [Full Text: https://doi.org/10.1006/geno.2000.6425]
Hong, J.-W., Allen, C. E., Wu, L.-C. Inhibition of NF-kappa-B by ZAS3, a zinc-finger protein that also binds to the kappa-B motif. Proc. Nat. Acad. Sci. 100: 12301-12306, 2003. [PubMed: 14530385] [Full Text: https://doi.org/10.1073/pnas.2133048100]
Jones, D. C., Schweitzer, M. N., Wein, M., Sigrist, K., Takagi, T., Ishii, S., Glimcher, L. H. Uncoupling of growth plate maturation and bone formation in mice lacking both Schnurri-2 and Schnurri-3. Proc. Nat. Acad. Sci. 107: 8254-8258, 2010. [PubMed: 20404140] [Full Text: https://doi.org/10.1073/pnas.1003727107]
Jones, D. C., Wein, M. N., Oukka, M., Hofstaetter, J. G., Glimcher, M. J., Glimcher, L. H. Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3. Science 312: 1223-1227, 2006. [PubMed: 16728642] [Full Text: https://doi.org/10.1126/science.1126313]
Oukka, M., Kim, S. T., Lugo, G., Sun, J., Wu, L.-C., Glimcher, L. H. A mammalian homolog of Drosophila schnurri, KRC, regulates TNF receptor-driven responses and interacts with TRAF2. Molec. Cell 9: 121-131, 2002. [PubMed: 11804591] [Full Text: https://doi.org/10.1016/s1097-2765(01)00434-8]
Oukka, M., Wein, M. N., Glimcher, L. H. Schnurri-3 (KRC) interacts with c-Jun to regulate the IL-2 gene in T cells. J. Exp. Med. 199: 15-24, 2004. [PubMed: 14707112] [Full Text: https://doi.org/10.1084/jem.20030421]