Deregulation of HIF1 and mTOR as a cause of Birt-Hogg-Dubé syndrome
Projectomschrijving
Het Birt-Hogg-Dubé syndroom is een zeldzame ziekte die zich voornamelijk uit door goedaardige huidtumoren, een verhoogde kans op nierkanker en/of een klaplong veroorzaakt door longcysten. De ziekte wordt veroorzaakt door mutaties in het gen dat codeert voor het eiwit folliculine. Men wil onderzoeken wat folliculine doet en zo mogelijk medicijnen ontwikkelen die de gevolgen van mutaties kunnen ondervangen
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Titel: The 3rd Birt-Hogg-Dubé Symposium
Auteur: Arjan Houweling, Lieke M. Gijezen, Marianne A. Jonker, Martijn B. A. Van Doorn, Rogier A. Oldenburg, Karin Y. Van Spaendonck-Zwarts, Edward M. Leter, Theo A. Van Os, Nicole C. T. Van Grieken, Elisabeth H. Jaspars, Mirjam M. De Jong, Ernie M. H. F. Bongers, Paul C. Johannesma, Pieter E. Postmus, R. Jeroen A. Van Moorselaar, Jan-Hein T. M. Van Waesberghe, Theo M. Starink, Maurice A. M. Van Steensel, Johan J. P. Gille, Fred H. Menko
Auteur: Arjan Houweling, Lieke M. Gijezen, Marianne A. Jonker, Martijn B. A. Van Doorn, Rogier A. Oldenburg, Karin Y. Van Spaendonck-Zwarts, Edward M. Leter, Theo A. Van Os, Nicole C. T. Van Grieken, Elisabeth H. Jaspars, Mirjam M. De Jong, Ernie M. H. F. Bongers, Paul C. Johannesma, Pieter E. Postmus, R. Jeroen A. Van Moorselaar, Jan-Hein T. M. Van Waesberghe, Theo M. Starink, Maurice A. M. Van Steensel, Johan J. P. Gille, Fred H. Menko
Titel: FLCN-dependent regulation of HIF-2alpha
Titel: The Second Birt Hogg Dubé Symposium
Auteur: Michael S Nahorski, Anne Reiman, Derek HK Lim, Lynn Martin, Johan JP Gille, Kirsten McKay, Pauline K Rehal, H. Martijn Ploeger, Maurice van Steensel, Ian P Tomlinson, Farida Latif, Fred H Menko, Eamonn R Maher
Auteur: Michael S Nahorski, Anne Reiman, Derek HK Lim, Lynn Martin, Johan JP Gille, Kirsten McKay, Pauline K Rehal, H. Martijn Ploeger, Maurice van Steensel, Ian P Tomlinson, Farida Latif, Fred H Menko, Eamonn R Maher
Titel: The Inaugural Birt-Hogg-Dube ́ (BHD) Symposium
Auteur: Weppler, S.A., Claessens, T., van Geel, M, and van Steensel, M.A.M.
Auteur: Weppler, S.A., Claessens, T., van Geel, M, and van Steensel, M.A.M.
