Transcription factor Jun

Transcription factor Jun is a

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.[9]^[10]

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.^[11]

It is activated through double phosphorylation by the

Phosphorylation of Jun at serines 63 and 73 and threonine 91 and 93 increases transcription of the c-jun target genes.^[12] 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.^[13] Another study showed that oncogenic transformation by ras and fos also requires Jun N-terminal phosphorylation at Serine 63 and 73.^[14]

Cell cycle progression

Studies have shown that c-jun is required for progression through the G1 phase of the cell cycle, and c-jun null cells show increased G1 arrest. C-jun regulates the transcriptional level of cyclin D1, which is a major Rb 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 of p53 (cell cycle arrest inducer) and p21 (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.^[15]

Anti-apoptotic activity

UV irradiation can activate c-jun expression and the JNK signaling pathway. C-jun protects cells from UV-induced

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 gene noxa. Also, c-jun can protect hepatocytes from apoptosis, as hepatocytes 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.^[16]

Clinical significance

It is known that c-jun plays a role in cellular proliferation and apoptosis of the endometrium throughout the menstrual 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 prevent stromal cells from entering into apoptosis during the late secretory phase.^[17]

Cancer

In a study using

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 and angiogenesis.^[19]

Tumor initiation

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.^[16]

Breast cancer

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 enzyme

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. This finding suggests that c-jun plays a critical role in the metastasis of breast cancer.[21]

In mammary tumors, endogenous c-jun was found to play a key role in

C-jun has been observed overexpressed in Vulvar Squamous Cell Carcinoma samples, in association with hypermethylation-Induced inactivation of the RARB tumor suppressor gene.^[9] Indeed, mRNA levels of c-Jun tested higher in Vulvar 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.^[9]

Cellular differentiation

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 human liposarcoma) can block or delay adipocytic differentiation of those cells.^[23]

Nerve and spinal cord regeneration

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.^[24]

As anti-cancer drug target

Since c-jun has been observed overexpressed in cancer,^[9] 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.^[14] 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.^[12] Therefore, targeting the N-terminal phosphorylation of Jun (or the JNK signaling pathway) can be a potential strategy for inhibiting tumor growth.

In melanoma-derived B16-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.^[25]

Anti-cancer property of c-jun

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.^[26]

p16

p16^INK4a is a tumor suppressor and a cell cycle inhibitor, and a study shows that c-jun acts as “bodyguard” to p16^INK4a by preventing methylation of the p16^INK4a promoter. Therefore, c-jun can prevent silencing of the gene p16^INK4a.^{[citation needed]}

Tylophorine

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.^[27]

Interactions

C-jun has been shown to

See also

• c-Jun N-terminal kinases

References