JUNB

Official Full Name

JunB proto-oncogene, AP-1 transcription factor subunit

Organism

Homo sapiens

GeneID

3726

Background

Enables sequence-specific double-stranded DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. Part of transcription factor AP-1 complex. Implicated in head and neck squamous cell carcinoma and melanoma. Biomarker of gastrointestinal system cancer (multiple); lung non-small cell carcinoma; and lymphoma (multiple). [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

AP-1;

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Detailed Information

Recent Research

The jun gene family (c-jun, junB and junD) encode nuclear phosphoproteins that are components of the mammalian transcription factor Activator Protein-1 (AP-1). AP-1 complexes are composed of protein dimers of the Jun family and heterodimers of the Jun and Fos (c-Fos, Fra1, Fra2 and FosB) families. AP-1 can convert extracellular signals into changes in the transcription of many cellular and viral genes. Signals affecting AP-1 activity include tumor promoters, growth factors, cytokines, carcinogens and specific oncogenes. Besides, AP-1 is also critically involved in processes such as apoptosis as well as in the cell response to genotoxic agents.

There is enough evidence that the AP-1 complex participates in the malignant transformation of keratinocytes. Blocking of AP-1 activity, for example, leads to the suppression of growth factor-induced transformation and squamous cell carcinoma development. JunB can promote or inhibit tumor formation. Over-expression of JunB has been reported to be associated with neoplastic transformation of thyroid cells and the gene is either structurally altered, amplified or over-expressed in cervical and ovarian cancers. Furthermore, constitutive over-expression of JunB in a human fibrosarcoma cell line causes induction of collagenase-1 expression, a matrix metalloproteinase (MMP), which is closely associated with the invasive and metastatic potential of malignant cells. However, other reports indicate that JunB can inhibit cellular transformation, suggesting that in certain systems it may act as a tumor suppressor. In addition, aberrantly expressed c-Jun and JunB are a hallmark of a common human lymphoma. Some reports show that the c-Jun and JunB transcription factors are constitutively expressed at a high level in primary and cultivated tumor cells of classical Hodgkin’s disease (cHD).

Some reports showed thatAP-1 plays a potential role in cell cycle progression, during mitosis, the level of c-Jun protein remains constant, while JunB decreases. Moreover, the Jun proteins undergo specific post-translational modifications during M and early G1 phases. JunB is phosphorylated by the Cdc2– cyclin B complex on specific amino acids that are not conserved in c-Jun or JunD, triggering its degradation. The c-Jun becomes phosphorylated on its N-terminal serines. Moreover, these stage-specific Jun modifications are important for cell cycle progression. It has been demonstrated that changing the c-Jun to JunB ratio in the cell affects cyclin D1 gene transcription.

JunB has been extensively studied in cancer models where it acts as a tumor suppressor. In cellular models of type 1 diabetes (cytokine- treated b-cells), JunB was shown to promote b-cell survival by inhibiting NF-kB activity and regulating ATF3 expression. GLP-1 agonists such as exendin-4, used for the treatment of T2D, have been shown to improve insulin secretion and preserve b-cell mass. Part of their protective effect is mediated by up-regulation of JunB expression and consequent protection against FFA-induced b-cell apoptosis. In fact, JunB mainly modulates the endoplasmic reticulum (ER) stress response and AKT signaling. JunB stimulates XBP1 expression via the transcription factor c/EBP during ER stress, and forced expression of XBP1s rescued the viability of JunB-deficient cells, constituting an important anti-apoptotic mechanism. JunB silencing inhibited AKT activation and activated the proapoptotic Bcl-2 protein BAD via its dephosphorylation. BAD knockdown reversed lipotoxic b-cell death potentiated by JunB siRNA. Moreover, XBP1s links JunB and AKT signaling as XBP1 knockdown also reduced AKT phosphorylation. GLP-1 agonists induced cAMP-dependent AKT phosphorylation leading to b-cell protection against palmitate-induced apoptosis. JunB and XBP1 knockdown or IRE1 inhibition decreased AKT activation by cAMP, leading to b-cell apoptosis.

It is reported that JunB plays an important nonredundant role in the regulation of vascular endothelial growth factor (VEGF) production and angiogenesis. When the different Jun members were deleted in mice, only the loss of JunB affected vascular development. More recent studies have demonstrated that JunB can bind directly to an AP-1 consensus sequence within a 1.2 kb region of the mouse VEGF promoter and up-regulate VEGF production in response to hypoxia or hypoglycemia independently of hypoxia-inducible factor-1 (HIF-1) signaling.

JunB is widely expressed throughout embryonic development and its expression is maintained at a low level in adult tissues. Embryos lacking a functional JunB protein die between embryonic day E8.5 and E10.0 of development due to defective feto-maternal interactions. The reason is inability of JunB-deficient embryos to establish proper vascular interactions with the maternal circulation due to multiple defects in extra-embryonic tissues. Most importantly, gene expression and function in cells of extra-embryonic tissues, such as trophoblast giant cells, as well as endothelial cells of the yolk sac and placental cell types are affected. In trophoblasts, the lack of JunB causes a deregulation of proliferin, matrix metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (uPA) gene expression, resulting in a defective neovascularization of the decidua. As a result of down-regulation of the VEGF-receptor1 (flt-1), blood vessels in the yolk sac mesoderm appeared dilated. Mutant embryos which escape these initial defects finally die from a non-vascularized placental labyrinth.

References:

Robinson C M, et al. Overexpression of JunB in undifferentiated malignant rat oral keratinocytes enhances the malignant phenotype in vitro without altering cellular differentiation. International Journal of Cancer, 2015, 91(5):625-630.
Ryzhov S, et al. Role of JunB in adenosine A2B receptor-mediated vascular endothelial growth factor production.Molecular Pharmacology, 2014, 85(1):62-73.
Schorpp‐Kistner M, et al. JunB is essential for mammalian placentation. Embo Journal, 2014, 18(4):934-948.
Bakiri L, Lallemand D, et al. Cell cycle‐dependent variations in c‐Jun and JunB phosphorylation: a role in the control of cyclin D1 expression. Embo Journal, 2014, 19(9):2056-2068.
Cunha DA, et al. JunB protects β-cells from lipotoxicity via the XBP1-AKT pathway. Cell Death & Differentiation, 2014, 21(8):1313-1324.
Mathas S, et al. Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-κB. Embo Journal, 2014, 21(15):4104-4113.

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