Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin

J Med Genet. 2010 Mar;47(3):182-9. doi: 10.1136/jmg.2009.072009. Epub 2009 Oct 19.

Abstract

Background: Renal cell carcinoma (RCC) comprises five major molecular and histological subtypes. The Birt-Hogg-Dubé (BHD) syndrome is a hereditary human cancer syndrome that predisposes affected individuals to develop renal carcinoma of nearly all subtypes, in addition to benign fibrofolliculomas, and pulmonary and renal cysts. BHD is caused by loss-of-function mutations in the folliculin (FLCN) protein. The molecular function of FLCN is still largely unknown; opposite and conflicting evidence of the role of FLCN in mammalian target of rapamycin signalling/phosphorylated ribosomal protein S6 (p-S6) activation had recently been reported.

Results and methods: Here, the expression pattern of murine Flcn was described, and it was observed that homozygous disruption of Flcn results in embryonic lethality early during development. Importantly, heterozygous animals manifest early preneoplastic kidney lesions, devoid of Flcn expression, that progress towards malignancy, including cystopapillary adenomas. A bona fide tumour suppressor activity of FLCN was confirmed by nude mouse xenograft assays of two human RCC cell lines with either diminished or re-expressed FLCN. It was observed that loss of FLCN expression leads to context-dependent effects on S6 activation. Indeed, solid tumours and normal kidneys show decreased p-S6 upon diminished FLCN expression. Conversely, p-S6 is found to be elevated or absent in FLCN-negative renal cysts.

Conclusion: In accordance with clinical data showing distinct renal malignancies arising in BHD patients, in this study FLCN is shown as a general tumour suppressor in the kidney.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / pathology
  • Cell Proliferation
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor / physiology*
  • Genetic Predisposition to Disease
  • Humans
  • Kidney Diseases, Cystic / genetics
  • Kidney Diseases, Cystic / pathology
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / pathology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Multiprotein Complexes
  • Precancerous Conditions / genetics
  • Proteins
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Ribosomal Protein S6 Kinases / metabolism
  • Syndrome
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology*

Substances

  • FLCN protein, human
  • Multiprotein Complexes
  • Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases
  • Mitogen-Activated Protein Kinase 3