AP-1 (Activating protein-1) is a transcription factor that controls various cellular processes including differentiation, proliferation, and apoptosis. These proteins were primarily considered as oncogenic, but recent studies have challenged this view. Continue to read to know more about the various effects of AP-1 on Cancer and other factors in Human health.
- Introduction: What is it?
- Effects of AP-1 on Human Health
- 1) Suppression of AP-1 Factors Maintains Breast Cancer Cell Growth
- 2) AP-1 Contributes to Degenerative Bone Diseases
- 3) AP-1 Promotes Tumor Lesions Caused by Cervical Cancer
- 4) AP-1 Assists in Wound Healing
- 5) AP-1 Contributes to Melanoma and Tumorigenesis
- 6) Photoaging Driven by AP-1 Pathways
- 7) AP-1 Regulates Inflammatory Skin Disease
- 8) UVB Irradiation-Induced Skin Damage
- 9) AP-1 Inhibition Prevents Initiation of Atherosclerosis
- 10) AP-1 Pathways Targeted for Rheumatoid Arthritis Therapeutic Strategies
- 11) AP-1 Inhibition Alleviates Ulcerative Colitis by LL202
- AP-1 inhibitors
Introduction: What is it?
AP-1 stands for activating protein-1. It is a dimeric transcription comprised of the sub-units Jun (c-jun, junB, junD), Fos (c-fos, fra-1, fra-2), or ATF (activating transcription factor).
They bind to a common DNA site, which is referred to as an AP-1 binding site.
Gene knockout mice studies have helped scientists understand the complexity of these factors and that AP-1 can control different genes and perform specific biological functions.
Effects of AP-1 on Human Health
1) Suppression of AP-1 Factors Maintains Breast Cancer Cell Growth
By blocking AP-1 complex, multiple growth signals that cause breast cell proliferation and transformation may be restrained.
To increase breast cancer cells, there need to be signals from specific growth factors like estrogen, peptide growth factors, epidermal growth factor (EGF), transforming growth factor α (TGFα), interleukins, hematopoietic cytokines, and heregulin and insulin-like growth factors (IGFs).
All these elements stimulate an increase in the activity of this transcription factor in different ways.
For instance, in connective tissue (fibroblast), an excess of AP-1 activity can cause cell growth (proliferation), but in hematopoietic and neuronal cells it causes cell production.
Tam67, a cJun dominant-negative mutant, is used to inhibit AP-1 factors causing a blockade.
The AP-1 blockade restrains cell cycle division during the first stage of the cell cycle (G1 phase), therefore decreasing the prevalence of G1 proteins that initiate nuclear division (cyclins) at production and protein levels.
It also restrains the signals that cause breast cell overproduction by causing a cell cycle blockade in Activating Protein transcription factors.
This is extremely important because many breast cancer cells become resistant to anti-estrogen treatments, and understanding other targets for breast cancer can help researchers identify other chemopreventive and chemotherapeutic strategies (R, R2).
2) AP-1 Contributes to Degenerative Bone Diseases
The Fos subunit of AP-1 is a major contributor in bone development. C-fos is a differentiation-specific transcription factor for cells that resorb bone tissue (osteoclasts).
Fra-2 is an important element for cartilage cells in differentiation and formative cells in human embryos.
Studies found that newborns lacking Fra-2 have an increased size and number of osteoclasts, in organisms. This is caused by impaired leukemia inhibitory factor (LIF) transmission factors and a reduced amount of oxygen to body tissues.
Therefore, the imbalance or underexpression of Fra-2 could be a contributing factor for developing weakening bone diseases (osteoclastogenesis) like Stuve-Wiedemann syndrome, Paget’s disease, and the transfer of bone disease (metastasis) (R).
A study on knockout mice also found that Fra-2 broadly expressed by the histamine promoter in numerous organs can cause severe fibrotic disease in the lung, highly cancerous tumors, and an increase in bone mass (R2).
3) AP-1 Promotes Tumor Lesions Caused by Cervical Cancer
AP-1 subunits differ in their activity to either activate or transpress HPV-linked cancer (carcinogenesis) of the uterine cervix.
However, this transcription factor plays a major role in the HPV oncogene (a gene within the chromosomes of tumor cells that turn normal cells into cancer cells) expression.
It does so by being a major component of signal transduction (a signal like a hormone converted into a biomedical response) by combining short-term stimulation to cells with long term modification to genes.
The high binding activity of AP-1 also promotes the formation of tumor lesions and can occur in cervical lesions that were and were not caused by HPV.
During the binding activity of AP-1, c-fos expression highly increased and Fra-1 expression decreased in relation to the increasing severity of the cervical lesions.
As the disease severity became invasive, Fras-1 decreased to nearly zero. JunB is another subunit of Activating Protein-1 that is involved with the DNA binding activity, and it has higher levels within carcinoma cells (R, R2).
4) AP-1 Assists in Wound Healing
AP-1 moderates gene management in response to extracellular stimuli like growth factors, cytokines, oncogenes, tumor promoters, and chemical cancer.
Sub-units of this transcription factor have various contributing factors to different layers of skin.
