BHD Research Blog

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263 posts · 154,450 views

BHD Research Blog is the official blog of BHDSyndrome.org, the primary online resource for anyone interested in Birt-Hogg-Dubé Syndrome, a rare genetic condition linked to benign skin growths, collapsed lung and kidney cancers. In the BHD Research Blog, we focus on analysing current research in BHD and related fields, as well as considering wider issues relating to rare diseases.

Joana Guedes
263 posts

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  • August 17, 2012
  • 06:15 AM
  • 526 views

Rabs, GEFs and DENNs

by Joana Guedes in BHD Research Blog

Last week’s blog described the crystal structure of the C-terminal domain of FLCN, which was published in a recent paper by Nookala et al. (2012). FLCN was found to have a similar structure to that of DENN domain proteins, which … Continue reading →... Read more »

Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montano B, Donaldson JC, Blaszczyk BK, Chirgadze DY, Barr FA, Bazan JF, Blundell TL. (2012) Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. . Open Biol . DOI: 10.1098/rsob.120071  

Wu X, Bradley MJ, Cai Y, Kümmel D, De La Cruz EM, Barr FA, & Reinisch KM. (2011) Insights regarding guanine nucleotide exchange from the structure of a DENN-domain protein complexed with its Rab GTPase substrate. Proceedings of the National Academy of Sciences of the United States of America, 108(46), 18672-7. PMID: 22065758  

Chow VT, & Lee SS. (1996) DENN, a novel human gene differentially expressed in normal and neoplastic cells. DNA sequence : the journal of DNA sequencing and mapping, 6(5), 263-73. PMID: 8988362  

Marat AL, Dokainish H, & McPherson PS. (2011) DENN domain proteins: regulators of Rab GTPases. The Journal of biological chemistry, 286(16), 13791-800. PMID: 21330364  

Yoshimura S, Gerondopoulos A, Linford A, Rigden DJ, & Barr FA. (2010) Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors. The Journal of cell biology, 191(2), 367-81. PMID: 20937701  

  • August 10, 2012
  • 10:57 AM
  • 600 views

The crystal structure of FLCN suggests a novel function as a Rab GEF

by Joana Guedes in BHD Research Blog

BHD Syndrome was first described in 1977 and although the FLCN gene was discovered in 2002 by Nickerson et al., the function of the protein has remained unknown. The majority of FLCN mutations found in BHD patients result in truncation … Continue reading →... Read more »

  • August 3, 2012
  • 04:29 AM
  • 461 views

PTTG1 and clear cell renal cell carcinoma

by Joana Guedes in BHD Research Blog

Deletion of the VHL gene, which is located on chromosome 3p, is known to be involved in the development of clear cell renal cell carcinoma (ccRCC). The second most common cytogenetic abnormality associated with ccRCC is thought to be an … Continue reading →... Read more »

Chen M, Ye Y, Yang H, Tamboli P, Matin S, Tannir NM, Wood CG, Gu J, & Wu X. (2009) Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays. International journal of cancer. Journal international du cancer, 125(10), 2342-8. PMID: 19521957  

Wondergem B, Zhang Z, Huang D, Ong CK, Koeman J, Van't Hof D, Petillo D, Ooi A, Anema J, Lane B.... (2012) Expression of the PTTG1 oncogene is associated with aggressive clear cell renal cell carcinoma. Cancer research. PMID: 22805307  

Yoshimoto T, Matsuura K, Karnan S, Tagawa H, Nakada C, Tanigawa M, Tsukamoto Y, Uchida T, Kashima K, Akizuki S.... (2007) High-resolution analysis of DNA copy number alterations and gene expression in renal clear cell carcinoma. The Journal of pathology, 213(4), 392-401. PMID: 17922474  

  • July 27, 2012
  • 09:02 AM
  • 487 views

FH-deficiency leads to increased AMPK activity and protection from apoptosis

by Joana Guedes in BHD Research Blog

Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a kidney cancer syndrome caused by mutation of Fumarate Hydratase (FH), a TCA cycle enzyme which catalyses the conversion of fumarate to malate. The accumulation of fumarate in FH-deficient cells results in … Continue reading →... Read more »

