4-PBA as evident in significant decrease in activated caspase-12

4-PBA is a low-molecular weight fatty acid which
has been found to have chaperone-like activities. 4-PBA is approved for clinical
use as an ammonia scavenger in children with urea cycle disorders Engin and
Hotamisligil, 2010).


has also been considered as a hopeful candidate in the treatment of
thalassemias, because it has been reported that it induces the transcription of
?- and ? -globin proteins (Collins et al., 1995).
It was also suggested as a chemotherapeutic reagent because of its capacity to
inhibit histone deacetylases (HDACs) at high concentrations (Takai and
Narahara, 2010).

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chaperone-like activity was first discovered when investigating its influence on
the trafficking of cystic fibrosis transmembrane conductance regulator protein
(CFTR) (Kerem, 2005). Mutations in this protein have been associated
with a failure of CFTR to be properly processed in the ER and its subsequent
failure to transport to the cell surface. PBA could act to stabilize and
prevent mutant protein to be directed to degradation pathway in the ER and
facilitate its translocation to the cell surface (Inden et al., 2007).


     4-PBA administration also results in
approximately 45% reduction in apoptosis, as evident in significant decrease in
activated caspase-12 and proapoptotic CHOP protein levels (Jian et al.,


has been suggested that it stabilizes the misfolded proteins (Figure 1.8),
decrease their aggregation, assist the mutant proteins to escape the cell’s
quality control systems and alter the activity of endogenous molecular
chaperones to assist the transportation of mutant proteins to the right subcellular
localization. Furthermore, it is proposed that 4-PBA may potentially alleviate
the ER stress by affecting protein trafficking through its HDAC inhibitor
activity. The HDAC inhibitory activity
of PBA enables it to regulate the transcription of several genes involved in
the UPR system (Engin and Hotamisligil, 2010).


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