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Gene expression profiling of BHDS-associated renal tumors

ABSTRACT: Renal tumors that arise in individuals with BHD Syndrome represent a molecularly distinct form of renal cancer. In addition, BHD syndrome is due to a mutation the folliculin gene (FLCN). While the folliculin gene is an important tumor suppressor gene, the molecular function of this gene is not well defined. By analyzing tumor samples that contain FLCN mutations, we demonstrate that the FLCN gene is an important regulator of mitochondrial function. Gene expression profiling of BHDS tumors and normal kidney tissues

ORGANISM(S): Homo sapiens

SUBMITTER: Jeff Klomp

PROVIDER: E-GEOD-21816 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression.

Klomp Jeff A JA Petillo David D Niemi Natalie M NM Dykema Karl J KJ Chen Jindong J Yang Ximing J XJ Sääf Annika A Zickert Peter P Aly Markus M Bergerheim Ulf U Nordenskjöld Magnus M Gad Sophie S Giraud Sophie S Denoux Yves Y Yonneau Laurent L Méjean Arnaud A Vasiliu Viorel V Richard Stéphane S MacKeigan Jeffrey P JP Teh Bin T BT Furge Kyle A KA

BMC medical genomics 20101216

<h4>Background</h4>Germline mutations in the folliculin (FLCN) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of spontaneous pneumothorax, and the development of renal neoplasias. The majority of renal tumors that arise in BHDS-affected individuals are histologically similar to sporadic chromophobe renal cell carcinoma (RCC) and sporadic renal oncocytoma. However, most sporadic tumors lack FLCN mutati ...[more]

PMID: 21162720

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Phosphoproteomic analysis of the Folliculin (FLCN) tumor suppressor reveals FLCN-dependent kinase signaling and TFEB regulation

Project description:In Birt-Hogg-Dubé (BHD) syndrome, germline mutations in the Folliculin (FLCN) gene lead to an increased risk of renal cancer. To address if FLCN is involved regulating cellular signaling pathways via protein and receptor phosphorylation we determined comprehensive complete phosphoproteomic profiles of FLCNPOS and FLCNNEG human renal tubular epithelial cells (RPTEC/TERT1). In total, 15744 phosphorylated peptides were identified, residing on 4329 phosphorylated proteins. Kinase activity inference analysis revealed that FLCN loss elevates phosphorylation of numerous kinases, including tyrosine kinases EPHA2 and MET, as well as activation of downstream MAPK1/3/6 and 8. Three non-canonical phosphorylation sites on EGFR (Tyr1125, Tyr1138 and Tyr1172) were higher phosphorylated upon FLCN loss together with enhanced phosphorylated EGFR substrates ABI, EPS8, ERRFL1, STAT1, PTK2 and CTNND1. In concordance, phosphosite specific signature analyses revealed an enrichment for EGFR signaling in FLCNNEG cells. Interestingly, we detected FLCN dependent phosphorylation of PIK3CD but no canonical downstream Akt/mTOR activation. In agreement with the induction of the E-box transcriptional gene expression signature upon FLCN loss, here we identified that phosphorylation of TFEB on Ser109, Ser114 and Ser122 is dependent on FLCN and absence of this phosphorylation results in constitutive nuclear localization of this transcription factor in FLCNNEG cells. Together, our study reveals enhanced phosphorylation of specific kinases and substrates in FLCNNEG renal epithelial cells, providing important insights in BHD-associated renal tumorigenesis and offering novel handles for the design of targeted therapies.

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