  • July 20, 2012
  • 04:53 AM
  • 430 views

FNIP1 and autophagy

by Joana Guedes in BHD Research Blog

Autophagy is a process which is used to degrade cellular components and infectious agents, such as viruses, organelles and defective proteins. It is also activated during periods of bioenergetic stress in order to provide nutrients for cellular homeostasis. Previous blog … Continue reading →... Read more »

Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL.... (2006) Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America, 103(42), 15552-7. PMID: 17028174  

Behrends C, Sowa ME, Gygi SP, & Harper JW. (2010) Network organization of the human autophagy system. Nature, 466(7302), 68-76. PMID: 20562859  

  • July 13, 2012
  • 05:03 AM
  • 422 views

Fourth BHD Symposium Abstracts

by Joana Guedes in BHD Research Blog

The abstracts from the Fourth BHD Symposium have now been published online in the journal Familial Cancer. The Symposium was held in March 2012 in Cincinnati, USA, and hosted over 90 BHD researchers, clinicians and patients. The latest findings and … Continue reading →... Read more »

  • June 29, 2012
  • 04:20 AM
  • 492 views

FNIP1 deletion leads to increased apoptosis in pre-B cells

by Joana Guedes in BHD Research Blog

The work of Dr Masaya Baba, at the National Cancer Institute, was highlighted in last week’s blog. Dr Baba was part of the team who identified Folliculin-interacting protein 1 (FNIP1) and a recent paper by this group now suggests a … Continue reading →... Read more »

Park H, Staehling K, Tsang M, Appleby MW, Brunkow ME, Margineantu D, Hockenbery DM, Habib T, Liggitt HD, Carlson G.... (2012) Disruption of fnip1 reveals a metabolic checkpoint controlling B lymphocyte development. Immunity, 36(5), 769-81. PMID: 22608497  

Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL.... (2006) Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America, 103(42), 15552-7. PMID: 17028174  

  • June 22, 2012
  • 06:13 AM
  • 494 views

Video Interview: Dr Masaya Baba – National Cancer Institute, NIH, USA

by Joana Guedes in BHD Research Blog

As more Video Interviews are added to the Features and Events section of BHDSyndrome.org, this month we would like to introduce you to the work of Dr Masaya Baba. Dr Baba is a staff scientist in the laboratory of Dr … Continue reading →... Read more »

Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL.... (2006) Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America, 103(42), 15552-7. PMID: 17028174  

Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, Wu X, Korolevich S, Nathanson KL, Stolle CA.... (2011) Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome. Genes, chromosomes , 50(6), 466-77. PMID: 21412933  

Hasumi Y, Baba M, Ajima R, Hasumi H, Valera VA, Klein ME, Haines DC, Merino MJ, Hong SB, Yamaguchi TP.... (2009) Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proceedings of the National Academy of Sciences of the United States of America, 106(44), 18722-7. PMID: 19850877  

Hasumi H, Baba M, Hong SB, Hasumi Y, Huang Y, Yao M, Valera VA, Linehan WM, & Schmidt LS. (2008) Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene, 415(1-2), 60-7. PMID: 18403135  

  • June 15, 2012
  • 06:56 AM
  • 498 views

VHL and autophagy continued

by Joana Guedes in BHD Research Blog

Last week’s blog post described a clear cell renal cell carcinoma (ccRCC) paper which suggests that microRNA-204 (MiR-204) acts as a VHL-regulated tumour suppressor through the inhibition of LC3B-associated autophagy (Mikhaylova et al., 2012). In this study, immunofluorescence experiments showed that … Continue reading →... Read more »

  • June 8, 2012
  • 10:18 AM
  • 609 views

MicroRNAs, autophagy and clear cell renal cell carcinoma

by Joana Guedes in BHD Research Blog

The loss of VHL and the subsequent dysregulation of HIF signalling are known to play a role in the development of clear cell renal cell carcinoma (ccRCC). However, a recent paper by Mikhaylova et al. (2012) has now suggested that … Continue reading →... Read more »

