GTP cyclohydrolase feedback regulatory protein controls cofactor 6-tetrahydrobiopterin synthesis in the cytosol and in the nucleus of epidermal keratinocytes and melanocytes.
Journal - The Journal of investigative dermatology (United States )
(6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH4) is crucial in the hydroxylation of L-phenylalanine-, L-tyrosine-, and L-tryptophan-regulating catecholamine and serotonin synthesis as well as tyrosinase in melanogenesis. The rate-limiting step of 6BH4 de novo synthesis is controlled by guanosine triphosphate (GTP) cyclohydrolase I (GTPCHI) and its feedback regulatory protein (GFRP), where binding of L-phenylalanine to GFRP increases enzyme activities, while 6BH4 exerts the opposite effect. Earlier it was demonstrated that the human epidermis holds the full capacity for autocrine 6BH4 de novo synthesis and recycling. However, besides the expression of epidermal mRNA for GFRP, the presence of a functioning GFRP feedback has never been shown. Therefore, it was tempting to investigate whether this important mechanism is present in epidermal cells. Our results identified indeed a functioning GFRP/GTPCHI axis in epidermal keratinocytes and melanocytes in the cytosol, adding the missing link for 6BH4 de novo synthesis which in turn controls cofactor supply for catecholamine and serotonin biosynthesis as well as melanogenesis in the human epidermis. Moreover, GFRP expression and GTPCHI activities have been found in the nucleus of both cell types. The significance of this result warrants further investigation.
|ISSN : ||1523-1747|
|Mesh Heading : ||Biopterin Blotting, Western Cell Nucleus Cells, Cultured Cytosol Epidermis GTP Cyclohydrolase Humans Intracellular Signaling Peptides and Proteins Keratinocytes Melanocytes biosynthesis chemistry metabolism chemistry metabolism ultrastructure analysis metabolism analysis genetics ultrastructure ultrastructure|
|Mesh Heading Relevant : ||analogs & derivatives metabolism metabolism metabolism metabolism|
Senile hair graying: H2O2-mediated oxidative stress affects human hair color by blunting methionine sulfoxide repair
Journal - The FASEB Journal
Senile graying of human hair has been the subject of intenseresearch since ancient times. Reactive oxygen species have beenimplicated in hair follicle melanocyte apoptosis and DNA damage.Here we show for the first time by FT-Raman spectroscopy invivo that human gray/white scalp hair shafts accumulate hydrogenperoxide (H2O2) in millimolar concentrations. Moreover, we demonstratealmost absent catalase and methionine sulfoxide reductase Aand B protein expression via immunofluorescence and Westernblot in association with a functional loss of methionine sulfoxide(Met-S=O) repair in the entire gray hair follicle. Accordingly,Met-S=O formation of Met residues, including Met 374 in theactive site of tyrosinase, the key enzyme in melanogenesis,limits enzyme functionality, as evidenced by FT-Raman spectroscopy,computer simulation, and enzyme kinetics, which leads to gradualloss of hair color. Notably, under in vitro conditions, Metoxidation can be prevented by L-methionine. In summary, ourdata feed the long-voiced, but insufficiently proven, conceptof H2O2-induced oxidative damage in the entire human hair follicle,inclusive of the hair shaft, as a key element in senile hairgraying, which does not exclusively affect follicle melanocytes.This new insight could open new strategies for interventionand reversal of the hair graying process.—Wood, J. M.,Decker, H., Hartmann, H., Chavan, B., Rokos, H., Spencer, J.D., Hasse, S., Thornton, M. J., Shalbaf, M., Paus, R., Schallreuter,K. U. Senile hair graying: H2O2-mediated oxidative stress affectshuman hair color by blunting methionine sulfoxide repair.
|Keywords : ||MSRA&B • tyrosinase • catalase • follicle cells|
Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediated oxidation: a possible repair mechanism for DNA damage
Journal - The FASEB Journal
Vitiligo is characterized by a patchy loss of inherited skincolor affecting 0.5% of individuals of all races. Despite theabsence of the protecting pigment and the overwhelming evidencefor hydrogen peroxide (H2O2)-induced oxidative stress in theentire epidermis of these patients, there is neither increasedphotodamage/skin aging nor a higher incidence for sun-inducednonmelanoma skin cancer. Here we demonstrate for the first timeincreased DNA damage via 8-oxoguanine in the skin and plasmain association with epidermal up-regulated phosphorylated/acetylatedp53 and high levels of the p53 antagonist p76MDM2. Short-patchbase-excision repair via hOgg1, APE1, and polymeraseß DNArepair is up-regulated. Overexpression of Bcl-2 and low caspase3 and cytochrome c levels argue against increased apoptosisin this disease. Moreover, we show the presence of high epidermalperoxynitrite (ONOO–) levels via nitrotyrosine togetherwith high nitrated p53 levels. We demonstrate by EMSA that nitrationof p53 by ONOO– (300x10–6 M) abrogates DNA binding,while H2O2-oxidized p53 (10–3 M) enhances DNA bindingcapacity and prevents ONOO–-induced abrogation of DNAbinding. Taken together, we add a novel reactive oxygen speciesto the list of oxidative stress inducers in vitiligo. Moreover,we propose up-regulated wild-type p53 together with p76MDM2as major players in the control of DNA damage/repair and preventionof photodamage and nonmelanoma skin cancer in vitiligo.—Salem,M. M. A. E. L., Shalbaf, M., Gibbons, N. C. J., Chavan, B.,Thornton, J. M., Schallreuter, K. U. Enhanced DNA binding capacityon up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediatedoxidation: a possible repair mechanism for DNA damage.
|Keywords : ||peroxynitrite • catalase • 8-oxoG • p76MDM2 • cell cycle arrest • skin cancer • apoptosis|