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Transcription factor Jun is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
that in humans is encoded by the ''JUN''
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. c-Jun, in combination with protein c-Fos, forms the AP-1 early response
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the JUN gene. c-jun was the first
oncogenic Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
transcription factor discovered. The proto-oncogene c-Jun is the cellular homolog of the viral oncoprotein v-jun (). The viral homolog v-jun was discovered in avian sarcoma virus 17 and was named for ''ju-nana'', the Japanese word for 17. The human JUN encodes a protein that is highly similar to the viral protein, which interacts directly with specific target DNA sequences to regulate
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.


Function


Regulation

Both Jun and its dimerization partners in AP-1 formation are subject to regulation by diverse extracellular stimuli, which include peptide growth factors, pro-inflammatory
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...
s, oxidative and other forms of cellular stress, and UV irradiation. For example, UV irradiation is a potent inducer for elevated c-jun expression. 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. 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. It is activated through double phosphorylation by the JNK pathway but has also a phosphorylation-independent function. c-jun
knockout A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, a ...
is lethal, but transgenic animals with a mutated c-jun that cannot be phosphorylated (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. 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. Another study showed that oncogenic transformation by ras and fos also requires Jun N-terminal phosphorylation at Serine 63 and 73.


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 or RB may stand for: Arts and entertainment * Rebecca Black, an American pop singer * Richard Blackwood, a British rapper * Rhythm and blues, a music genre combining blues, gospel and jazz influences * '' Rock Band'', a music video game series ...
. 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. In cells absent of c-jun, the expression of p53 (cell cycle arrest inducer) and
p21 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associate ...
(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.


Anti-apoptotic activity

UV irradiation can activate c-jun expression and the JNK signaling pathway. C-jun protects cells from UV-induced apoptosis, and it cooperates with NF-κB to prevent apoptosis induced by
TNFα Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
. 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. 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.


Clinical significance

It is known that c-jun plays a role in
cellular proliferation Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...
and apoptosis of the
endometrium The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional laye ...
throughout the
menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
. 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.


Cancer

In a study using non-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. 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.


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.


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 MMP-9, increased in vitro chemoinvasion, and tumor formation in nude mice in the absence of exogenous estrogens. The MCF-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. 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. In mammary tumors, endogenous c-jun was found to play a key role in ErbB2-induced migration and invasion of mammary epithelial cells. Jun transcriptionally activates the promoters of SCF (
stem cell factor Stem cell factor (also known as SCF, KIT-ligand, KL, or steel factor) is a cytokine that binds to the c-KIT receptor (CD117). SCF can exist both as a transmembrane protein and a soluble protein. This cytokine plays an important role in hematopoie ...
) and CCL5. 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.


Vulvar cancer

C-jun has been observed overexpressed in Vulvar Squamous Cell Carcinoma samples, in association with hypermethylation-Induced inactivation of the RARB tumor suppressor gene. 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.


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.


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.


As anti-cancer drug target

Since c-jun has been observed overexpressed in cancer, 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. 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. 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.


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.


p16

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.


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.


Interactions

C-jun has been shown to interact with: * ATF2 * AR *
ASCC3 Activating signal cointegrator 1 complex subunit 3 is a protein that in humans is encoded by the ''ASCC3'' gene. Interactions ASCC3 has been shown to interact with RELA, C-jun and Serum response factor Serum response factor, also known as SR ...
* ATF3 * BCL3 *
BCL6 Bcl-6 (B-cell lymphoma 6) is a protein that in humans is encoded by the ''BCL6'' gene. BCL6 is a master transcription factor for regulation of T follicular helper cells (TFH cells) proliferation. BCL6 has three evolutionary conserved structural do ...
* BRCA1 * C-Fos *
CSNK2A1 Casein kinase II subunit alpha is an enzyme that in humans is encoded by the ''CSNK2A1'' gene. Casein kinase II is a serine/threonine protein kinase that phosphorylates acidic proteins such as casein. The kinase exists as a tetramer and is comp ...
*
COPS5 COP9 constitutive photomorphogenic homolog subunit 5 (Arabidopsis), also known as COPS5 or Csn5, is a gene conserved from humans to Saccharomyces cerevisiae. Function The protein encoded by this gene is one of the eight subunits of COP9 signal ...
* CREBBP * CSNK2A2 * DDX21, *
DDIT3 DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptosis, apoptotic transcription factor that is encoded by the ''DDIT3'' gene. It is a member of the CCAAT-enhancer-binding proteins, CCAAT/enhancer-bind ...
* ERG *
ETS2 Protein C-ETS2 is a protein that in humans is encoded by the ''ETS2'' gene. The protein encoded by this gene belongs to the ETS family of transcription factors. Interactions ETS2 has been shown to interact with: * C-jun, * Cyclin-depen ...
, * FOSL1 * GTF2B *
MAPK8 Mitogen-activated protein kinase 8 (also known as JNK1) is a ubiquitous enzyme that in humans is encoded by the ''MAPK8'' gene. Function The protein encoded by this gene is a member of the MAP kinase and JNK family. MAP kinases act as an integ ...
* MyoD * NACA * NELFB * NFE2L1 * NFE2L2 * NCOR2 * NCOA1 * PIN1 *
RBM39 RNA-binding protein 39 is a protein that in humans is encoded by the ''RBM39'' gene. Function The protein encoded by this gene is an RNA binding protein and possible splicing factor. The encoded protein is found in the nucleus, where it coloca ...
* RELA * RB1 *
RFWD2 E3 ubiquitin-protein ligase RFWD2 is an enzyme that in humans is encoded by the ''RFWD2'' gene. Interactions RFWD2 has been shown to interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501 ...
* RUNX1 * RUNX2 * SMAD3 * STAT1 * STAT3 * TBP *
TGIF1 Homeobox protein TGIF1 is a protein that, in humans, is encoded by the ''TGIF1'' gene. Alternative splicing has been observed at this locus and eight variants, encoding four distinct isoforms, are described. Function The protein encoded by thi ...


See also

* c-Jun N-terminal kinases


References


Further reading

* * * * *


External links

* *
''Drosophila'' ''Jun-related antigen'' - The Interactive Fly
* * {{Transcription factors, g1