Transcription factor Jun is aprotein that in humans is encoded by theJUNgene. c-Jun, in combination withprotein c-Fos, forms theAP-1 early responsetranscription factor. It was first identified as the Fos-binding proteinp39 and only later rediscovered as the product of the JUN gene. c-jun was the firstoncogenic transcription factor discovered.[5] The proto-oncogene c-Jun is the cellular homolog of the viraloncoprotein v-jun (P05411).[6] The viral homolog v-jun was discovered in avian sarcoma virus 17 and was named forju-nana, theJapanese word for 17.[7] The human JUN encodes a protein that is highly similar to the viral protein, which interacts directly with specific target DNA sequences to regulategene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.[8]
Both Jun and its dimerization partners in AP-1 formation are subject to regulation by diverse extracellular stimuli, which include peptide growth factors, pro-inflammatorycytokines, oxidative and other forms of cellular stress, andUV irradiation. For example, UV irradiation is a potent inducer for elevated c-jun expression.[6]
As with otherimmediate early genes, induction ofc-jun transcription can occur using existing proteins in the cell, and it can be induced even when protein synthesis is blocked experimentally.[9]
c-jun transcription is autoregulated by its own product, Jun. The binding of Jun (AP-1) to a high-affinity AP-1 binding site in the jun promoter region induces jun transcription. This positive autoregulation by stimulating its own transcription may be a mechanism for prolonging the signals from extracellular stimuli. This mechanism can have biological significance for the activity of c-jun in cancer.[10][11]
Also, the c-jun activities can be regulated by the ERK pathway. Constitutively active ERK is found to increase c-jun transcription and stability through CREB and GSK3. This results in activated c-jun and its downstream targets such as RACK1 and cyclin D1. RACK1 can enhance JNK activity, and activated JNK signaling subsequently exerts regulation on c-jun activity.[12]
It is activated through double phosphorylation by theJNK pathway but has also a phosphorylation-independent function. c-junknockout is lethal, buttransgenic animals with a mutated c-jun that cannot bephosphorylated (termed c-junAA) can survive.
Phosphorylation of Jun at serines 63 and 73 and threonine 91 and 93 increases transcription of the c-jun target genes.[13] Therefore, regulation of c-jun activity can be achieved through N-terminal phosphorylation by the Jun N-terminal kinases (JNKs). It is shown that Jun's activity (AP-1 activity) in stress-induced apoptosis and cellular proliferation is regulated by its N-terminal phosphorylation.[14] Another study showed that oncogenic transformation by ras and fos also requires Jun N-terminal phosphorylation at Serine 63 and 73.[15]
Studies have shown that c-jun is required for progression through theG1 phase of thecell cycle, and c-jun null cells show increased G1 arrest. C-jun regulates the transcriptional level ofcyclin D1, which is a majorRb kinase. Rb is a growth suppressor, and it is inactivated by phosphorylation. Therefore, c-jun is required for maintaining sufficient cyclin D1 kinase activity and allowing cell cycle progression.[6]
In cells absent of c-jun, the expression ofp53 (cell cycle arrest inducer) andp21 (CDK inhibitor and p53 target gene) is increased, and those cells exhibit cell cycle defects. Overexpression of c-jun in cells results in decreased level of p53 and p21, and exhibits accelerated cell proliferation. C-jun represses p53 transcription by binding to a variant AP-1 site in the p53 promoter. Those results indicate that c-jun downregulates p53 to control cell cycle progression.[16]
UV irradiation can activate c-jun expression and the JNK signaling pathway. C-jun protects cells from UV-inducedapoptosis, and it cooperates withNF-κB to prevent apoptosis induced byTNFα. The protection from apoptosis by c-jun requires serines 63/73 (involved in phosphorylation of Jun), which is not required in c-jun-mediated G1 progress. This suggests that c-jun regulates cell cycle progression and apoptosis through two separated mechanisms.[6]
A study utilized liver-specific inactivation of c-jun in hepatocellular carcinoma, which showed impaired tumor development correlated with increased level of p53 protein and the mRNA level of the p53 target genenoxa. Also, c-jun can protect hepatocytes from apoptosis, ashepatocytes lacking c-jun showed increased sensitivity to TNFα-induced apoptosis. In those hepatocytes lacking c-jun, deletion of p53 can restore resistance toward TNFα. Those results indicate that c-jun antagonizes the proapoptotic activity of p53 in liver tumor.[17]
It is known that c-jun plays a role incellular proliferation and apoptosis of theendometrium throughout themenstrual cycle. The cyclic change of the c-jun protein levels is significant in the proliferation and apoptosis of glandular epithelial cells. The persistent stromal expression of c-jun protein may preventstromal cells from entering into apoptosis during the late secretory phase.[18]
In a study usingnon-small cell lung cancers (NSCLC), c-jun was found to be overexpressed in 31% of the cases in primary and metastatic lung tumors, whereas normal conducting airway and alveolar epithelia in general did not express c-jun.[19]
A study with a group consisted of 103 cases of phase I/II invasive breast cancers showed that activated c-jun is expressed predominantly at the invasive front of breast cancer and is associated with proliferation andangiogenesis.[20]
A study was done with liver-specific inactivation of c-jun at different stages of tumor development in mice with chemically induced hepatocellular carcinomas. The result indicates that c-jun is required at the early stage of tumor development, and deletion of c-jun can largely suppress tumor formation. Also, c-jun is required for tumor cell survival between the initiation and progression stages. In contrast to that, inactivation of c-jun in advanced tumors does not impair tumor progression.[17]
Overexpression of c-jun in MCF-7 cells can result in overall increased aggressiveness, as shown by increased cellular motility, increased expression of a matrix-degrading enzymeMMP-9, increased in vitro chemoinvasion, and tumor formation in nude mice in the absence of exogenousestrogens. TheMCF-7 cells with c-jun overexpression became unresponsive to estrogen and tamoxifen, thus c-jun overexpression is proposed to lead to an estrogen-independent phenotype in breast cancer cells. The observed phenotype for MCF-7 cells with c-jun overexpression is similar to that observed clinically in advanced breast cancer, which had become hormone unresponsive.[21]
The invasive phenotype contributed by c-jun overexpression is confirmed in another study. In addition, this study showed increased in vivo liver metastasis by the breast cancer with c-jun overexpression.[22] There is also a study showing that dominant-negative c-Jun deficiency can inhibit in vivo bone metastasis in luminal-type breast cancer, and that c-Jun inhibitors may be a potential treatment for bone metastasis in breast cancer .[23] These findings suggest that c-jun plays a critical role in the metastasis of breast cancer.
