Alteration of p53, p53 Family Proteins and Their Isoforms by H Pyroli in Gastric Cancer

Therefore, the most notable P53-induced mechanisms in mediating this response are cell cycle arrest and apoptosis [18], which activation depends on the cellular context and the extent of damage [20].

The purpose of this research was to determine the mechanisms in naked mole-rats that restricts cell proliferation and tumor formation. Contact inhibition is a mechanism observed where cell proliferation stops when two cells come in contact with one another. This process is caused by elevated levels of p27 cyclin-dependent kinase inhibitor which stops cells in the G1 phase from dividing. The cylcin-dependent kinase inhibitor p16 is also thought to regulate contact inhibition but its levels do not change in mice or human samples. Tumor-suppressor genes Rb and p53 are present in high concentration during contact inhibition to help control cell proliferation and apoptosis respectively. It was hypothesized that the naked mole-rats' cancer resistivity

Besides inducing apoptosis and controlling the cell cycle, p53 has been demonstrated to be a central component and key regulator of the metabolic stress machinery. The metabolic balance between glycolysis and oxidative phosphorylation is heavily coordinated by p53 activity, which is activated by

Mutations (for most cancers) must appear in both tumour suppressing genes and oncogenes for cancers to form. The tumour suppressing genes and oncogenes act in complementary fashion to one another; one pulls forward, and the other pushes back ensuring that the cell cycle occurs in a controlled manner (Sherr, 2004).

Stomach Cancer is cancer of the stomach which is also known as Gastric Cancer. It is a disease where malignant cells arise from the lining of the stomach which could eventually grow into a tumor found in the upper part of the abdomen and just below the ribs. Since the stomach is a part of the body’s digestive system, it produces acids and enzymes that break down food before passing through the small intestine which can cause the cancer to develop in any part of the stomach and spreads up towards the esophagus. The cancer happens over a period of a few years of bad acids being ate or inhaled which causes inflammation in your gut called gastritis, long-lasting anemia that continues to grow in the stomach that can also put you at a higher risk to get cancer. Although, not knowing exactly what makes stomach cancer cells, smoking, being overweight, exposure to coal, metal, timber industries all put you at a higher risk of receiving the cancer.

The p53 protein’s primary function is to protect an organism against proliferation of cells containing damaged DNA, this is done in several ways, including cell cycle arrest and apoptosis.43, 44 MDM2 has been shown to be the principal negative regulator of p53, inhibiting its tumour suppressing abilities and thus leading to tumour propagation. To this end disruption of the MDM2/p53 interface is an attractive strategy in cancer therapeutics.45, 46 Independently Grasberger and Vassilev both successfully used HTS of large compound libraries to discover small molecule inhibitors of MDM2.47, 48 Grasberger’s benzodiazepinedione and Vassilev’s cis-imidazoline (Nutlin) were both able to bind to MDM2 at the MDM2/p53 binding region, disrupting the interface and thus blocking the interaction. Subsequent medicinal chemistry optimisation of the Nutlin molecule class (3) yielded the drug compound RG7112 (4, Figure 4).49 RG7112 has been subject to several exploratory human trials showing favourable outcomes, inducing apoptosis and decreasing tumour proliferation in patients with leukaemia and various other

Under normal conditions, cells balance division and apoptosis, and these processes are accomplished and preserved by several biochemical “checkpoints” during the cell cycle2. When these checkpoints are affected, uncontrolled cellular proliferation and cancer can result. Two general classes of cancer genes are oncogenes and tumor suppressor genes. Oncogenes facilitate tumor formation by directly accelerating cell division, whereas tumor suppressor genes, when affected, allow uncontrolled growth that was normally suppressed2. Tumor suppressor gene loss usually affects a cell’s phenotype when both copies of the gene are lost, so null alleles can be present in a heterozygous state in cells without affecting cell and tissue phenotype. The loss of these genes can occur through genetic mutation or the epigenetic silencing of genes via promoter

Functional studies have demonstrated that combination of primary BRAF or NRAS driver genes together with additional genetic alterations such as deletion of CDKN2A or PTEN and inactivation of tumor protein p53 (TP53) tumor suppressor gene as a necessary event to bypass OIS79–82. High frequency BRAF mutation in concert with loss of function in tumor suppressors (PTEN, p53) and cell-cycle control genes (CDKN2A) has also been observed in ~40% human melanoma and most melanoma cell lines further highlighting the importance of co-operating pathways to fully form

Transformation-Related Protein 53, also known as TP53, is a tumor suppressor gene. It is named after its molecular mass. The gene was discovered by Arnold Levine, David Lane, and William Old in 1979 and was voted molecule of the year by science magazine in 1993. Although, it was not until 1989 that it was revealed to be a tumor suppressor gene. It was previously thought of as an oncogene. TP53 encodes for a protein, called p53 protein, that helps to regulate the cell cycle and inhibits mutations in the genome as well. Both of these functions help to conserve stability. One of the reasons for TP53’s high importance, and the extensive research on the gene, is its function to suppress cancer cells in multicellular organisms, including humans (Vijayaraj).

CYP1A1*2A genetic variations have been indicated to raise risk for several cancers, such as cervical cancer, lung cancer, prostate cancer and laryngeal cancer(49,50,51,52). However, poor relations between polymorphic CYP1A1*2A and gastric cancer, colorectal cancer, esophageal cancer and breast cancer risks have been found (53,54,55). Therefore, polymorphism of CYP1A1 MspI might play different roles in different cancers.

Histone acetylation is regulated by two covalent modifying enzymes, acetylases and deacetylases, and plays a key role in gene expression of eukaryotes. It has been revealed that histone deacetylase (HDAC), which is overexpressed in several tumor cells. plays a critical role in carcinogenesis. Moreover, plenty of studies have showed that the expression of tumor suppressors including p53, p21, and gelsolin, are repressed, whereas, tumor activators including hypoxia-induced factor-1 and vascular endothelial growth factor, are up-regulated in HDAC-overexpressed cells.

. The TP53 gene is located on the short (p) arm of chromosome 17 at position 13.1. [7]. TP53 has many important mechanisms of anticancer function and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms: p53 can activate DNA, and repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging. The gene has a very important location in the nucleus of our cells, where it binds directly to DNA. TP53 can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition. If it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to

This includes covalent modifications of the p53 gene (altering positive and negative feedback loops in the signaling pathway). P53 gene can be modified at twenty sites, which can change the protein’s behavior in a number of ways. Phosphorylation can inhibit or stimulate protein activity. The attachment or removal of modifying groups controls the behavior of a protein changing it’s activity or stability, which could permit the production of large quantities of the desired protein. Through posttranslational modifications of the p53 gene, this could mediate the control of P53 gene expression through the wnt signaling pathway. The p53 circuit communicates with the Wnt-beta-catenin, IGF-1-AKT, Rb-E2F, p38 MAP kinase, cyclin-cdk, p14/19 ARF pathways. Wnt proteins bind to receptors on the surface of a cell, switching on an intracellular signaling pathway that ultimately leads to the activation of a set of genes that influence cell growth. Wnt transmits its signal by promoting accumulation of free beta-catenin proteins which migrate from the cytoplasm to the nucleus to bind to TCF transcription regulators, creating a complex that activates the transcription of various Wnt-responsive genes, including genes whose products stimulate cell

In the spot assay, p53 mutant T155N was tested for binding by the color it develops. On the high adenine agar plate, the p53 strains, wild type (wt), mutant T155N (mut), and deletion (del), produced white cultures with all p53 response element (RE) sites, consensus (con), p21, and BAX. Therefore, all p53 strains showed transactivation because there was already enough ADE2 protein on the plate (see Figure 1B). Unlike the high adenine agar plate, the low adenine agar plate showed significant differences between the p53 strains and the p53 REs. The p53 wt strain developed white cultures while the p53 deletion strain developed red cultures. The p53 mut strain developed a pink culture with p53 RE con and red cultures with p53 RE p21 and BAX. In this case, p53 wt shows transactivation and a high binding affinity with all three p53 REs. Contrarily, the p53 del strain shows no transactivation and binding affinity with all the p53

The central DNA binding domain is the most highly conserved region of p53, when compared to its other family members, p63 and p73. Loss of tumor suppressor function of p53, as seen in most cancers, results from missense mutations in the DNA