Abstract
Cytosolic RNase inhibitor binds to and neutralizes most members of the pancreatic type RNase superfamily. However, there are a few exceptions, e.g. amphibian onconase and bovine seminal RNase, and these are endowed with cytotoxic activity. Also, RNase variants created by mutagenesis to partially evade the RNase inhibitor acquire cytotoxic activity. These findings have led to the proposal that the cytosolic inhibitor acts as a sentry to protect mammalian cells from foreign RNases. We silenced the expression of the gene encoding the cytosolic inhibitor in HeLa cells and found that the cells become more sensitive to foreign cytotoxic RNases. However foreign, non-cytotoxic RNases remain non-cytotoxic. These results indicate that the cytosolic inhibitor neutralizes those foreign RNases that are intrinsically cytotoxic and have access to the cytosol. However, its normal physiological role may not be to guard against foreign RNases in general.
Highlights
Cytosolic RNase inhibitor binds to and neutralizes most members of the pancreatic type RNase superfamily
We silenced the expression of the gene encoding the cytosolic inhibitor in HeLa cells and found that the cells become more sensitive to foreign cytotoxic RNases
Cases have been reported of RNases of the pancreatic type superfamily that have been engineered into cytotoxic RNase variants, yet are inhibited by cRI [12, 13]
Summary
It seemed of interest to investigate the role of cRI in RNase cytotoxicity by suppressing cellular cRI through the silencing of the mRNA transcribed from the cRI gene This technology, based on the phenomenon of RNA interference [16], involves the use, or the intracellular production by DNA engineering [17], of a double-stranded RNA complementary to the mRNA encoding the protein programmed to be suppressed. The results of this investigation indicate that the cytosolic inhibitor may not be a guardian against foreign RNases in general, as it only affects those foreign RNases that are intrinsically cytotoxic but not those that are non-cytotoxic
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