TCP-1 α Activators

TCP-1 α activators, as highlighted in the table, are a class of chemicals that act by influencing the cellular stress responses, specifically the heat shock response and the unfolded protein response. These responses are activated when cells encounter conditions that lead to the accumulation of misfolded proteins, and they function to restore cellular homeostasis by enhancing the protein folding capacity of the cell. Geldanamycin and 17-AAG are heat shock protein 90 (Hsp90) inhibitors that can indirectly activate TCP-1 α by promoting the activation of heat shock factor 1 (HSF1), which in turn enhances the expression of various heat shock proteins, including TCP-1 α. Similarly, Celastrol can activate TCP-1 α by directly activating HSF1, leading to the upregulation of heat shock proteins.

The proteasome inhibitors MG132 and Bortezomib also indirectly activate TCP--1 α by inhibiting the degradation of misfolded proteins, leading to the activation of the heat shock response and increased expression of TCP-1 α. Tunicamycin, Thapsigargin, DTT, and Aze all operate by promoting the accumulation of misfolded proteins, either by inhibiting protein glycosylation, reducing ER calcium stores, reducing disulfide bonds, or encouraging the incorporation of unnatural amino acids into proteins, respectively. This accumulation of misfolded proteins triggers the unfolded protein response, leading to the upregulation of TCP-1 α. The chemical chaperone 4-PBA can modulate the expression of TCP-1 α by assisting in protein folding and reducing ER stress. This reduction in ER stress can influence the balance of chaperone proteins within the cell and leads to increased levels of TCP-1 α. Finally, Salubrinal and Guanabenz can indirectly activate TCP-1 α by selectively inhibiting eIF2α dephosphorylation, which prolongs the unfolded protein response and subsequently leads to an increase in the expression of TCP-1 α