In mammary tumors, endogenous c-jun was found to play a key role inErbB2-induced migration and invasion of mammary epithelial cells. Jun transcriptionally activates the promoters of SCF (stem cell factor) andCCL5. The induced SCF and CCL5 expression promotes a self-renewing mammary epithelial population. It suggests that c-jun mediates the expansion of breast cancer stem cells to enhance tumor invasiveness.[24]
C-jun has been observed overexpressed inVulvar Squamous Cell Carcinoma samples, in association with hypermethylation-Induced inactivation of theRARB tumor suppressor gene.[10] Indeed, mRNA levels of c-Jun tested higher inVulvar cancer samples when compared with those of normal skin and preneoplastic vulvar lesions, thus underscoring a cross-link between RARB gene and the oncogene c-Jun.[10]
Ten undifferentiated and highly aggressive sarcomas showed amplification of the jun gene and JUN overexpression at both RNA and protein levels. Overexpression of c-jun in 3T3-L1 cells (a preadipocytic non-tumoral cell line that resembles humanliposarcoma) can block or delay adipocytic differentiation of those cells.[25]
Peripheral nerve injury in rodents rapidly activates JNK signaling which in turn activates c-Jun. In contrast, nerve injury in the central nervous system does not. c-Jun is sufficient to promote axon regeneration in both the peripheral and central nervous systems as overexpression in both dorsal root ganglion neurons and cortical neurons leads to increased regeneration.[26]
Since c-jun has been observed overexpressed in cancer,[10] several studies highlighted the hypothesis that this gene might be a target for cancer therapy. A study showed that oncogenic transformation by ras and fos requires Jun N-terminal phosphorylation at Serine 63 and 73 by the Jun N- terminal kinases (JNK). In this study, the induced skin tumor and osteosarcoma showed impaired development in mice with a mutant Jun incapable of N-terminal phosphorylation.[15] Also, in a mouse model of intestinal cancer, genetic abrogation of Jun N-terminal phosphorylation or gut-specific c-jun inactivation attenuated cancer development and prolonged lifespan.[13] Therefore, targeting the N-terminal phosphorylation of Jun (or the JNK signaling pathway) can be a potential strategy for inhibiting tumor growth.
In melanoma-derivedB16-F10 cancer cells, c-jun inactivation by a pharmacological JNK/jun inhibitor SP combined with JunB knockdown can result in cytotoxic effect, leading to cell arrest and apoptosis. This anti-JunB /Jun strategy can increase the survival of mice inoculated with tumor cells, which suggests a potential antitumor strategy through Jun and JunB inhibition.[27]
Most research results show that c-jun contributes to tumor initiation and increased invasiveness. However, a few studies discovered some alternative activities of c-jun, suggesting that c-jun may actually be a double-edge sword in cancer.[28]
p16INK4a is a tumor suppressor and a cell cycle inhibitor, and a study shows that c-jun acts as “bodyguard” to p16INK4a by preventing methylation of the p16INK4a promoter. Therefore, c-jun can prevent silencing of the gene p16INK4a.[citation needed]
Tylophorine is a type of plant-derived alkaloid with anticancer activity by inducing cell cycle arrest. A study demonstrated that tylophorine treatment increased c-jun protein accumulation. Then c-jun expression in conjunction with tylophorine promotes G1 arrest in carcinoma cells through the downregulation of cyclin A2. Therefore, the result indicates that the anticancer mechanism of tylophorine is mediated through c-jun.[29]
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^Han Y, Katayama S, Futakuchi M, Nakamichi K, Wakabayashi Y, Sakamoto M, et al. (September 2023). "Targeting c-Jun Is a Potential Therapy for Luminal Breast Cancer Bone Metastasis".Molecular Cancer Research.21 (9):908–921.doi:10.1158/1541-7786.MCR-22-0695.PMID37310848.
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^Zhong H, Zhu J, Zhang H, Ding L, Sun Y, Huang C, et al. (December 2004). "COBRA1 inhibits AP-1 transcriptional activity in transfected cells".Biochemical and Biophysical Research Communications.325 (2):568–73.doi:10.1016/j.bbrc.2004.10.079.PMID15530430.
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