Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of enhancement of enzymatic activity by heating at 56 degrees C or by limited treatment with dimethylsulfoxide, trypsin and cathepsin D on two forms (Mr = 50 kDa and 72 kDa) of human epidermal transglutaminase were studied by immunoblots using rabbit antihuman epidermal transglutaminase. Both 50 kDa and 72 kDa transglutaminase bands were detected without any alteration in the mobility of the transglutaminase bands during activation induced by heating at 56 degrees C or by pretreatment with dimethylsulfoxide. With a preincubation period longer than 60 min, the trypsin pretreated sample showed progressive disappearance of the 72 kDa transglutaminase band in conjunction with the loss of transglutaminase activity. On the other hand, samples preincubated with cathepsin D showed a complete disappearance of the 50 kDa band after 180 min. These studies suggest the different forms of human epidermal transglutaminase may regulate enzyme activity each other during normal epidermal differentiation.
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PMID:Alteration of human epidermal transglutaminase during its activation. 198 21

The activity of crude human epidermal transglutaminase was enhanced remarkably following 24 hr preincubation at low pH (pH 4.5), whereas the pure human epidermal transglutaminase did not show enhancement of enzyme activity at low pHs. Preincubation of pure transglutaminase with rat liver lysosomal fractions (100 microgram/ml) caused a time-dependent enhancement of activity at pH 4.5, up to 4.5 times of the initial activity. This enhancement was specific for lysosomal fractions among the several rat liver subcellular fractions tested. The activity of purified transglutaminase stimulated by lysosomal fractions was inhibited by pepstatin (50 microgram/ml), chymostatin (50 microgram/ml) and EDTA (1 mM). Preincubation of purified transglutaminase with 5 to 100 microgram/ml cathepsin D caused a time-dependent enhancement of activity up to 9.5-fold over control. This enhancement was specific for cathepsin D among the several lysosomal enzymes tested. These in vitro observations suggest possible activation mechanisms of epidermal transglutaminase in vivo. Epidermal transglutaminase may be activated by lysosomal acid proteinases, such as cathepsin B1 and cathepsin D, which are released and activated during the autolytic stages in granular layer in epidermis.
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PMID:Mechanism of regulation of human epidermal transglutaminase. 611 35

The hair follicles exhibit an intrinsic hair cycle that is divided into three phases; growth (anagen), transition (catagen) and quiescence (telogen). To make sure of the effects on hair growth by chemical substances, we should evaluate the induction of the anagen phase and/or elongation of the anagen period and delay in catagen separately, but the regulatory mechanism of the hair cycle is unclear. We have investigated the levels of biochemical markers in the third hair cycle period of C3H mouse (8 weeks, male) after depilation and compared them with those in a non-treated group. The dorsal areas (2 cm x 4 cm) were clipped and depilated with hair remover. The dorsal skin samples were collected 1, 8, 11, 15 and 18 days after depilation and the levels of biochemical markers, i.e. skin transglutaminase, skin sulfhydryl oxidase, cathepsin D, gamma-glutamyl transpeptidase, alkaline phosphatase, acid phosphatase, tyrosinase activities and histamine content in each skin sample were examined. The levels of gamma-glutamyl transpeptidase, tyrosinase and alkaline phosphatase were relevant to hair re-growth in the control group, but not skin transglutaminase, skin sulfhydryl oxidase, cathepsin D activities. The histamine content increased just after depilation treatment and returned to the normal level within two weeks, compared with the non-treated group. All these results suggest that the markers examined in this C3H mice model are useful for studying the distinctive process of hair re-growth caused by active substances.
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PMID:Evaluation of biochemical indices as a hair cycle marker in C3H mice. 884 Jan 42

Cathepsin D is an ubiquitously expressed lysosomal aspartic proteinase, with well-determined structural and chemical properties but a less clearly defined biological role. In stratified epithelia, the chronology of cathepsin D activation and degradation can be connected with stages of cellular differentiation. We partially purified cathepsin D from human epidermis and from separated stratum corneum by standard biochemical procedures, monitored by SDS-PAGE and Western blotting, and verified its identity as to molecular mass, pH optimum, N-terminal sequencing, reactivity with the specific antibody, inhibition by pepstatin A, and specific enzyme activity. It had hemoglobin-degrading activity over the acid range, with maximum at pH 3. It also degraded bovine serum albumin, human keratins, and stratum corneum extracts at pH 4. We discerned all three isoforms of human cathepsin D (the 52 kDa proenzyme and the active forms at 48 kDa and 33 kDa) in the epidermis; both active forms were also seen in the stratum corneum, but the proenzyme was not. Gene expression of cathepsin D in epidermal keratinocytes resembled that of suprabasal structural proteins (involucrin, keratin K10, transglutaminase) in its response to the calcium switch. An antibody to the 33 kda isoform immunolocalized to the granular layer and the stratum corneum (whereas antibodies to the 48 kDa isoform have been reported to stain mainly the upper spinous and granular layers). A plausible hypothesis to harmonize these results is that cathepsin D is first expressed as the proenzyme in the upper spinous layer, is activated in the lysosomes in the granular layer to the 48 kDa form, and is degraded to the 33 kDa form in the transition zone between the granular layer and the stratum corneum. As the stratum corneum is an acid environment, with an ambient pH of approximately 4.5, cathepsin D is available and suited to contribute to desquamation.
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PMID:Isoforms of cathepsin D and human epidermal differentiation. 981 Apr 67

