How Does P53 Regulate Metabolism

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

Another mechanism is the activated polyol pathway during hyperglycaemia consuming NADPH which is the essential cofactor for regenerating reduced glutathione. Depletion of glutathione lowers the threshold for intracellular oxidative damage.

There are many ways for cancer to get in the body, like exposure to uranium and oxidative stress. [8]. When the mechanisms of the body loose the protein Glutathione it leads to making oxygen free radical neutral. Two of the most important proteins in the body are glutathione (GSH) and superoxide dismutase (SOD). Glutathione (GSH) works as an antioxidant [9]. Also, glutathione (GSH) has an important job that removes toxic metals out of the body because glutathione (GSH) has a sulphydryl group. This group strongly binds with toxic metals, effectively [3]. When uranium enters the body, it will reduce glutathione (GSH). When there is a reduction of glutathione (GSH), it leads to an increase of the

Under normal condition, ROS production in the brain is balanced by the endogenous enzymatic and non-enzymatic anti-oxidative mechanisms. The enzymes include superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase. SOD catalyzes dismutation of superoxide to hydrogen peroxide, providing the first line against ROS damage [46, 70]. GPX and catalase further metabolize hydrogen peroxide to water and oxygen [71]. In the process, reduced glutathione (GSH) is oxidized to oxidized glutathione (GSSG) and it can be recycled by the NADPH-dependent GSSG reductase [72]. Non-enzymatic endogenous anti-oxidative small molecules also play very important roles in defending against oxidative stress, especially in extracellular space that the enzymes are absent or in very low levels [73]. Small-molecule anti-oxidant can be water-soluble or lipid-soluble, these molecules include glutathione, vitamin E and C (inhibits

GSH is playing an important role in protecting some brain cells from reactive oxygen species which mean that the deficient in G6PD could be a risk factor for some neurodegenerative diseases. On the other hand, in different brain region and different cell types the oxidative damage of these area could have associated with pathological factors such as increasing the neuronal nuclear diameter, increased vaculation and increased prevalence of chromatolytic neurons which could happen after losing Purkinje cells

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

ROS has been shown to contribute to cellular signaling and further affecting almost all aspects of cellular functions such as cell proliferation, cell migration, gene expression and cell death [6]. Generally, there are thought to be three main pathways for the generation of ROS during ischemia-reperfusion injury: conversion of xanthine dehydrogenase to xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and uncoupling

The intracellular redox state is a dynamic system which may modify on many factors. Mitochondria are essential to sustain life and the main intracellular source for fuel generation; moreover engaged in the regulation of many intracellular functions such as redox homeostasis and cell fate. The mitochondrial dynamics have changed and reactive oxygen species (ROS) generation could encourage the induction of oxidative DNA damage, inactivation of phosphatases and transcription factors. Moreover the mitochondrial dysfunction may constantly accompanied and contributed for a broad range of human diseases. Mitochondrial disrepair will result in oxidative stress, which is one of the underlying causal factors for a variety of diseases. High levels of

Second, they may oxidize signaling pathways directly. And third, ROS may target and modify transcription factors where the eventual effect may bring about change in gene expression. Furthermore, ROS activate MAPK signaling cascades which is central for mediating cellular responses to multiple stresses (Abouzari and fakheri, 2015). They do so through Calcium ion (Ca2+) (Price et al., 1994). Furthermore, key signaling proteins such as tyrosine phosphatase sense ROS directly through the oxidation of conserved cysteine residues (Xiong et al., 2002). On the other hand, ROS take part in redox cycling of cysteinyl thiols which is crucial to establish protein-protein and protein-DNA

The role of oxidative stress is the imbalance of detoxified free radicals. When the body fails to detoxify free radicals, the free radicals take an electron from another molecule. As a result, the molecule is no longer stable. An unstable molecule can lead to damage within the cell and cause the cell to function improperly. Therefore, preventing oxidative stress is very important for the cell to maintain its proper function. If the cell does not function properly, an increase in antioxidants can help to repair the cell. Antioxidants are produced by the cell but increasing antioxidants for example in ones diet can reduce the amount of free radicals in the body that cause harm and as a result lead to oxidative stress in the body.

A missing or defective p53 protein is usually the culprit in cancer, being that is in over 50% of cancers. The p53 gene codes for a protein that stops the growth as well as the development of tumors, as well as other functions. This is known as a tumor suppressor gene. If the gene is mutated, it allows damaged cells to survive and make tumors. The p53 gene can be mutated by cancer-causing substances in the environment. The p53 is responsible for proteins that fix damaged cells or cause damaged cells to die (apoptosis). It does this so the damaged cells do not pass on. The p53 gene prevents irregular cells from turning into tumors.

Accumulation of DNA damage occurs with increasing age, causing cells to deteriorate and malfunction. While DNA damages incur constantly in cells of living organisms, most of the damages are repaired in healthy individuals. However, some DNA damage accumulate as the DNA polymerases and other repair mechanisms cannot correct defects at a rapid enough pace as the rate of damage. In particular, damage to mitochondrial DNA may lead to mitochondrial dysfunction. Maintenance of metabolic homeostasis along with appropriate stress responses absolutely requires proper mitochondrial function. Mitochondrial dysfunction is known to play a critical role in aging and as well as other numerous human diseases, for example cancer and neurodegenerative disorders

Absence of GDH, mitochondrial matrix enzyme indicates that amino acids are not important oxidative substrates

During ischemia, adenine nucleotide catabolism results in an increase the intracellular concentration of hypoxanthine, which is then converted into toxic reactive oxygen species (ROS) upon the reoxygenation of tissue(Collard et al.,2001).

stress conditions, GSH accumulates in response to increased ROS, or to compensate for decreases in the defense capability of other antioxidants like catalase.,