Folliculin regulates cyclin D1 expression through cis-acting elements in the 3' untranslated region of cyclin D1 mRNA

Int J Oncol. 2013 May;42(5):1597-604. doi: 10.3892/ijo.2013.1862. Epub 2013 Mar 21.


Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominantly inherited disease characterized by spontaneous pneumothorax, hair folliculomas and renal tumors. The responsible gene, BHD, is a tumor suppressor and encodes folliculin. Folliculin is an evolutionarily conserved protein (~67 kDa) with no apparent functional motif and its role has not yet been fully elucidated. In this study, we found that knockdown of BHD increased the levels of cyclin D1 in HeLa cells. A reporter assay with the cyclin D1 gene (CCND1) promoter region indicated that this increase was not caused by activation of transcription through known cis-acting elements. We examined the possibility of post-transcriptional mechanism using reporter constructs containing fragments of the cyclin D1 3' untranslated region (3'UTR). Transfection of control cells with a construct carrying a medial 1.3 kb 3'UTR fragment resulted in a significant reduction in luciferase activity. This effect was largely prevented by knockdown of BHD. Our results suggest that the post-transcriptional regulation of the CCND1 expression by BHD may be associated with microRNA(s) or RNA binding protein(s) that bind to the 3'UTR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Birt-Hogg-Dube Syndrome / genetics*
  • Birt-Hogg-Dube Syndrome / metabolism
  • Birt-Hogg-Dube Syndrome / pathology
  • Cyclin D1 / genetics*
  • Cyclin D1 / metabolism
  • Gene Expression Regulation, Neoplastic*
  • HeLa Cells
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • MicroRNAs / genetics
  • Plasmids / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / genetics
  • Rats
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • 3' Untranslated Regions
  • CCND1 protein, human
  • FLCN protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • Cyclin D1