Encouraging this partnership might provide a possible treatment for muscle wasting disorders. The article will appear in the December 15, 2008 issue of The Journal of Cell Biology (JCB).

Mutations in 'Four and a half LIM domains 1' (FHL1), a human gene, are present in several myopathies, including reducing-body myopathy (RBM), but until now, both the molecular mechanisms causing the disease, and the regular function of FHL1 in healthy tissue, remained unknown.

To address this, Cowling et al. overexpressed FHL1 in both transgenic mice and cultured myoblasts. The mice developed skeletal muscle hypertrophy, and showed increased strength and endurance. Overexpression in myoblasts also increased cell fusion, resulting in hypertrophic myotubes. These phenotypes are similar to those caused by the calcineurin/NFAT pathway and, indeed, inhibiting calcineurin blocked the effects of FHL1 overexpression in vitro. The authors showed that FHL1 binds to and enhances the transcriptional activity of NFATc1 in vitro and in vivo.

So what goes wrong when FHL1 is mutated? In RBM, mutant FHL1 accumulates in cytoplasmic aggregates called reducing bodies, probably as a result of misfolding. When these mutants were expressed in cultured myoblasts, they also aggregated, and did not induce hypertrophy. Cowling and colleagues found that NFATc1 was sequestered to the aggregates, and was therefore unable to activate its target genes.

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However, disease classification by gene expression is imprecise because cells taken from a single tumor sample often are heterogeneous; genes switched on in cells from one part of the tumor may not be active elsewhere in the tumor.

In addition, the expression profiles from a range of patients with the "same" type and grade of tumor can differ significantly.

Ideker and Chuang's approach may change diagnostics so that a patient's diagnosis could go beyond, for example, estrogen responsive breast cancer to a particular subtype of estrogen responsive breast cancer with poor or good prognosis.

The U.S.-Korean researchers are now extending their new integrated analysis to other cancers including leukemia, prostate cancer and lung cancer.

They are identifying "condition-responsive" genes within signaling and transcriptional pathways that could be used as a measure of activation levels and could provide another useful tool for diagnosis and prognosis, they say.

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