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Lens epithelium-derived growth factor relieves transforming growth factor-beta1-induced transcription repression of heat shock proteins in human lens epithelial cells.
J Biol Chem. 2003 May 30; 278(22):20037-46.JB

Abstract

Lens epithelium-cell derived growth factor (LEDGF) is a transcriptional activator. It protects the cells by binding to cis-stress response ((A/T)GGGG(T/A)), and heat shock (HSE; nGAAn) elements in the stress genes and activating their transcription. Transforming growth factor-beta (TGF-beta) has been implicated in the control of tissue homeostasis, terminal differentiation, and apoptosis. Here we provide evidence that TGF-beta1 down-regulates LEDGF expression and diminishes its affinity for DNA during TGF-beta1-induced phenotypic changes and apoptosis in human lens epithelial cells. Surprisingly, TGF-beta1 treatment for 48 h markedly decreased the LEDGF, Hsp27, and alphaB-crystallin promoter activities with the decrease of abundance of LEDGF mRNA and protein. Deletion mutants of the LEDGF promoter showed that one TGF-beta1 inhibitory element (TIE) like sequence nnnTTGGnnn (-444 to -433) contributed to this negative regulation. Mutation of TIE (TTGG to TATT) abolished the down-regulation of the LEDGF promoter. Gel mobility and supershift assays showed that LEDGF in the nuclear extracts of TGF-beta1-treated human lens epithelial cells did not bind to stress-response elements and HSE. The TGF-beta1-induced down-regulation of LEDGF, Hsp27, and alphaB-crystallin promoters activity was reversed by cotransfection with a plasmid expressing LEDGF. Because overexpression of LEDGF was able to relieve TGF-beta1 and/or stress-induced changes, it would be a candidate molecule to postpone age-related degenerating disorders.

Authors+Show Affiliations

Center for Ophthalmic Research, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12649267

Citation

Sharma, Preeti, et al. "Lens Epithelium-derived Growth Factor Relieves Transforming Growth Factor-beta1-induced Transcription Repression of Heat Shock Proteins in Human Lens Epithelial Cells." The Journal of Biological Chemistry, vol. 278, no. 22, 2003, pp. 20037-46.
Sharma P, Fatma N, Kubo E, et al. Lens epithelium-derived growth factor relieves transforming growth factor-beta1-induced transcription repression of heat shock proteins in human lens epithelial cells. J Biol Chem. 2003;278(22):20037-46.
Sharma, P., Fatma, N., Kubo, E., Shinohara, T., Chylack, L. T., & Singh, D. P. (2003). Lens epithelium-derived growth factor relieves transforming growth factor-beta1-induced transcription repression of heat shock proteins in human lens epithelial cells. The Journal of Biological Chemistry, 278(22), 20037-46.
Sharma P, et al. Lens Epithelium-derived Growth Factor Relieves Transforming Growth Factor-beta1-induced Transcription Repression of Heat Shock Proteins in Human Lens Epithelial Cells. J Biol Chem. 2003 May 30;278(22):20037-46. PubMed PMID: 12649267.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lens epithelium-derived growth factor relieves transforming growth factor-beta1-induced transcription repression of heat shock proteins in human lens epithelial cells. AU - Sharma,Preeti, AU - Fatma,Nigar, AU - Kubo,Eri, AU - Shinohara,Toshimichi, AU - Chylack,Leo T,Jr AU - Singh,Dhirendra P, Y1 - 2003/03/20/ PY - 2003/3/22/pubmed PY - 2003/7/11/medline PY - 2003/3/22/entrez SP - 20037 EP - 46 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 278 IS - 22 N2 - Lens epithelium-cell derived growth factor (LEDGF) is a transcriptional activator. It protects the cells by binding to cis-stress response ((A/T)GGGG(T/A)), and heat shock (HSE; nGAAn) elements in the stress genes and activating their transcription. Transforming growth factor-beta (TGF-beta) has been implicated in the control of tissue homeostasis, terminal differentiation, and apoptosis. Here we provide evidence that TGF-beta1 down-regulates LEDGF expression and diminishes its affinity for DNA during TGF-beta1-induced phenotypic changes and apoptosis in human lens epithelial cells. Surprisingly, TGF-beta1 treatment for 48 h markedly decreased the LEDGF, Hsp27, and alphaB-crystallin promoter activities with the decrease of abundance of LEDGF mRNA and protein. Deletion mutants of the LEDGF promoter showed that one TGF-beta1 inhibitory element (TIE) like sequence nnnTTGGnnn (-444 to -433) contributed to this negative regulation. Mutation of TIE (TTGG to TATT) abolished the down-regulation of the LEDGF promoter. Gel mobility and supershift assays showed that LEDGF in the nuclear extracts of TGF-beta1-treated human lens epithelial cells did not bind to stress-response elements and HSE. The TGF-beta1-induced down-regulation of LEDGF, Hsp27, and alphaB-crystallin promoters activity was reversed by cotransfection with a plasmid expressing LEDGF. Because overexpression of LEDGF was able to relieve TGF-beta1 and/or stress-induced changes, it would be a candidate molecule to postpone age-related degenerating disorders. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/12649267/Lens_epithelium_derived_growth_factor_relieves_transforming_growth_factor_beta1_induced_transcription_repression_of_heat_shock_proteins_in_human_lens_epithelial_cells_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12649267 DB - PRIME DP - Unbound Medicine ER -