Loss of functional Folliculin (FLCN) leads to development of renal tumours. This tumourigenesis has been linked to increased mTOR signalling and mitochondrial mitogenesis mediated through AMPK and PPARGC1 (also known as PGC1a) signalling.
New research from Hasumi et al., 2015 has now identified a comparably important role for FLCN interacting proteins Fnip1 and Fnip2 in kidney tumour suppression in mouse models. Conditional knockout of Fnip1 or Fnip2 in the mouse kidneys did not result in any significant phenotype, consistent with the hypothesis of functional redundancy between Fnip1 and Fnip2. In contrast double knockout Fnip1/Fnip2 mice developed enlarged, polycystic kidneys associated with reduced survival. Molecular analysis showed an increase in Ppargc1 expression, mTOR signalling and mitochondrial biogenesis, as seen in Flcn knockout kidneys. Additional inactivation of Flcn in the Fnip1/Fnip2 null kidneys did not enhance their size or alter the histology, suggesting that all of the mutations are acting through the same pathway. If true then tumourigenesis seen following FLCN mutations could be due to loss of a functional interaction between FLCN, FNIP1/2 and a downstream target such as AMPK.
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