Titel: The Second Birt Hogg Dube ́ Symposium
Auteur: L.M.C. Gijezen, F.H. Menko, T.M. Starink, M.A.M. van Steensel
Auteur: L.M.C. Gijezen, F.H. Menko, T.M. Starink, M.A.M. van Steensel
Titel: The 3rd Birt-Hogg-Dubé Symposium
Auteur: M. N. H. Luijten, T. Claessens, M. Vernooij, B. J. Coull, M. A. M. van Steensel
Auteur: M. N. H. Luijten, T. Claessens, M. Vernooij, B. J. Coull, M. A. M. van Steensel
Titel: The 3rd Birt-Hogg-Dubé Symposium
Auteur: Andrew R. Tee, Rachael S. Preston, Andrew Philip, Tijs Claessens, Lieke Gijezen, Anders B. Dydensborg, Elaine A. Dunlop, Katy T. Harper, Tjinta Brinkhuizen, Fred H. Menko, D. Mark Davies, Stephen C. Land, Arnim Pause, Keith Baar, Maurice A.M. van Steensel
Auteur: Andrew R. Tee, Rachael S. Preston, Andrew Philip, Tijs Claessens, Lieke Gijezen, Anders B. Dydensborg, Elaine A. Dunlop, Katy T. Harper, Tjinta Brinkhuizen, Fred H. Menko, D. Mark Davies, Stephen C. Land, Arnim Pause, Keith Baar, Maurice A.M. van Steensel
Titel: The 3rd Birt-Hogg-Dubé Symposium
Auteur: Anders Dydensborg, Rachael Preston, Ming Yan, Daina Avizonis, Sylvie Sabourin, Russel Jones, Maurice Van Steensel, Andrew R. Tee, Arnim Pause
Auteur: Anders Dydensborg, Rachael Preston, Ming Yan, Daina Avizonis, Sylvie Sabourin, Russel Jones, Maurice Van Steensel, Andrew R. Tee, Arnim Pause
Titel: The 3rd Birt-Hogg-Dubé Symposium
Auteur: Marigje Vernooij, M. N. H. Luijten, T. Claessens, B. J. Coull, M. A. M. van Steensel
Auteur: Marigje Vernooij, M. N. H. Luijten, T. Claessens, B. J. Coull, M. A. M. van Steensel
Titel: The 2nd Birt-Hogg-Dubé Symposium
Auteur: A.C. Houweling, L.M. Gijezen, M.A. Jonker, M.B. van Doorn, R. Oldenburg, K.Y. van Spaerndonck-Zwarts, E.M. Leter, T.A. van Os, M.M de Jong, J.J. Gille, E.M. Bongers, H. M. Ploeger, M.T. Kramer, P.E Postmus, P.C. Johannesma, R.J. van Moorselaar, J.H. van Waesberghe, T.M. Starink, M.A. van Steensel, F.H. Menko
Auteur: A.C. Houweling, L.M. Gijezen, M.A. Jonker, M.B. van Doorn, R. Oldenburg, K.Y. van Spaerndonck-Zwarts, E.M. Leter, T.A. van Os, M.M de Jong, J.J. Gille, E.M. Bongers, H. M. Ploeger, M.T. Kramer, P.E Postmus, P.C. Johannesma, R.J. van Moorselaar, J.H. van Waesberghe, T.M. Starink, M.A. van Steensel, F.H. Menko
Titel: The 2nd Birt-Hogg-Dubé symposium
Auteur: Derek HK Lim, Pauline K Rehal, Michael Nahorski, Fiona Macdonald, Tijs Claessens, Michel Van Geel, Lieke Gijezen, Johan JP Gille, Sophie Giraud, Stephane Richard, Maurice van Steensel, Fred Menko, and Eamonn R Maher
Auteur: Derek HK Lim, Pauline K Rehal, Michael Nahorski, Fiona Macdonald, Tijs Claessens, Michel Van Geel, Lieke Gijezen, Johan JP Gille, Sophie Giraud, Stephane Richard, Maurice van Steensel, Fred Menko, and Eamonn R Maher
Titel: The 2nd Birt-Hogg-Dubé Symposium
Auteur: Rachael S. Preston, Andrew Philp, Tijs Claesens, Elaine A. Dunlop, Lieke Gijezen, Katy T. Harper, Tjinta Brinkhuizen, D. Mark Davies, Stephen S. Land, Keith Baar, Maurice van Steensel and Andrew R. Tee
Auteur: Rachael S. Preston, Andrew Philp, Tijs Claesens, Elaine A. Dunlop, Lieke Gijezen, Katy T. Harper, Tjinta Brinkhuizen, D. Mark Davies, Stephen S. Land, Keith Baar, Maurice van Steensel and Andrew R. Tee
Titel: Lack of SSH1 mutations in Dutch patients with disseminated superficial actinic porokeratosis: is there really an association?
Auteur: Frank J, van Steensel MA, van Geel M
Magazine: Human Mutation
Auteur: Frank J, van Steensel MA, van Geel M
Magazine: Human Mutation
Titel: Wilms tumour as an early manifestation of hereditary leiomyomatosis and renal cell cancer.
