ABSTRACT
Modification of the transforming growth factor ß (TGF-ß) signaling components by (de)ubiquitination is emerging as a key regulatory mechanism that controls cell signaling responses in health and disease. Here, we show that the deubiquitinating enzyme UBH-1 in Caenorhabditis elegans and its human homolog, ubiquitin C-terminal hydrolase-L1 (UCH-L1), stimulate DAF-7/TGF-ß signaling, suggesting that this mode of regulation of TGF-ß signaling is conserved across animal species. The dauer larva-constitutive C. elegans phenotype caused by defective DAF-7/TGF-ß signaling was enhanced and suppressed, respectively, by ubh-1 deletion and overexpression in the loss-of-function genetic backgrounds of daf7, daf-1/TGF-ßRI, and daf4/R-SMAD, but not of daf-8/R-SMAD. This suggested that UBH-1 may stimulate DAF-7/TGF-ß signaling via DAF-8/R-SMAD. Therefore, we investigated the effect of UCH-L1 on TGF-ß signaling via its intracellular effectors, i.e. SMAD2 and SMAD3, in mammalian cells. Overexpression of UCH-L1, but not of UCH-L3 (the other human homolog of UBH1) or of the catalytic mutant UCH-L1C90A, enhanced TGF-ß/SMAD-induced transcriptional activity, indicating that the deubiquitination activity of UCH-L1 is indispensable for enhancing TGF-ß/SMAD signaling. We also found that UCH-L1 interacts, deubiquitinates, and stabilizes SMAD2 and SMAD3. Under hypoxia, UCH-L1 expression increased and TGF-ß/SMAD signaling was potentiated in the A549 human lung adenocarcinoma cell line. Notably, UCH-L1-deficient A549 cells were impaired in tumorigenesis, and, unlike WT UCH-L1, a UCH-L1 variant lacking deubiquitinating activity was unable to restore tumorigenesis in these cells. These results indicate that UCH-L1 activity supports DAF-7/TGF-ß signaling and suggest that UCH-L1's deubiquitination activity is a potential therapeutic target for managing lung cancer.
Subject(s)
Caenorhabditis elegans Proteins/metabolism , Carcinogenesis/metabolism , Transforming Growth Factor beta/metabolism , Ubiquitin Thiolesterase/metabolism , Animals , Caenorhabditis elegans , Cell Transformation, Neoplastic , Deubiquitinating Enzymes , Larva/metabolism , Lung/metabolism , Signal Transduction/genetics , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Ubiquitin Thiolesterase/physiology , UbiquitinationABSTRACT
We used spectral-domain optical coherence tomography (SD-OCT) to compare the foveal and parafoveal structures of 19 subjects aged 16-58 years (8 men, 11 women): 6 amblyopic patients with eccentric fixation, 5 amblyopic patients with central fixation, and 8 visually normal controls. We obtained foveal horizontal line scans using SD-OCT on all of the patients and controls. The total and layer thicknesses at foveal areas were analyzed. The mean (SD) ages of individuals in the eccentric fixation, central fixation, and control groups were 43.0 (13.9), 42.2 (16.3), and 38.5 (15.5) years, respectively. We observed no significant differences in the foveal or parafoveal retinal thicknesses at 500 and 1,500 µm from the foveal center among the 3 groups or between the amblyopic and fellow eyes. No significant differences were observed in the thickness of the ganglion cell complex layer or outer retinal layer at 500 and 1,500 µm from the foveal center among the three groups or between the two eyes. Overall, our SD-OCT analyses revealed no characteristic structural change in foveal regions in amblyopic eyes irrespective of the fixation behavior.
Subject(s)
Amblyopia , Fovea Centralis , Strabismus , Tomography, Optical Coherence , Adolescent , Adult , Female , Humans , Male , Middle Aged , Young AdultSubject(s)
Alkaptonuria/diagnosis , Brain/metabolism , Cerebrovascular Circulation/physiology , Monitoring, Physiologic/methods , Ochronosis/diagnosis , Oxygen Consumption/physiology , Oxygen/metabolism , Spectroscopy, Near-Infrared/instrumentation , Aged , Alkaptonuria/physiopathology , Brain/diagnostic imaging , Humans , Magnetic Resonance Angiography , Male , Ochronosis/physiopathologyABSTRACT
PURPOSE: To ascertain whether conventional treatment can improve visual function in adults with amblyopia. METHODS: Sixteen patients aged 21-67 years old were instructed to wear glasses for refractive correction and to patch the non-amblyopic eye for at least 1 h per day. Visual acuity, measured with crowded optotypes for distance and near acuity, was checked every 3 months, and followed for a mean (SD) of 14.1 (4.2) months. Prognostic factors related to the subsequent results, an improvement of 3 or more lines logMAR in distance visual acuity, were evaluated. RESULTS: Of 16 patients, 5 (31 %) improved 3 or more lines of distance and 5 (31 %) in near acuity. The mean improvement in distance was 2.4 lines logMAR (95 % CI 1.4-3.5) and 2.4 lines logMAR for near acuity (95 % CI 1.5-3.3). Patients aged under 45 years (p = 0.0357) and with severe amblyopia (p = 0.0337), defined as a corrected distance visual acuity of worse than -0.699 logMAR, were associated with a good response. CONCLUSIONS: Conventional treatment may improve the visual acuity of amblyopic eyes even in adult patients.
