The Birt-Hogg-Dubé tumor suppressor Folliculin negatively regulates ribosomal RNA synthesis.
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.
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Kriti
K
Gaur
Jinghong
J
Li
Dakun
D
Wang
Pranabananda
P
Dutta
Shian-Jang
SJ
Yan
Amy
A
Tsurumi
Hartmut
H
Land
Guan
G
Wu
Willis X
WX
Li
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D058249:Birt-Hogg-Dube Syndrome / Q000235:genetics* / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004275:DNA, Ribosomal / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011485:Protein Binding; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D012322:RNA Precursors / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis / Q000235:genetics*; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
C514513:BHD protein, Drosophila; D002352:Carrier Proteins; D004275:DNA, Ribosomal; D029721:Drosophila Proteins; C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D012322:RNA Precursors; D012335:RNA, Ribosomal; D025521:Tumor Suppressor Proteins; D000251:Adenosine Triphosphatases; D018631:ras Proteins