A Molecular Meeting

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Science Translational Medicine  03 Jul 2013:
Vol. 5, Issue 192, pp. 192ec108
DOI: 10.1126/scitranslmed.3006877

Although cancer and type 2 diabetes are among the most investigated, deliberated, and dreaded diseases of the 21st century, the precise biological basis for the epidemiological link between the two has eluded investigators. Now, Ezzat and colleagues describe a mechanistic thread that might explain the statistical association. The study focused on the gene that encodes fibroblast growth factor receptor 4 (FGFR4), which in some individuals carries a single-nucleotide polymorphism (SNP) associated with increased cancer risk and poor prognosis. The resulting protein, FGFR4-R388, carries a G-to-R substitution at amino acid 388.

The authors began by studying the function of FGFR4-R388 in insulin secretion using a rat pancreatic islet cell line (RINm5F) and mice in which FGFR4-R385 was knocked in (R385 is the mouse analog for the human R388 SNP), which were compared with prototypic FGFR4-G388 mice. Experiments in the islet cell cultures and mouse models revealed that FGFR4-R388 promoted activation of the STAT3/5 transcription factor, which in turn induced transcription of the gene (Grb14) that encodes growth factor receptor–bound protein 14 (Grb14). Increased expression of Grb14 resulted in enhanced insulin secretion, thus identifying Grb14 as a critical mediator that links the cancer-associated FGFR4-R388 SNP with pancreatic insulin production. The researchers then assessed the pharmacological action of FGF19, a GFR4 ligand, and found that it improved glucose tolerance in FGFR4-R385 mice with substantially enhanced insulin secretion. Last, with human epidemiological (allele-association) studies, the authors demonstrated a role for the FGFR4-R388 allele in a person’s risk of developing type 2 diabetes. The human data revealed some gender differences and raised the possibility of a role for parental gene imprinting in Grb14 function.

This study illustrates the importance of human genomic data in unearthing disease relationships that illuminate the molecular mechanisms that underlie human disease—which, in turn, pinpoint partially validated therapeutic targets. With this approach, we move—molecule by molecule—toward therapeutic strategies for harrowing human diseases.

S. Ezzat et al., The cancer-associated FGFR4-G388R polymorphism enhances pancreatic insulin secretion and modifies the risk of diabetes. Cell Metab. 17, 929–940 (2013). [Abstract]

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