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Full-Text Articles in Physical Sciences and Mathematics
Small Molecule Proteostasis Regulators That Reprogram The Er To Reduce Extracellular Protein Aggregation, L. Plate, Christina B. Cooley, J. J. Chen, R. J. Paxman, C. M. Gallagher, F. Madoux, J. C. Genereux, W. Dobbs, D. Garza, T. P. Spicer, L. Scampavia, S. J. Brown, H. Rosen, E. T. Powers, P. Hodder, R. L. Wiseman, J. W. Kelly
Small Molecule Proteostasis Regulators That Reprogram The Er To Reduce Extracellular Protein Aggregation, L. Plate, Christina B. Cooley, J. J. Chen, R. J. Paxman, C. M. Gallagher, F. Madoux, J. C. Genereux, W. Dobbs, D. Garza, T. P. Spicer, L. Scampavia, S. J. Brown, H. Rosen, E. T. Powers, P. Hodder, R. L. Wiseman, J. W. Kelly
Christina B Cooley
Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy …
Broadly Applicable Methodology For The Rapid And Dosable Small Molecule-Mediated Regulation Of Transcription Factors In Human Cells, M. D. Shoulders, L. M. Ryno, Christina B. Cooley, J. W. Kelly, R. L. Wiseman
Broadly Applicable Methodology For The Rapid And Dosable Small Molecule-Mediated Regulation Of Transcription Factors In Human Cells, M. D. Shoulders, L. M. Ryno, Christina B. Cooley, J. W. Kelly, R. L. Wiseman
Christina B Cooley
Direct and selective small molecule control of transcription factor activity is an appealing avenue for elucidating the cell biology mediated by transcriptional programs. However, pharmacologic tools to modulate transcription factor activity are scarce because transcription factors are not readily amenable to small molecule-mediated regulation. Moreover, existing genetic approaches to regulate transcription factors often lead to high nonphysiologic levels of transcriptional activation that significantly impair our ability to understand the functional implications of transcription factor activity. Herein, we demonstrate that small molecule-mediated conformational control of protein degradation is a generally applicable, chemical biological methodology to obtain small molecule-regulated transcription factors that …