Scientists from the Florida campus of The Scripps Research Institute
(TSRI) have confirmed the ribosome assembly process as a potentially
fertile new target for anti-cancer drugs by detailing the essential
function of a key component in the assembly process.
"This study confirms that ribosome assembly is a good therapeutic
target in cancer," said Katrin Karbstein, a TSRI associate professor who
led the study. "Whether or not we have pinpointed the best molecule
remains to be shown, but this is a vindication of our basic research.
There should be effort devoted to exploring this pathway."
Understanding ribosome assembly, which involves about 200 essential
proteins known as "assembly factors" in addition to the four RNA
molecules and 78 ribosomal proteins that are part of the mature
ribosome--has become a fruitful area of research in recent years because
of the importance of ribosome assembly for cell growth.
The new study highlights the molecules Casein kinase 1δ (CK1δ) and
CK1ε, which are essential for human ribosome assembly. The expression of
CK1δ is elevated in several tumor types, as well as Alzheimer's and
Parkinson's disease--and CK1δ inhibitors have shown promise in some
pre-clinical animal studies.
In the new study, Karbstein and her group, working closely with three
labs across the state of Florida, including the laboratory of William
Roush at Scripps Florida, used Hrr25, the yeast equivalent of Casein
kinase 1δ (CK1δ) and CK1ε, as a research model.
In biochemical experiments, the team showed that Hrr25 is necessary
for ribosome assembly and that the molecule normally adds a phosphate
group to an assembly factor called "Ltv1," allowing it to separate from
other subunits and mature. If Hrr25 is inactivated or a mutation blocks
the release of Ltv1, the assembly process is doomed.
"Inhibiting Hrr25 and the subsequent release of Ltv1 blocks the
formation of other subunits that are required for maturation and the
subsequent production of proteins,"
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