Their upregulation in several pathologies has motivated the design of reporters and therapeutics that can be targeted by local protease activation, with demonstrated success in vivo.
Examples of biochemical modifications that lead to resistance include the production of enzymes that inactivate the drug; the alteration of the protein, enzyme, or receptor targeted by the drug; the activation of drug efflux pumps that deliberately remove the drug from the cell; and the alteration of cell-wall proteins that inhibit drug uptake.
Insulin induces the activation of glycogen synthase, mainly by stimulating the dephosphorylation of the serine residues in glycogen synthase that are targeted by GSK3, and stimulates the activation of eIF2B by promoting the dephosphorylation of Ser535.
Fusions of MLL with, for example, CBP, t(11 16)(q23;p13.3), retain the HAT domain of CBP, and might lead to leukaemia by promoting histone acetylation of genomic regions targeted by MLL, and allowing transcriptional activation (Sobulo et al, 1997).
The UPR can be targeted by two ways including the activation of components of the adaptive mechanism of UPR and inhibition of those involved in the proapoptotic pathways of UPR.
T-lymphocyte activation can be targeted by blocking co-stimulatory pathways or inhibiting major histocompatibility complex protein interactions.
A significant increase in NO production was found in isolated macrophages from human APOE4 targeted transgenic mice by activation of cationic amino acid transporters (CAT) with up-regulated innate immune system [ 41].
Only R-SMADs are targeted for activation via phosphorylation by the active type I receptor kinase.
The PI3K C-terminus, which we propose to be equivalent to the PRD and FATC domains of PIKKs, is in close proximity to the activation loop of the KD, suggesting that in PIKKs, the PRD and FATC domains may regulate kinase activity by targeting the activation loop.
The increase in gene targeting by ZFNs is achieved by the activation of DNA repair mechanisms.