Auteur: Sadhanna Badeloe, Karin Y. van Spaendonck-Zwarts, Maurice A.M van Steensel, Ariënne M.W. van Marion, Anthonie J. van Essen, Marcel F. Jonkman, Peter M. Steijlen, Michel van Geel, and Jorge Frank
Magazine: British Journal of Dermatology
Auteur: Sadhanna Badeloe, Karin Y. van Spaendonck-Zwarts, Maurice A.M van Steensel, Ariënne M.W. van Marion, Anthonie J. van Essen, Marcel F. Jonkman, Peter M. Steijlen, Michel van Geel, and Jorge Frank
Magazine: British Journal of Dermatology
Titel: Shprintzen-Goldberg syndrome associated with a novel missense mutation in TGFBR2
Auteur: Maurice A.M. van Steensel, Michel van Geel, Lizelotte J.M.T. Parren, Constance T.R.M. Schrander-Stumpel and Dominique Marcus-Soekarman
Magazine: Experimental Dermatology
Auteur: Maurice A.M. van Steensel, Michel van Geel, Lizelotte J.M.T. Parren, Constance T.R.M. Schrander-Stumpel and Dominique Marcus-Soekarman
Magazine: Experimental Dermatology
Titel: Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer.
Auteur: Nahorski MS, Lim DH, Martin L, Gille JJ, McKay K, Rehal PK, Ploeger HM, van Steensel M, Tomlinson IP, Latif F, Menko FH, Maher ER.
Magazine: Journal of Medical Genetics
Auteur: Nahorski MS, Lim DH, Martin L, Gille JJ, McKay K, Rehal PK, Ploeger HM, van Steensel M, Tomlinson IP, Latif F, Menko FH, Maher ER.
Magazine: Journal of Medical Genetics
Titel: Molecular pathways involved in hair follicle tumor formation: all about mammalian target of rapamycin?
Auteur: M.A.M. van Steensel, S. Badeloe, M. van Geel J. Frank.
Magazine: Experimental Dermatology
Auteur: M.A.M. van Steensel, S. Badeloe, M. van Geel J. Frank.
Magazine: Experimental Dermatology
Titel: Novel EBP gene mutations in Conradi-Hünermann-Happle syndrome
Auteur: Steijlen PM, van Geel M, Vreeburg M, Marcus-Soekarman D, Spaapen LJ, Castelijns FC, Willemsen M, van Steensel MA.
Magazine: British Journal of Dermatology
Auteur: Steijlen PM, van Geel M, Vreeburg M, Marcus-Soekarman D, Spaapen LJ, Castelijns FC, Willemsen M, van Steensel MA.
Magazine: British Journal of Dermatology
Titel: The Wnt signalling ligand RSPO4, causing inherited anonychia, is not mutated in a patient with congenital nail hypoplasia/aplasia with underlying skeletal defects
Auteur: Seitz CS, van Steensel M, Frank J, Senderek J, Zerres K, Hamm H, Bergmann C.
Magazine: British Journal of Dermatology
Auteur: Seitz CS, van Steensel M, Frank J, Senderek J, Zerres K, Hamm H, Bergmann C.
Magazine: British Journal of Dermatology
Titel: Emerging drugs in ichthyosis
Auteur: M.A.M. van Steensel
Magazine: Expert Opinion on Emerging Drugs
Auteur: M.A.M. van Steensel
Magazine: Expert Opinion on Emerging Drugs
Titel: Loss-of-function mutations of an inhibitory upstream open reading frame in the human hairless transcript lead to a dominant form of genetic hair loss
Auteur: Yaran Wen, Yang Liu, Yiming Xu, Yiwei Zhao, Rui Hua, Kaibo Wang, Miao Sun, Yuanhong Li, Sen Yang, Xue-Jun Zhang, Roland Kruse, Sven Cichon, Regina C. Betz, Markus M. Nöthen, Maurice A. M. van Steensel, Peter M. Steijlen, Daniel Hohl, Marcel Huber, Giles S. Dunnill, Cameron Kennedy, Andrew Messenger, Colin S. Munro, Alessandro Terrinoni, Alain Hovnanian, Amy S Paller, Alan D. Irvine, Rod Sinclair, Jack Green, Leona Yip, Dandan Shang, Qing Liu, Yang Luo, Li Jiang, Hong-Duo Chen, Wilson H- Y. Lo,
Magazine: Nature Genetics
Auteur: Yaran Wen, Yang Liu, Yiming Xu, Yiwei Zhao, Rui Hua, Kaibo Wang, Miao Sun, Yuanhong Li, Sen Yang, Xue-Jun Zhang, Roland Kruse, Sven Cichon, Regina C. Betz, Markus M. Nöthen, Maurice A. M. van Steensel, Peter M. Steijlen, Daniel Hohl, Marcel Huber, Giles S. Dunnill, Cameron Kennedy, Andrew Messenger, Colin S. Munro, Alessandro Terrinoni, Alain Hovnanian, Amy S Paller, Alan D. Irvine, Rod Sinclair, Jack Green, Leona Yip, Dandan Shang, Qing Liu, Yang Luo, Li Jiang, Hong-Duo Chen, Wilson H- Y. Lo,
Magazine: Nature Genetics
Titel: Lymphedema, cardiac septal defects, and characteristic facies: possible new case of Irons-Bianchi syndrome
Auteur: van Steensel MA, van Geel M, Schrander-Stumpel C, Steijlen PM, Veraart JC
Magazine: American Journal of Medical Genetics A
Auteur: van Steensel MA, van Geel M, Schrander-Stumpel C, Steijlen PM, Veraart JC
Magazine: American Journal of Medical Genetics A
Titel: Neuroendocrine carcinoma in a patient with Birt-Hogg-Dubé syndrome.
