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Anti-cancer drugs may hold promise for premature aging disorder

g lamin A to integrate properly into the nuclear lamina.

Because progerin carries the farnesylation tag but lacks the second cleavage tag, Capell speculated that progerin was becoming permanently stuck to the inner nuclear membrane. There, he suspected, it enmeshed other scaffolding proteins, preventing their proper integration into the lamina. If progerin's tendency to stick to the inner nuclear membrane is indeed the culprit in nuclear blebbing and the root of the progeria defect, Capell and his colleagues reasoned that they could prevent these defects by blocking farnesylation of progerin.

The researchers' hunch proved correct. When they changed one amino acid within progerin's farnesylation tag to prevent the addition of a farnesyl group and tested the effect in cells grown in the laboratory, progerin did not anchor itself to the inner nuclear membrane and instead clumped within the nucleus. Moreover, they observed no nuclear blebbing.

The researchers then tried treating the cells carrying progerin with FTIs, which are drugs originally developed to inhibit certain cancer-causing proteins that require farnesylation for function. FTIs are now being tested in phase III clinical trials of patients with myeloid leukemia. So far, clinical trials using FTIs have found little toxicity, even when the drug treatment significantly raises levels of unfarnesylated proteins.

After FTI treatment, the progerin-carrying cells showed no blebbing. More importantly, researchers saw the same effect when they used FTIs to treat cells grown from skin biopsies of progeria patients: Cell blebbing decreased to near normal levels.

In addition to Capell and his colleagues in NHGRI's Genome Technology Branch, researchers from the University of North Carolina at Chapel Hill and the University of Michigan School of Public Health in Ann Arbor took part in the study.

The HHMI/NIH Research Scholars Program gives outstanding medical and dental stu
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Source:NIH/National Human Genome Research Institute


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