Parkhitko A, Myachina F, Morrison TA, Hindi KM, Auricchio N, Karbowniczek M, Wu JJ, Finkel T, Kwiatkowski DJ, Yu JJ.... (2011) Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proceedings of the National Academy of Sciences of the United States of America, 108(30), 12455-60. PMID: 21746920  

  • June 1, 2012
  • 05:02 AM
  • 534 views

A role for FNIP1 in B cell development

by Joana Guedes in BHD Research Blog

Folliculin-interacting protein 1 (FNIP1) was identified in 2006 by Baba et al. as a protein which interacts with the C-terminus of FLCN. Although the function of FNIP1 is unknown, the protein was also found to interact with and be phosphorylated … Continue reading →... Read more »

Park H, Staehling K, Tsang M, Appleby MW, Brunkow ME, Margineantu D, Hockenbery DM, Habib T, Liggitt HD, Carlson G.... (2012) Disruption of fnip1 reveals a metabolic checkpoint controlling B lymphocyte development. Immunity, 36(5), 769-81. PMID: 22608497  

Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL.... (2006) Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America, 103(42), 15552-7. PMID: 17028174  

  • May 18, 2012
  • 04:00 AM
  • 1,022 views

mTOR signalling and BHD-associated lung and kidney lesions

by Joana Guedes in BHD Research Blog

Pulmonary cysts and pneumothorax are key indicators of BHD syndrome. However, very little is known about the pathophysiology of these lung cysts. A recent Japanese study of 9 families has now shown that not only are BHD cysts different from … Continue reading →... Read more »

Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, Hsu YH, Fujii T, Okada A, Kuroda N.... (2012) Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. The American journal of surgical pathology, 36(4), 589-600. PMID: 22441547  

  • May 11, 2012
  • 09:17 AM
  • 630 views

Video Interview: Lindsay Middelton – National Cancer Institute, NIH, USA

by Joana Guedes in BHD Research Blog

This week we introduce Lindsay Middelton R.N., C.G.C, who is a genetic counsellor with the National Cancer Institute (NCI) of the National Institutes of Health, USA. Lindsay is part of the Urologic Oncology Branch at the NCI, which treats patients … Continue reading →... Read more »

Middelton L, Dimond E, Calzone K, Davis J, & Jenkins J. (2002) The role of the nurse in cancer genetics. Cancer nursing, 25(3), 196-206. PMID: 12040228  

Singer EA, Bratslavsky G, Middelton L, Srinivasan R, & Linehan WM. (2011) Impact of genetics on the diagnosis and treatment of renal cancer. Current urology reports, 12(1), 47-55. PMID: 21128028  

Zbar B, Glenn G, Merino M, Middelton L, Peterson J, Toro J, Coleman J, Pinto P, Schmidt LS, Choyke P.... (2007) Familial renal carcinoma: clinical evaluation, clinical subtypes and risk of renal carcinoma development. The Journal of urology, 177(2), 461. PMID: 17222609  

  • May 4, 2012
  • 04:00 AM
  • 528 views

DNA methylation and kidney cancer

by Joana Guedes in BHD Research Blog

Mutations in genes such as FLCN and VHL are implicated in the development of renal cell carcinoma (RCC). However, DNA methylation and transcriptional silencing at gene promoters can also be involved, as is the case with RASSF1A, which is rarely … Continue reading →... Read more »

Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K, Ludlow J, Knapp R, Giraud S, Richard S.... (2003) Inactivation of BHD in sporadic renal tumors. Cancer research, 63(15), 4583-7. PMID: 12907635  

Ricketts CJ, Morris MR, Gentle D, Brown M, Wake N, Woodward ER, Clarke N, Latif F, & Maher ER. (2012) Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma. Epigenetics : official journal of the DNA Methylation Society, 7(3), 278-90. PMID: 22430804  

