Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human epidermis with an area of 1.8 m(2) is the outer most layer of the human body. Hence, this organ plays a pivotal role in the defence against reactive oxygen species (ROS) generated by UV or X-ray exposure, heat and other sources. Consequently, a plethora of defence mechanisms exist controlling the redox status in this compartment. The role of thioredoxin reductase (TR), thioredoxin (T) in antioxidant defence has gained widespread recognition. In the past it has been shown that thioredoxin protects against UVB-induced skin injury, as well as against peroxidative damage. Under normal conditions, TR reduces oxidised thioredoxin in the presence of NADPH. Reduced thioredoxin serves as an electron donor for thioredoxin peroxidase (TPx) which consequently reduces H(2)O(2) to H(2)O. In this context, it has been demonstrated that membrane associated TR correlates with different skin photo types I-VI (Fitzpatrick classification), where darker skin has significantly higher enzyme activity compared to very fair skin, underlining the importance of this system in ROS defence. Moreover, it was only recently demonstrated in vivo with non-invasive Fourier-Transform Raman spectroscopy that UVB generates H(2)O(2) in the epidermis in a dose-dependent manner. H(2)O(2) can oxidise the selenocysteine residue in the penultimate position of the carboxyl terminus of TR with a K(m) of 2.5 mM. This oxidation is followed by an upregulation of mRNA expression of the enzyme. Hence, it can be concluded that UVB generated H(2)O(2) induces TR. However, permanent H(2)O(2) levels induce the tumour suppressor p53 which in turn downregulates cytosolic TR. Therefore TR activities are under fine control by H(2)O(2). This conclusion is also supported by the observation that thioredoxin, the substrate for TR, migrates from the cytosol to the nucleus after UVB exposure. A new function for the TR/T/TPx system in epidermal cells has been discovered in the control of the important cofactor (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH(4)) homeostasis. Full oxidation of 6BH(4) to 6 biopterin via H(2)O(2) can lead to a cytotoxic environment for epidermal melanocytes. This cascade of events is observed in the depigmentation disorder vitiligo, where millimolar levels of H(2)O(2) can accumulate in the epidermis of affected individuals, consequently leading to cellular vacuolation in this compartment.
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PMID:Thioredoxin reductase - its role in epidermal redox status. 1174 5

Targeted therapies against cancer have improved both survival and quality of life of patients. However, metabolic rewiring evokes cellular mechanisms that reduce therapeutic mightiness. Resistant cells generate more glutathione, elicit nuclear factor erythroid 2-related factor 2 (NRF2) activation, and overexpress many anti-oxidative genes such as superoxide dismutase, catalase, glutathione peroxidase, and thioredoxin reductase, providing stronger antioxidant capacity to survive in a more oxidative environment due to the sharp rise in oxidative metabolism and reactive oxygen species generation. These changes dramatically alter tumour microenvironment and cellular metabolism itself. A rational design of therapeutic combination strategies is needed to flatten cellular homeostasis and accomplish a drop in cancer development. Context-dependent glutaminase isoenzymes show oncogenic and tumour suppressor properties, being mainly associated to MYC and p53, respectively. Glutaminases catalyze glutaminolysis in mitochondria, regulating oxidative phosphorylation, redox status and cell metabolism for tumour growth. In addition, the substrate and product of glutaminase reaction, glutamine and glutamate, respectively, can work as signalling molecules moderating redox and bioenergetic pathways in cancer. Novel synergistic approaches combining glutaminase inhibition and redox-dependent modulation are described in this review. Pharmacological or genetic glutaminase regulation along with oxidative chemotherapy can help to improve the design of combination strategies that escalate the rate of therapeutic success in cancer patients.
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PMID:Glutaminases regulate glutathione and oxidative stress in cancer. 3268 Nov 90