HGNC Approved Gene Symbol: JUNB
Cytogenetic location: 19p13.13 Genomic coordinates (GRCh38): 19:12,791,486-12,793,315 (from NCBI)
By screening human cDNA libraries with a fragment of the JUN (165160) clone, Nomura et al. (1990) cloned human JUNB and JUND (165162) cDNAs. The predicted open reading frame of JUNB encodes a deduced 347-amino acid protein.
Jacobs-Helber et al. (2002) studied the role of JUNB in erythroid differentiation in an erythropoietin (EPO; 133170)-dependent cell line and in primary mouse and human erythroid cells. They identified an initial EPO-dependent induction of JUNB expression that was insufficient to induce differentiation. A second EPO-independent peak of JUNB expression was associated with erythroid cell differentiation as measured by increased expression of erythroid-specific proteins.
Mathas et al. (2002) found AP1 constitutively activated, with robust JUN (165160) and JUNB overexpression, in all cell lines derived from patients with classical Hodgkin lymphoma (236000) and anaplastic large cell lymphoma (ALCL), but not in other lymphoma types. AP1 supported proliferation of Hodgkin cells, but suppressed apoptosis of ALCL cells. Mathas et al. (2002) noted that, whereas JUN is upregulated by an autoregulatory process, JUNB is under the control of nuclear factor kappa-B (NFKB; 164011). They found that AP1 and NFKB cooperate and stimulate expression of the cell cycle regulator cyclin D2 (123833), the protooncogene MET (164860), and the lymphocyte homing receptor CCR7 (600242), which are all strongly expressed in primary Hodgkin/Reed-Sternberg (HRS) cells.
Gao et al. (2004) found in the case of c-JUN and JUNB that extracellular stimuli modulate protein turnover by regulating the activity of an E3 ligase by means of its phosphorylation. Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) cascade after T cell stimulation accelerated degradation of c-JUN and JUNB through phosphorylation-dependent activation of the E3 ligase ITCH (606409). Gao et al. (2004) found that this pathway modulates cytokine production by effector T cells.
Using Usp38 (618322)-deficient mice, Chen et al. (2018) showed that Usp38 deubiquitinated polyubiquitination of JunB to block JunB protein turnover in T-cell receptor signaling, thereby promoting T-helper-2 (Th2) cytokine production and Th2 cell differentiation.
In comparisons of the murine and human junB loci, Phinney et al. (1995) found 9 regions of distal 5-prime and 3-prime flanking DNA that exhibited greater than 72% sequence identity. More than 50% of the JUNB locus is contained in these flanking evolutionarily conserved sequences (FECSs), which may be required for effecting the proper transcriptional regulation of the gene. Comparative sequence analyses involving kilobases of distal flanking DNAs for only a small number of vertebrate genes suggested that FECSs may emerge as common yet important functional components of genes. If they account for a large fraction of the conserved sequence within a disease-related locus, then deleterious mutations might frequently occur in these regions and go undetected with current strategies.
Zenz et al. (2005) found reduced JunB expression in lesional skin of severe psoriasis and intermediate expression in mild psoriasis.
Mattei et al. (1990) mapped 3 members of the JUN protooncogene family in the mouse: JUN to mouse chromosome 4 and JUNB and JUND (165162) to the same region of mouse chromosome 8. RFLP analysis of interspecific hybrids confirmed the mapping of JUNB and JUND and showed that they are situated about 7.3 cM apart. Using the same probes for in situ hybridization, Mattei et al. (1990) showed that the human genes are located on 19p13.2, a region that is involved in chromosome translocations in cases of leukemia. By fluorescence in situ hybridization, Trask et al. (1993) assigned the JUNB gene to 19p13.2.
Passegue et al. (2001) created transgenic mice specifically lacking JunB expression in the myeloid lineage. These mice developed a transplantable myeloproliferative disease, eventually progressing to blast crisis, that resembled human chronic myeloid leukemia. Similarly, mice reconstituted with embryonic stem cell-derived JunB -/- fetal liver cells also developed a myeloproliferative disease. In both cases, the absence of JunB expression resulted in increased numbers of granulocyte progenitors that displayed enhanced granulocyte-macrophage colony-stimulating factor (GMCSF, or CSF2; 138960)-mediated proliferation and extended survival, associated with changes in the expression levels of the GMCSF receptor-alpha (CSF2RA; 306250), the antiapoptotic proteins BCL2 (151430) and BCLX (600039), and the cell cycle regulators p16INK4A (CDKN2A; 600160) and JUN. Ectopic expression of JunB fully reverted the immature and hyperproliferative phenotype of JunB-deficient myeloid cells. These results identified JUNB as a key transcriptional regulator of myelopoiesis and a potential tumor suppressor gene.
Passegue et al. (2004) investigated the function of JunB during normal and leukemic hematopoiesis using a JunB transgenic mouse model associated with myeloproliferative disorder (Passegue et al., 2001), as well as several models of conditional inactivation and overexpression of JunB in hematopoietic stem cells (HSCs). They showed that JunB regulates the numbers of HSCs. JunB overexpression decreased the frequency of long-term HSCs, while JunB inactivation specifically expanded the numbers of long-term HSCs and granulocyte/macrophage progenitors, resulting in chronic myeloproliferative disorder. Passegue et al. (2004) demonstrated that JunB inactivation must have taken place in long-term HSCs, and not at later stages of myelopoiesis, to induce myeloproliferative disorder, and that only JunB-deficient long-term HSCs were capable of transplanting the myeloproliferative disorder to recipient mice. These results demonstrated a stem cell-specific role for JunB in normal and leukemic hematopoiesis and provided experimental evidence that leukemic stem cells can reside at the long-term HSC stage of development in a mouse model of myeloproliferative disorder.