  • April 27, 2012
  • 06:36 AM
  • 478 views

Patient and Family sessions at the Fourth BHD Symposium

by Joana Guedes in BHD Research Blog

Around 30 patients and family members participated in the Fourth BHD Symposium in Cincinnati, Ohio last month. Such a record turnout had a significant effect on the flow of the Symposium – for example, by providing researchers with many opportunities … Continue reading →... Read more »

  • April 6, 2012
  • 04:00 AM
  • 1,076 views

Characterisation of the RCC susceptibility locus on chromosome 11

by Joana Guedes in BHD Research Blog

A blog post from January last year described a paper by Purdue et al. (2011) in which a genome-wide association study (GWAS) identified two renal cell carcinoma (RCC) susceptibility loci within HIF2α (on chromosome 2) and an uncharacterised intergenic region (on … Continue reading →... Read more »

  • March 16, 2012
  • 12:27 PM
  • 546 views

Single-cell exome sequencing of a ccRCC sample

by Joana Guedes in BHD Research Blog

Recent advances in DNA sequencing have led to the discovery of genes and mutations which drive tumourigenesis. In this blog, we have previously described papers by Varela et al. (2011), Dalgliesh et al. (2011) and Guo et al. (2011) which … Continue reading →... Read more »

  • March 9, 2012
  • 03:00 AM
  • 882 views

Lab-profile: Professor Arnim Pause – McGill University, Canada

by Joana Guedes in BHD Research Blog

Our lab-profile for this month introduces the work of Professor Arnim Pause, an Associate Professor in the Department of Biochemistry and a Canada Research Chair in Molecular Oncology at McGill University, Canada. Much of Professor Pause’s early work involved researching … Continue reading →... Read more »

Hudon V, Sabourin S, Dydensborg AB, Kottis V, Ghazi A, Paquet M, Crosby K, Pomerleau V, Uetani N, & Pause A. (2010) Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin. Journal of medical genetics, 47(3), 182-9. PMID: 19843504  

Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, Klausner RD, & Pause A. (1999) Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proceedings of the National Academy of Sciences of the United States of America, 96(22), 12436-41. PMID: 10535940  

  • March 2, 2012
  • 04:33 AM
  • 562 views

The role of HIF-2α in renal cell carcinoma

by Joana Guedes in BHD Research Blog

Hypoxia Inducible Factor (HIF) regulates key processes within the cell and its dysregulation is involved in the development of renal cell carcinoma (RCC), including those associated with VHL, HLRCC, TSC and also BHD syndrome. HIF is a potential therapeutic target … Continue reading →... Read more »

Schietke RE, Hackenbeck T, Tran M, Günther R, Klanke B, Warnecke CL, Knaup KX, Shukla D, Rosenberger C, Koesters R.... (2012) Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts. PloS one, 7(1). PMID: 22299048  

Rosenberger C, Mandriota S, Jürgensen JS, Wiesener MS, Hörstrup JH, Frei U, Ratcliffe PJ, Maxwell PH, Bachmann S, & Eckardt KU. (2002) Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. Journal of the American Society of Nephrology : JASN, 13(7), 1721-32. PMID: 12089367  

Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Min BW, Tan MH, Zhang Z, Yang XJ.... (2011) An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer cell, 20(4), 511-23. PMID: 22014576  

Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, Pugh CW, Maxwell PH, Harris AL, & Ratcliffe PJ. (2005) Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Molecular and cellular biology, 25(13), 5675-86. PMID: 15964822  

  • February 17, 2012
  • 03:00 AM
  • 482 views

Overview of the NCRI, BTS and BAD meetings

by Joana Guedes in BHD Research Blog

In November last year, the 7th National Cancer Research Institute (NCRI) Cancer Conference was held in Liverpool, UK. This conference focussed on all aspects of cancer research, from basic research to clinical care. Of note, Prof. Dr. Michael Hall from … Continue reading →... Read more »

Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, Hedley A.... (2011) Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature, 477(7363), 225-8. PMID: 21849978  

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