Traf4 Case Study

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 normal function of the p53 gene is to bind to other genes like miRNA34a (which codes for p21)(3). P21 is a protein that acts as signal for the shut of DNA replication, so mutation in P53 causes no direct signal to the p21 gene and there is uncontrolled growth and proliferation.

TP53, also called tumor protein 53 is a tumor suppressor gene that encodes p53 and acts as a control center for the cell to act on when stressed (Brachova). Human p53 is a nuclear phsophoprotein of molecular weight 53kDa located on chromosome 17 containing 11 exons and 10 introns (Ling). One of its primary roles is as a transcription factor and in its active state is a homotetramer comprised of four 393 amino acid residues (Joerger , The tumor suppressor p53). Another main role p53 plays is as a tumor suppressor and once activated, protects against cancer by “functioning as a sequence-specific transcription factor, through protein-protein interactions, activating cell cycle arrest, apoptosis, and DNA damage repair (Brachova).”

The P53 prevents cancer formation by acting as a tumour suppressor gene. Also known as the TP53. It plays important roles in multicellular organisms by stopping genome mutations. The name p53 was established in 1979 describing the molar mass indicating that it is a 53kDa protein. It was first discovered in 1979 and was thought to be an oncogene (a gene capable of transforming regular cells into tumour cells). However in 1989 further research by Bert Vogelstein from John Hopkins School of medicine discovered that it was actually a tumour suppressor gene. The p53 protein consists of 393 amino acids. This protein can activate other proteins that have the ability to fix

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).

Majority of the patients with TMD have relatively mild or infrequent symptoms which may improve on their own within weeks or months with basic home therapy. Following simple remedies like eating soft foods, applying ice or moist heat, and avoiding extreme jaw movements may aid in easing symptoms. According to the NIH, because more studies are needed on the safety and effectiveness of most treatments for jaw joint and muscle disorders, experts strongly recommend using the most conservative, reversible treatments possible. Although TMJ disorders have become persistent, most patients still do not need any aggressive types of treatment.

The article then looks at the role, in solid tumours, of areas of low oxygen (hypoxia) in selecting for those cells that have mutations in the p53 tumour supressing gene. A common feature inside solid tumours is hypoxia and an increase of cell death. This happens because often the rate of growth in a solid tumour outstrips the supply of oxygen to the cells. The normal reaction of a group of cells, expressing the normal p53 gene, when exposed to an hypoxic region, is an increase in the rate of apoptosis. However, in a solid tumour there are many cells with many different types of mutations. In the battle against solid tumours, some tumours resistant to treatment have cropped up. The article takes a look at the role of hypoxia possibly selecting for those cells resistant to apoptosis.

More than four thousands mutations of p53 genes have been identified in human tumors. p53 mutation in human skin cancers is consider to be unique mutation among other cancers mutations. p53 mutation in human skin cancers is mostly found to be C to T transitions. These transitions are located on dipyrimidine sites that are the specific target for UV radiation (Dumaz et. al, 1997). Alteration of tumor suppressor gene p53 will hinder p53 to repair damaged DNA or perform apoptosis as needed, which then results in precancerous cell (Madan et. al,

In response to γ-irradiation mediated DNA damage, ATM kinase activates the tumor suppressor protein, p53, via phosphorylation. Once activated, p53 initiates two negative feedback loops. The first negative feedback loop is caused by p53 activating the expression of the E3 ubiquitin ligase Mdm2, allowing Mdm2 to target p53 for degradation. The second negative feedback loop is the result of p53 activating the expression of the phosphatase Wip1, which dephosphorylates p53 and therefore reduces its stability. Wip1 also targets ATM kinase, which requires phosphorylation in order to be in the active state. Therefore, the increased activity of Wip1 silences ATM kinase, which prevents the activation of p53. If DNA damage persists in the cell, ATM kinase activates p53 once more after Wip1 expression levels have subsided. Pulsing of p53 activity results in cell-cycle arrest and DNA repair, and continues until DNA damage has been completely repaired.

We will evaluate if FLRT3 increases MAPK activation for normal thyroid cells, PTC cell lines harboring mutations, and FTC cell lines containing in the presence or absence of FLRT3 treated or not treated with ectopic expression of FLRT3 via western blot analysis for p-ERK. We will quantify FLRT3’s effect on MAPK activation by using qPCR for c-fos and c-jun for indicated PTC mutant cell lines with or without FLRT3 in order to compare the relative expression of these downstream MAPK response genes. To assess if FLRT3 increases the binding affinity of FGF8 for RTKs, we will perform a binding assay using varying treatment times of GST-FGF8 followed by a GST-pull down and subsequent western blot for PTC cells harboring mutations with or

The PI3K/AKT pathway, when activated, will lead to cell survival, growth and proliferation (18). PI3K phosphorylates phosphatidylinositol triphosphate (PIP3). Once PIP3 is formed a Protein Kinase B (PKB) or AKT molecule is tethered to a pleckstrin homology (PH) domain, which will then lead to the activation of AKT/PKB as a kinase (11). If AKT is activated it can lead to the activation of mammalian target of rapamycin (mTOR) and nuclear factor kappa B (NF-κB) and inhibition of glycogen synthase kinase 3 beta (GSK-3β) and BAD (Figure 2) (13). The activation of mTOR leads to the phosphorylation of p70S6 kinase (p70S6K), which is an activator of translation that turns on cell growth. NF-κB is a transcription factor that, when liberated from IκB, translocates to the nucleus to activate anti-apoptotic and mitogenic genes. When GSK-3β is inactivated, β-catenin is released from the complex resulting in the stimulation of cell proliferation. Phosphorylation of AKT results in the inhibition of BAD and ultimately apoptosis (45). PTEN dephosphorylates PIP3 back to PIP2. It is a negative regulator of PI3K. This dephosphorylation results in the inhibition of AKT signaling pathway. PI3K pathway can be overactive if PTEN faulty

. 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

A gene that encodes for a protein to function as a tumor suppressor as well as to regulate the cell cycle are called p53, TP 53 or tumor protein. A mature p53 mRNA is found to be 2.2-2.5 kb in size and can be found mostly in the spleen and thymus, this gene is separated by 10 introns and are split into 11 exons. As said in the chapter one of the “p53 suppressor genes” book, the final product of the p53 genome was first identified as an antigen that bound to a simian virus T antigen and adenovirus E1B oncoproteins. (Mukhopadhyay, Maxwell & Roth 1995). Mutations, deletion, insertion or rearrangement of this gene p53 which changes the biochemical and the biophysical properties is strongly associated with an increase to cancer as the article “p53 in health and disease” describes. (Vousden & Lane 2007). The mutated genes are called oncogenes, where the DNA is altered from its original form. These gene help in growth regulation and division of the cells and are often causes the cells to divide out of control causing cancer to develop from the mutations of the gene p53.

We have also shown that MALAT1, SRSF1, and SRSF protein kinase 1 (SRPK1) form a complex. Interestingly, SRSF1 has been demonstrated to stabilize tumor suppressor p53 by preventing its ubiquitin-proteasome system-mediated degradation via complex formation with mouse double minute 2 homolog (Mdm2), a ubiquitin ligase, in the nucleus (20). The resulting phenomenon is oncogene-induced senescence (OIS) (21), a protective antiproliferative mechanism activated by oncogenic signaling upon stress-induced inactivation of a tumor suppressor. Based on our preliminary results, in conjunction with literature evidence, we hypothesize that MALAT1 overexpression disrupts RRM2 and RS domain interaction in SRSF1, subsequently impairing RS domain phosphorylation and SRSF1 nuclear translocation. This change in subcellular localization destabilizes p53, leading to loss of OIS in HPV-negative cervical cancer (HNCC). The goal of our lab is to examine the role of MALAT1 in SRSF1/p53-mediated OIS via HNCC in vitro (Aim 1) and in vivo (Aim 2) experimental models utilizing MALAT1-specific antisense oligonucleotide (ASO) therapy. Completion of this project will lead to a clearer understanding of whether MALAT1 is an underlying cause of HNCC development. The results generated from this proposal will improve scientific knowledge and clinical practices by providing a new MALAT1-mediated mechanism underlying HNCC tumorigenesis and

This paper explores the events that contributed to the ambush of Task Force Ranger (TFR) and their Pyrrhic victory over the Somali National Alliance (SNA) from 3-4 October 1993. The majority of military and political historians concur that the Battle of Mogadishu hastened the departure of a tenuous US military presence in Somalia. TF Ranger was successful in accomplishing their objective of capturing six key lieutenants of Somali Warlord Mohamed Farrah Aidid, but failed in the ensuing extraction due to a complex ambush perpetrated by the SNA militia. This paper aims to illuminate the intelligence failures and how these factors effected the events of the battle. A comprehensive summary of the battle will lead to an analysis of the key actions and decisions, building to a possible outcome.