Login to Access Video or Poster Abstract: MP60-12
Sources of Funding: This work was supported by the Mildred Scheel Fellowship from the German Cancer Aid (MS) and NIH/NCI 1R01CA104574 (OI).

Introduction

Patients with Birt-Hogg-Dube (BHD) disease develop renal cancers of any known histology, skin fibrofolliculomas and spontaneous pneumothoraces. The disease is caused by a germline mutation in the tumor suppressor gene Folliculin (FLCN). Cancer associated mutations often result in a truncation of the C-terminus of the protein. The objective of our study was to discover novel insights into the molecular mechanism of tumor suppression by FLCN.

Methods

To gain further insight into the cellular function of FLCN, we isolated FLCN-containing protein complexes from the lysates of the FLCN-/- UOK257 human clear cell renal cell carcinoma cell line and its FLCN-replete isogenic derivative cells. Mass spectrometric analysis of affinity-purified complexes indicated that FLCN associates with several factors of the protein translation machinery, including the protein translation initiation factors.

Results

Here we report that FLCN localizes to the polysomes and associates with factors regulating the initiation of protein translation, including EIF2G and EIF5B. The FLCN C-terminal domain, which is deleted by tumor-associated FLCN mutations, is necessary for the interaction of FLCN with EIF2G and EIF5B. Reintroduction of wild type but not a C-terminus FLCN mutant into FLCN-/- cells results in suppression of serum or amino acid stimulated protein translation, independently of mTORC1/2 activity.

Conclusions

Our data provide insights into a novel mechanism of cell growth restriction by FLCN. Here we report that FLCN binds to protein translation initiation factors, resulting in repression of protein translation, downstream of mTORC1. This observation predicts that mTOR inhibitors may have limited efficacy in treating FLCN-related RCC and highlights protein translation as a therapeutic target for FLCN-related tumors.

Funding

This work was supported by the Mildred Scheel Fellowship from the German Cancer Aid (MS) and NIH/NCI 1R01CA104574 (OI).