Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The late type contact sensitizing effect of alkaline protease enzymes (PE) on the intact human skin has been investigated in the present study. The immune process of sensitisation was induced with "Tenzym prilled" (TP, Grindstedvoerket) and with "Maxatase" (M, Gist-Brocades) protease enzymes in the epicutaneous test (ET), using concentration series and various durations of application. The ETs were made on the intact (symptom-free) skin, as well as under conditions promoting the subcorneal penetration of PE. Challenge was carried out at 21 to 30 days following induction of 2092 subjects, and at 2 to 5 months on 1624 subjects. Despite the large number of subjects tested, contact sensitisation developed in none of the cases, although the inducing exposure took place under conditions promoting the immune process of sensitisation. In 60 individuals suffereing from occupational dermatitis on regular contact with PE and having no symptoms of early type inhalative allergy (mucous membrane changes, bronchial asthma-like symptoms) were challenged also by the intradermal test. No reaction was noted in any of them at 10 and 30 minutes, as well as at 24 and 48 hours following the test. Next the influence of PE is analysed in the induction or increased severity of the irritation caused by bioactive laundry detergents. The studies involved the use of serial dilutions of "Biopon" (Bn) laundry detergent containing TP or M, or not containing PE, respectively, by means of the ET. A total of 740 series (5220 tests) of the three variants were applied in dilution series to intact skin surface, as well as to pathologically and arteficially lsioned skin areas. The Bn variants containing and not containing PE increased the number of irratative reactions in essentially the same degree. This suggests that the irritative effect is not due to the presence of PE, but to the laundry-active detergents (WAS) of Bn in the first place, and to a lesser extent to its other ingredients.
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PMID:Skin irritancy and sensitivity to laundry detergents containing proteolytic enzymes. Part II. 12 49

Wiskott-Aldrich syndrome protein (WASP) is in a complex with WASP-interacting protein (WIP). WASP levels, but not mRNA levels, were severely diminished in T cells from WIP(-/-) mice and were increased by introduction of WIP in these cells. The WASP binding domain of WIP was shown to protect WASP from degradation by calpain in vitro. Treatment with the proteasome inhibitors MG132 and bortezomib increased WASP levels in T cells from WIP(-/-) mice and in T and B lymphocytes from two WAS patients with missense mutations (R86H and T45M) that disrupt WIP binding. The calpain inhibitor calpeptin increased WASP levels in activated T and B cells from the WASP patients, but not in primary T cells from the patients or from WIP(-/-) mice. Despite its ability to increase WASP levels proteasome inhibition did not correct the impaired IL-2 gene expression and low F-actin content in T cells from the R86H WAS patient. These results demonstrate that WIP stabilizes WASP and suggest that it may also be important for its function.
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PMID:WIP is a chaperone for Wiskott-Aldrich syndrome protein (WASP). 1721 9

Twist1 is a transcription factor driving epithelial-mesenchymal transition, invasion and metastasis of breast cancer cells. Mice with germ-line Twist1 knockout are embryonic lethal, while adult mice with inducible Twist1 knockout have no obvious health problems, suggesting that Twist1 is a viable therapeutic target for the inhibition of invasion and metastasis of breast cancer in adult patients. In this study, we expressed a luciferase protein or a Twist1-luciferase fusion protein in HeLa cells as part of a high throughput system to screen 1280 compounds in the Library of Pharmacologically Active Compounds (LOPAC) from Sigma-Aldrich for their effects on Twist1 protein expression. One of the most interesting compounds identified is tamoxifen, a selective estrogen receptor (ER) modulator used to treat ER-positive breast cancer. Tamoxifen treatment significantly accelerated Twist1 degradation in multiple cell lines including HEK293 human kidney cells, 4T1 and 168FARN mouse mammary tumor cells with either ectopically or endogenously expressed Twist1. Tamoxifen-induced Twist1 degradation could be blocked by the MG132 proteasome inhibitor, suggesting that tamoxifen induces Twist1 degradation through the ubiquitination-proteasome pathway. However, tamoxifen-induced Twist1 degradation was independent of Twist1 mRNA expression, estrogen signaling and MAPK-mediated Twist1 phosphorylation in these cells. Importantly, tamoxifen also significantly inhibited invasive behavior in Matrigel and lung metastasis in SCID-bg mice of ER-negative 4T1 mammary tumor cells, which depend on endogenous Twist1 to invade and metastasize. These results indicate that tamoxifen can significantly accelerate Twist1 degradation to suppress cancer cell invasion and metastasis, suggesting that tamoxifen can be used not only to treat ER-positive breast cancers but also to reduce Twist1-mediated invasion and metastasis in ER-negative breast cancers.
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PMID:Tamoxifen inhibits ER-negative breast cancer cell invasion and metastasis by accelerating Twist1 degradation. 2589 68