In humans, JunB and JunD are expressed in all layers of the epidermis but are at the highest levels in the baseline and spinous layers. JunC is restricted to granular layers, while c-fos is found in spinous and granular layers.
These expressions of AP-1 subunits indicates that the proteins are associated with cells of the epidermis that make keratin (keratinocyte). Keratin is extremely important because it is the main component of the epidermis, nails, and teeth.
AP-1 functioning is necessary for situations that require a rapid and temporary balance of keratinocyte multiplication and production.
Therefore, Activating Protein-1 functioning benefits skin (cutaneous) wound healing. This is by regulating the creation of regulatory proteins released by the immune system (cytokines) and cell growth factors.
Also, subunits like Jun, Fos, and ATP are receiving proteins to such factors (R).
5) AP-1 Contributes to Melanoma and Tumorigenesis
AP-1 expression and activity correlate with different changes in the development and progression stages of melanoma.
Studies on mice show that JunB and Jun-C function as progression factors for immediate stages of tumorigenesis. This was found due to the excess of JunB and Jun-C in cells of fibrous tumorlike nodules (fibromatosis).
AP-1 also contributes to the malignancy of epidermal cells.
Studies found AP-1 binding and transactivating ability in malignant cells. Phosphates added to c-Jun, Fra-1, Fra-2, and ATP-2 proteins are associated with malignancy, as well (R).
6) Photoaging Driven by AP-1 Pathways
The process of premature aging caused by ultraviolet rays (photoaging) involves the induction of AP-1 regulated matrix metalloproteinases (MMP).
7) AP-1 Regulates Inflammatory Skin Disease
AP-1 regulates inflammation by p65/NF-kB-dependent and -independent inflammatory mediators.
The reduction or imbalance of JunB and c-Jun can cause skin diseases like psoriasis (a chronic, non-contagious disease that causes lesions covered with silvery-white scabs of dead skin), lichen planus, and dermatofibrosis.
A reduction in the binding activity of this transcription factor was also found in lesions caused by psoriasis. The modulation of Jun in keratinocytes can trigger an oversupply of chemokine/cytokine.
8) UVB Irradiation-Induced Skin Damage
AP-1 has been proven to balance certain processes in the base (basal) of the epidermal layer of the skin.
Overexposure to ultraviolet radiation on the skin can have numerous adverse effects on the body like oxidative stress, inflammation, reactive oxygen species (ROS) mediated DNA damage, and cellular signaling pathways disorders.
Thyme vulgaris alcohol extracts were tested on mice for their antioxidative effects on UV radiation. The study concluded that thyme vulgaris protected the mice against ultraviolet rays that burn and damage the epidermis (UVB).
It does so by reducing the activation and deactivation of AP-1 signaling pathways in normal human dermal connective tissue (R).
9) AP-1 Inhibition Prevents Initiation of Atherosclerosis
AP-1 transmission pathways are involved in the initiation of the accumulation of waxy build up inside blood vessels (atherosclerosis).
Studies show that AP-1 increases during the development of progressive and non-progressive atherosclerosis, but is absent in the subsequent progressive stages of the disease.
Atherosclerosis is a large contributor to heart disease, and scientists have pinpointed AP-1 as a target for therapeutic interventions.
Doxycycline, an anti-inflammatory and immunomodulating agent, was tested on patients with atherosclerosis in arteries of the extremities (peripheral artery disease, PAD).
In cells, Doxycycline was proven to be an effective selective inhibitor of this transcription factor and is comparable to SP600125 (R).
10) AP-1 Pathways Targeted for Rheumatoid Arthritis Therapeutic Strategies
Curcumin, the main component of turmeric, has anti-inflammatory and anti-arthritic characteristics.
Studies conducted on rheumatoid arthritis patients concluded that curcumin administered in a dose-dependent manner can reduce bone reduction (osteoclastogenesis).
Osteoclastogenesis is done by suppressing protein expression levels of c-Fos (a sub-unit of Activating Protein-1) and MAPK, in peripheral blood mononuclear cells (PBMC).
AP-1 and other inflammatory transcription factors can be repressed by glucocorticoids. Glucocorticoid receptors prevent interactions between DNA-bound Activating Protein-1 complexes and other transcriptional co-activators.
This suppresses the pro-inflammatory characteristics of the Activating Protein, thus preventing autoimmune diseases like rheumatoid arthritis (R).
11) AP-1 Inhibition Alleviates Ulcerative Colitis by LL202
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD), which is a spontaneous (idiopathic), chronic, and recurrent inflammatory condition in the gastrointestinal tract.
AP-1 has transcriptional factors that play a large role in inflammation within the body. It has a model of gene adjustment that exacerbates chronic inflammatory diseases such as UC.
Studies performed on mice found that LL202 can protect the body against dextran sulfate sodium (DSS) colitis by constraining the expression, interaction, and translocation of Activating Protein-1, specifically c-Jun and c-Fos.
It also decreases protein levels of c-Jun and c-Fos in THP-1 cells stimulated by fat and carbohydrates (lipopolysaccharides).
LL202 is a recently manufactured flavonoid, which is a large class of odorless plant pigments that is a basis for white and yellow plant pigments (R).
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