Auteur: Claessens T, Weppler SA, van Geel M, Creytens D, Vreeburg M, Wouters B, van Steensel MA.
Magazine: Nature Reviews Urology
Auteur: Claessens T, Weppler SA, van Geel M, Creytens D, Vreeburg M, Wouters B, van Steensel MA.
Magazine: Nature Reviews Urology
Titel: Paraneoplastic hypertrichosis lanuginosa acquisita: uncommon or overlooked?
Auteur: Slee PH, van der Waal RI, Schagen van Leeuwen JH, Tupker RA, Timmer R, Seldenrijk CA, van Steensel MA.
Magazine: British Journal of Dermatology
Auteur: Slee PH, van der Waal RI, Schagen van Leeuwen JH, Tupker RA, Timmer R, Seldenrijk CA, van Steensel MA.
Magazine: British Journal of Dermatology
Titel: RSPO4 Is the Major Gene in Autosomal-Recessive Anonychia and Mutations Cluster in the Furin-Like Cysteine-Rich Domains of the Wnt Signaling Ligand R-spondin
Auteur: Brüchle NO, Frank J, Frank V, Senderek J, Akar A, Koc E, Rigopoulos D, van Steensel M, Zerres K, Bergmann C.
Magazine: Journal of Investigative Dermatology
Auteur: Brüchle NO, Frank J, Frank V, Senderek J, Akar A, Koc E, Rigopoulos D, van Steensel M, Zerres K, Bergmann C.
Magazine: Journal of Investigative Dermatology
Titel: Erysipelas as a sign of subclinical primary lymphedema: A prospective quantitative scintigraphic study of 40 patients with unilateral erysipelas of the leg
Auteur: R.J. Damstra, M.A.M. van Steensel, J.H.B. Boomsma, P. Nelemans, J.C.J.M. Veraart
Magazine: British Journal of Dermatology
Auteur: R.J. Damstra, M.A.M. van Steensel, J.H.B. Boomsma, P. Nelemans, J.C.J.M. Veraart
Magazine: British Journal of Dermatology
Titel: Birt-Hogg-Dubé syndrome: diagnosis and management.
Auteur: Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER; European BHD Consortium.
Magazine: Lancet Oncology
Auteur: Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER; European BHD Consortium.
Magazine: Lancet Oncology
Titel: Chanarin-Dorfman syndrome caused by a novel splice site mutation in ABHD5.
Auteur: S. Badeloe, M. van Geel, I. Nagtzaam, M.E. Rubio-Gozalbo, R.L. Oei, P.M. Steijlen, M.A.M. van Steensel.
Magazine: British Journal of Dermatology
Auteur: S. Badeloe, M. van Geel, I. Nagtzaam, M.E. Rubio-Gozalbo, R.L. Oei, P.M. Steijlen, M.A.M. van Steensel.
Magazine: British Journal of Dermatology
Titel: A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene.
Auteur: Lim DH, Rehal PK, Nahorski MS, Macdonald F, Claessens T, Van Geel M, Gijezen L, Gille JJ, Giraud S, Richard S, van Steensel M, Menko FH, Maher ER.