During the final steps of epidermal differentiation, extracellular calcium ions enter keratinocytes and induce transglutaminase activity and cornified envelope formation. In other cell types, entry of calcium mediated by ionophores has been reported to induce exocytosis of lysosomes. In this study, we investigated whether lysosomes of keratinocytes might exhibit a similar behaviour. Ionomycin treatment induced cornified envelope formation in keratinocytes, but also morphological changes including plasma membrane blebbing, although no immediate alteration in cell viability could be detected. The activity of the soluble lysosomal enzymes cathepsin C and beta-galactosidase in the culture medium was increased upon ionomycin treatment. Cell leakage did not seem to be responsible for this phenomenon, as suggested by measurements of the cytosolic enzymes adenylate kinase and dipeptidylpeptidase III in the culture medium. Metabolic labelling followed by immunoprecipitation showed that ionomycin induced release of cathepsin D into the culture medium. Simultaneously, lysosome-associated membrane proteins (Lamps) 1 and 2 were detected at the cell surface of ionomycin-treated keratinocytes by biochemical and morphological approaches. These results suggest that upon ionomycin treatment, calcium entry stimulates exocytosis of lysosomes in keratinocytes.
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PMID:Calcium entry into keratinocytes induces exocytosis of lysosomes. 1512 11

Dermatological diseases range from minor cosmetic problems to life-threatening conditions, as seen in some severe disorders of keratinization and cornification. These disorders are commonly due to abnormal epidermal differentiation processes, which result in disturbed barrier function of human skin. Elucidation of the cellular differentiation programs that regulate the formation and homeostasis of the epidermis is therefore of great importance for the understanding and therapy of these disorders. Much of the barrier function of human epidermis against the environment is provided by the cornified cell envelope (CE), which is assembled by transglutaminase (TGase)-mediated cross-linking of several structural proteins and lipids during the terminal stages of normal keratinocyte differentiation. The major constituents of the stratum corneum and the current knowledge on the formation of the stratum corneum will be briefly reviewed here. The discovery of mutations that underlie several human diseases caused by genetic defects in the protein or lipid components of the CE, and recent analyses of mouse mutants with defects in the structural components of the CE, catalyzing enzymes, and lipid processing, have highlighted their essential function in establishing the epidermal barrier. In addition, recent findings have provided evidence that a disturbed protease-antiprotease balance could cause faulty differentiation processes in the epidermis and hair follicle. The importance of regulated proteolysis in epithelia is well demonstrated by the recent identification of the SPINK5 serine proteinase inhibitor as the defective gene in Netherton syndrome, cathepsin C mutations in Papillon-Lefevre syndrome, cathepsin L deficiency infurless mice, targeted ablation of the serine protease Matriptase/MTSP1, targeted ablation of the aspartate protease cathepsin D, and the phenotype of targeted epidermal overexpression of stratum corneum chymotryptic enzyme in mice. Notably, our recent findings on the role of cystatin M/E and legumain as a functional dyad in skin and hair follicle cornification, a paradigm example of the regulatory functions exerted by epidermal proteases, will be discussed.
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PMID:Epidermal differentiation: the role of proteases and their inhibitors. 1567 20

Bathing suit ichthyosis (BSI) is a striking and unique clinical form of autosomal recessive congenital ichthyosis characterized by pronounced scaling on the bathing suit areas but sparing of the extremities and the central face. Here we report on a series of 10 BSI patients. Our genetic, ultrastructural and biochemical investigations show that BSI is caused by transglutaminase-1 (TGase-1) deficiency. Altogether, we identified 13 mutations in TGM1-among them seven novel missense mutations and one novel nonsense mutation. Structural modeling for the Tyr276Asn mutation reveals that the residue is buried in the hydrophobic interior of the enzyme and that the hydroxyl side chain of Tyr276 is exposed to solvent in a cavity of the enzyme. Cryosections of healthy skin areas demonstrated an almost normal TGase activity, in contrast to the affected BSI skin, which only showed a cytoplasmic and clearly reduced TGase-1 activity. The distribution of TGase-1 substrates in the epidermis of affected skin corresponded to the situation in TGase-1 deficiency. Interestingly, the expression of TGase-3 and cathepsin D was reduced. Digital thermography validated a striking correlation between warmer body areas and presence of scaling in patients suggesting a decisive influence of the skin temperature. In situ TGase testing in skin of BSI patients demonstrated a marked decrease of enzyme activity when the temperature was increased from 25 to 37 degrees C. We conclude that BSI is caused by TGase-1 deficiency and suggest that it is a temperature-sensitive phenotype.
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PMID:Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype. 1696 36

Cystatin M/E (CST6) is a nonredundant, epithelium-specific protease inhibitor with a presumed role in epidermal differentiation and tumor suppression. We have previously reported that cystatin M/E deficiency in Cst6(-/-) mice causes neonatal lethality because of excessive transepidermal water loss. Biochemical evidence suggests that cystatin M/E controls the activity of legumain, cathepsin L, cathepsin V, and transglutaminase-3. Using a genetic approach we sought to define the role of cystatin M/E in epithelial biology by identification of its target proteases and their downstream functions. Ablation of cathepsin L in a Cst6(-/-) background (Cst6(-/-)Ctsl(-/-) double-knockout mice) restored viability and resulted in normalization of stratum corneum morphology. Ablation of legumain or transglutaminase-3 in Cst6(-/-) mice, however, did not rescue the lethal phenotype. Intriguingly, both Cst6(-/-)Ctsl(-/-) and Cst6(-/-)Ctsl(+/-) mice were viable, but the absence of cystatin M/E caused scarring alopecia in adult animals. In the cornea of Cst6(-/-)Ctsl(+/-) mice, we observed keratitis, hyperplasia, and transition to a cornified epithelium. Evidence is provided that activation of cathepsin D and transglutaminase-1 are downstream events, dependent of cathepsin L activity. We conclude that a tightly regulated balance between cathepsin L and cystatin M/E is essential for tissue integrity in epidermis, hair follicles, and corneal epithelium.
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PMID:The cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles, and cornea. 2049 78