Abstract
Birt-Hogg-Dubé syndrome (BHD) is a human cancer disorder caused by mutations in the tumor suppressor gene Folliculin (FLCN) with unknown biological functions. Here, we show that the Drosophila homolog of FLCN, dFLCN (a.k.a. dBHD) localizes to the nucleolus and physically interacts with the 19S proteasomal ATPase, Rpt4, a nucleolar resident and known regulator of rRNA transcription. Downregulation of dFLCN resulted in an increase in nucleolar volume and upregulation of rRNA synthesis, whereas dFLCN overexpression reduced rRNA transcription and counteracted the effects of Rpt4 on rRNA production by preventing the association of Rpt4 with the rDNA locus. We further show that human FLCN exhibited evolutionarily conserved function and that Rpt4 knockdown inhibits the growth of FLCN-deficient human renal cancer cells in mouse xenografts. Our study suggests that FLCN functions as a tumor suppressor by negatively regulating rRNA synthesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases / metabolism
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Animals
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Animals, Genetically Modified
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Birt-Hogg-Dube Syndrome / genetics*
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Birt-Hogg-Dube Syndrome / metabolism*
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Carrier Proteins / metabolism
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Cell Line
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Cell Nucleus / metabolism
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DNA, Ribosomal / metabolism
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Drosophila / genetics
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Drosophila / metabolism
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Female
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Gene Expression
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Gene Expression Regulation*
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Gene Knockdown Techniques
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Humans
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Mice
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Mice, Nude
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Protein Binding
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Protein Transport
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins / physiology*
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RNA Precursors / metabolism
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RNA, Ribosomal / biosynthesis
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RNA, Ribosomal / genetics*
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Transplantation, Heterologous
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Tumor Burden / genetics
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Tumor Suppressor Proteins / physiology*
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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BHD protein, Drosophila
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Carrier Proteins
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DNA, Ribosomal
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Drosophila Proteins
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FLCN protein, human
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Proto-Oncogene Proteins
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RNA Precursors
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RNA, Ribosomal
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Tumor Suppressor Proteins
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Adenosine Triphosphatases
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ras Proteins