Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin
- PMID: 19843504
- DOI: 10.1136/jmg.2009.072009
Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin
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.
Similar articles
-
Knockdown of Slingshot 2 (SSH2) serine phosphatase induces Caspase3 activation in human carcinoma cell lines with the loss of the Birt-Hogg-Dubé tumour suppressor gene (FLCN).Oncogene. 2014 Feb 20;33(8):956-65. doi: 10.1038/onc.2013.27. Epub 2013 Feb 18. Oncogene. 2014. PMID: 23416984
-
Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia.PLoS One. 2008;3(10):e3581. doi: 10.1371/journal.pone.0003581. Epub 2008 Oct 30. PLoS One. 2008. PMID: 18974783 Free PMC article.
-
Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein.Oncogene. 2008 Sep 11;27(40):5339-47. doi: 10.1038/onc.2008.261. Epub 2008 Jul 28. Oncogene. 2008. PMID: 18663353
-
Birt-Hogg-Dubé syndrome: Clinical and molecular aspects of recently identified kidney cancer syndrome.Int J Urol. 2016 Mar;23(3):204-10. doi: 10.1111/iju.13015. Epub 2015 Nov 25. Int J Urol. 2016. PMID: 26608100 Review.
-
Association between Birt Hogg Dube syndrome and cancer predisposition.Anticancer Res. 2010 Mar;30(3):751-7. Anticancer Res. 2010. PMID: 20392993 Review.
Cited by
-
PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis.Hum Mol Genet. 2023 Mar 20;32(7):1223-1235. doi: 10.1093/hmg/ddac288. Hum Mol Genet. 2023. PMID: 36440963 Free PMC article.
-
Recurrent multifocal adult rhabdomyoma in an elderly woman diagnosed with Birt-Hogg-Dubé syndrome: A case report.Front Surg. 2022 Sep 30;9:1017725. doi: 10.3389/fsurg.2022.1017725. eCollection 2022. Front Surg. 2022. PMID: 36338635 Free PMC article.
-
Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.Science. 2022 Apr 15;376(6590):eabf8271. doi: 10.1126/science.abf8271. Epub 2022 Apr 15. Science. 2022. PMID: 35420934 Free PMC article.
-
The fission yeast FLCN/FNIP complex augments TORC1 repression or activation in response to amino acid (AA) availability.iScience. 2021 Oct 23;24(11):103338. doi: 10.1016/j.isci.2021.103338. eCollection 2021 Nov 19. iScience. 2021. PMID: 34805795 Free PMC article.
-
Genomic Copy Number Variants in CML Patients With the Philadelphia Chromosome (Ph+): An Update.Front Genet. 2021 Aug 10;12:697009. doi: 10.3389/fgene.2021.697009. eCollection 2021. Front Genet. 2021. PMID: 34447409 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases