Regulation of TIGR/MYOC gene expression in human trabecular meshwork cells.
Glucocorticoid (GC) treatment of human trabecular meshwork (HTM) cells produces delayed, progressive cellular and extracellular protein/glycoprotein inductions with characteristics matching those for intraocular pressure elevation with corticosteroid eyedrops. The cloning of the Trabecular Meshwork Inducible Glucocorticoid Response (TIGR) gene from this system has suggested possible environmental and genetic influences in relation to glaucoma mechanisms. As reported here, the major GC-induced increase of TIGR expression in HTM cells is reduced approximately 4-fold by basic fibroblast growth factor (bFGF, 100-1000 pM), with a somewhat smaller inhibition noted with the thyroid hormone triiodothyronine (T3, 100 nM). Such endogenous 'protective' factors could help balance stimulatory effects on TIGR gene expression from 'stress' and/or mechanical perturbations in the trabecular meshwork. TIGR coding region mutations affecting the gene's olfactomedin (OLF) homology domain may also perturb biosynthetic pathways and cellular homeostatic functions. Our recent studies have shown the OLF domain corresponds to a major translocational 'pause', an area where critical processes for normal TIGR biogenesis are expected to take place. Observations that Glu323Lys (and other mutations early in the OLF domain) altered the pattern of paused protein intermediates provide possible clues to previously unexplained pathogenetic mechanisms. HTM cell transfection studies using TIGR-green fluorescent protein (GFP) fusions showed increased and altered distribution of the expressed protein with constructs missing the OLF domain, an effect also found with the Pro370 Leu mutation for early-onset glaucoma. The data suggest an activation of stress/apoptotic pathways in HTM cells as a potential mechanism for environmental/genetic interactions in glaucoma pathogenesis.
Polansky
J R
JR
Department of Ophthalmology, University of California Medical Center, San Francisco 94143-0730, USA. drcarin@itsa.ucsf.edu
Fauss
D J
DJ
Zimmerman
C C
CC
D018929:Cell Culture Techniques; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014129:Trabecular Meshwork / Q000166:cytology / Q000378:metabolism*; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology; D000099179:Myocilin
D003598:Cytoskeletal Proteins; D003907:Dexamethasone; D005136:Eye Proteins; D016222:Fibroblast Growth Factor 2; D005938:Glucocorticoids; D006023:Glycoproteins; D012333:RNA, Messenger; D014284:Triiodothyronine; D000099179:Myocilin