Magazine: Human Mutation
Auteur: Lim DH, Rehal PK, Nahorski MS, Macdonald F, Claessens T, Van Geel M, Gijezen L, Gille JJ, Giraud S, Richard S, van Steensel M, Menko FH, Maher ER.
Magazine: Human Mutation
Titel: A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness.
Auteur: de Zwart-Storm EA, Hamm H, Stoevesandt J, Steijlen PM, Martin PE, van Geel M, van Steensel MA.
Magazine: Journal of Medical Genetics
Auteur: de Zwart-Storm EA, Hamm H, Stoevesandt J, Steijlen PM, Martin PE, van Geel M, van Steensel MA.
Magazine: Journal of Medical Genetics
Titel: Clinical research fellow in BHD
Titel: Oprichting European Birt-Hogg-Dubé consortium
Titel: The Regulation of Protein Synthesis by mTOR Signaling: a Potential Target for Cancer Treatment?
Auteur: S. Weppler
Auteur: S. Weppler
Titel: CANCER INTERVENTION AND SCREENING
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Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterised by the occurrence of disfiguring benign hair follicle tumors in the face called fibrofolliculomas, malignant kidney tumors and spontaneous pneumothorax caused by lung cysts(1). Men and women are equally affected. The first symptoms usually appear in the 2nd to 3rd decade of life.
By carefully analysing the BHD syndrome phenotype in connection to several recent findings in other, similar syndromes, we have developed an innovative hypothesis about the normal role of FLCN. BHD’s key symptoms place the syndrome in a larger group of related disorders that are all typified by skin tumors, kidney carcinomas and associated abnormalities including lung diseases (table 1). A common feature of each of these disorders is the deregulation of hypoxia inducible factor-1, a protein complex that regulates cellular reponses to oxygen tension (HIF1(4)). Under normal, baseline conditions, HIF1 is rapidly degraded. Hypoxia causes stabilization of HIF1. HIF1 then signals to a.o. the proteins VEGF, CA9 and GLUT1, stimulating angiogenesis(4). It also causes down-regulation of the protein kinase mTOR. This protein kinase integrates the nutrient sensing pathway AMPK-TSC1/2 with growth factor responses and regulates cell growth in response to nutrient availability(5). Thus, HIF1 can reduce the cell's energy requirements when there is too little oxygen. Deregulation of HIF1 has recently been directly implicated in the formation of several tumor types, such that tumor cell growth is no longer checked by hypoxia but, rather, stimulated(6). Although primarily regulated at the level of protein stability via oxygen, HIF1 synthesis is also regulated by mTOR (figure 1). HIF1 can inhibit mTOR, and vice versa, ensuring that cells do not grow inappropriately. Hair follicles are hypoxic and this means that hypoxia-dependent signaling process will be, to some degree, constitutively activated in hair follicles(7). Therefore, to maintain proper cell growth, careful control of HIF1 activity is necessary. In tuberous sclerosis (caused by mutations in TSC1 or TSC2) and FH deficiency, HIF1 is uncontrolled and its activation by the hypoxic environment of the hair follicle conceivably contributes to the development of tumours, more so because the disease mutations uncouple HIF1 from mTOR. Based on this observation, the similarity between BHD and syndromes such as TSC and Cowden syndrome and our own experiments, we hypothesized that FLCN is a negative regulator of HIF1- and mTOR-signaling. Its role in the kidney and lung will be similar. Our hypothesis predicts that loss of folliculin function will result in activation of mTOR, increased HIF1 signalling and consequently deregulated growth of these tissues.Preliminary results from a pilot study support our idea, showing activation of HIF1a, its target genes and mTOR. In the proposed project, we will employ a variety of genetic and biochemical methods to rigourously test our hypothesis. Finally, we will develop therapeutical applications in an animal model. Our project may have implications for general oncology. The hypoxia response pathway is central in the regulation of growth, both in normal and in malignant cells. Our project will enhance our knowledge of a biological system that is increasingly implicated in oncogenesis and could result in novel therapeutic approaches to (kidney) cancer or other tumors that depend on HIF and/or mTOR. We also anticipate that hair follicle, or possibly epithelial stem cell biology, will profit from our findings, since folliculin seems to be involved in regulating hair follicle growth in adults. Demonstrating that the regulation of the hypoxia response contributes to hair follicle growth could initiate promising new lines of research.