The JUN and JUNB components of the AP1 transcription factor are known to have antagonistic functions. Passegue et al. (2002) showed, by a knockin strategy and a transgenic complementation approach, that JunB can substitute for absence of Jun during mouse development. JunB can rescue both liver and cardiac defects in Jun-null mice in a manner dependent on gene dosage. JunB restores the expression of genes regulated by Jun/Fos (164810), but not those regulated by Jun/ATF (ATF1; 123803), thereby rescuing Jun-dependent defects in vivo as well as in primary fibroblasts and fetal hepatoblasts in vitro. Thus, the transcriptionally less active JunB has the potential to substitute for Jun, indicating that the spatial and temporal regulation of expression of the transcription factor AP1 may be more important than the coding sequence of its components.
Zenz et al. (2005) designed inducible, conditional, single- and double-knockout mice for JunB and c-Jun. Mutant mice and littermate controls were treated with tamoxifen at 8 weeks of age. Single-mutant mice did not show any skin phenotype up to 2 months after deletion. However, in JunB/c-Jun double-mutant mice, alterations to the hairless skin appeared 8 to 10 days after tamoxifen induction. After 18 days of tamoxifen treatment, 100% of the double-mutant mice showed a strong phenotype with scaly plaques affecting primarily ears, paws, and tail, and less frequently the hairy back skin. Histology of affected skin from mutant mice showed the hallmarks of psoriasis, such as a strongly thickened epidermis with prominent rete ridges, thickened keratinized upper layers (hyperkeratosis) and parakeratosis (nucleated keratinocytes in the cornified layer) and increased subepidermal vascularization. Arthritic lesions strongly reminiscent of psoriatic arthritis were observed with 100% penetrance.
Chen, S., Yun, F., Yao, Y., Cao, M., Zhang, Y., Wang, J., Song, X., Qian, Y. USP38 critically promotes asthmatic pathogenesis by stabilizing JunB protein. J. Exp. Med. 215: 2850-2867, 2018. [PubMed: 30224386] [Full Text: https://doi.org/10.1084/jem.20172026]
Gao, M., Labuda, T., Xia, Y., Gallagher, E., Fang, D., Liu, Y.-C., Karin, M. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306: 271-275, 2004. [PubMed: 15358865] [Full Text: https://doi.org/10.1126/science.1099414]
Jacobs-Helber, S. M., Abutin, R. M., Tian, C., Bondurant, M., Wickrema, A., Sawyer, S. T. Role of JunB in erythroid differentiation. J. Biol. Chem. 277: 4859-4866, 2002. [PubMed: 11726656] [Full Text: https://doi.org/10.1074/jbc.M107243200]
Mathas, S., Hinz, M., Anagnostopoulos, I., Krappmann, D., Lietz, A., Jundt, F., Bommert, K., Mechta-Grigoriou, F., Stein, H., Dorken, B., Scheidereit, C. Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-kappa-B. EMBO J. 21: 4104-4113, 2002. [PubMed: 12145210] [Full Text: https://doi.org/10.1093/emboj/cdf389]
Mattei, M. G., Simon-Chazottes, D., Hirai, S., Ryseck, R. P., Galcheva-Gargova, Z., Guenet, J. L., Mattei, J. F., Bravo, R., Yaniv, M. Chromosomal localization of the three members of the jun proto-oncogene family in mouse and man. Oncogene 5: 151-156, 1990. [PubMed: 2108401]
Nomura, N., Ide, M., Sasamoto, S., Matsui, M., Date, T., Ishizaki, R. Isolation of human cDNA clones of jun-related genes, jun-B and jun-D. Nucleic Acids Res. 18: 3047 only, 1990. [PubMed: 2112242] [Full Text: https://doi.org/10.1093/nar/18.10.3047]
Passegue, E., Jochum, W., Behrens, A., Ricci, R., Wagner, E. F. JunB can substitute for Jun in mouse development and cell proliferation. Nature Genet. 30: 158-166, 2002. [PubMed: 11818961] [Full Text: https://doi.org/10.1038/ng790]
Passegue, E., Jochum, W., Schorpp-Kistner, M., Mohle-Steinlein, U., Wagner, E. F. Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking JunB expression in the myeloid lineage. Cell 104: 21-32, 2001. [PubMed: 11163237] [Full Text: https://doi.org/10.1016/s0092-8674(01)00188-x]
Passegue, E., Wagner, E. F., Weissman, I. L. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119: 431-443, 2004. [PubMed: 15507213] [Full Text: https://doi.org/10.1016/j.cell.2004.10.010]
Phinney, D. G., Tseng, S. W., Ryder, K. Complex genetic organization of junB: multiple blocks of flanking evolutionarily conserved sequence at the murine and human junB loci. Genomics 28: 228-234, 1995. [PubMed: 8530030] [Full Text: https://doi.org/10.1006/geno.1995.1135]
Trask, B., Fertitta, A., Christensen, M., Youngblom, J., Bergmann, A., Copeland, A., de Jong, P., Mohrenweiser, H., Olsen, A., Carrano, A., Tynan, K. Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Genomics 15: 133-145, 1993. [PubMed: 8432525] [Full Text: https://doi.org/10.1006/geno.1993.1021]
Zenz, R., Eferl, R., Kenner, L., Florin, L., Hummerich, L., Mehic, D., Scheuch, H., Angel, P., Tschachler, E., Wagner, E. F. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437: 369-375, 2005. Note: Erratum: Nature 440: 708 only, 2006. [PubMed: 16163348] [Full Text: https://doi.org/10.1038/nature03963]