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https://www.readbyqxmd.com/read/27506764/coupling-of-mitochondrial-function-and-skeletal-muscle-fiber-type-by-a-mir-499-fnip1-ampk-circuit
#1
Jing Liu, Xijun Liang, Danxia Zhou, Ling Lai, Liwei Xiao, Lin Liu, Tingting Fu, Yan Kong, Qian Zhou, Rick B Vega, Min-Sheng Zhu, Daniel P Kelly, Xiang Gao, Zhenji Gan
Upon adaption of skeletal muscle to physiological and pathophysiological stimuli, muscle fiber type and mitochondrial function are coordinately regulated. Recent studies have identified pathways involved in control of contractile proteins of oxidative-type fibers. However, the mechanism for coupling of mitochondrial function to the muscle contractile machinery during fiber type transition remains unknown. Here, we show that the expression of the genes encoding type I myosins, Myh7/Myh7b and their intronic miR-208b/miR-499, parallels mitochondrial function during fiber type transitions...
October 4, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27353360/the-fnip-co-chaperones-decelerate-the-hsp90-chaperone-cycle-and-enhance-drug-binding
#2
Mark R Woodford, Diana M Dunn, Adam R Blanden, Dante Capriotti, David Loiselle, Chrisostomos Prodromou, Barry Panaretou, Philip F Hughes, Aaron Smith, Wendi Ackerman, Timothy A Haystead, Stewart N Loh, Dimitra Bourboulia, Laura S Schmidt, W Marston Linehan, Gennady Bratslavsky, Mehdi Mollapour
Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability...
June 29, 2016: Nature Communications
https://www.readbyqxmd.com/read/27303042/mutation-of-fnip1-is-associated-with-b-cell-deficiency-cardiomyopathy-and-elevated-ampk-activity
#3
Owen M Siggs, Alexander Stockenhuber, Mukta Deobagkar-Lele, Katherine R Bull, Tanya L Crockford, Bethany L Kingston, Greg Crawford, Consuelo Anzilotti, Violetta Steeples, Sahar Ghaffari, Gabor Czibik, Mohamed Bellahcene, Hugh Watkins, Houman Ashrafian, Benjamin Davies, Angela Woods, David Carling, Arash Yavari, Bruce Beutler, Richard J Cornall
Folliculin (FLCN) is a tumor-suppressor protein mutated in the Birt-Hogg-Dubé (BHD) syndrome, which associates with two paralogous proteins, folliculin-interacting protein (FNIP)1 and FNIP2, forming a complex that interacts with the AMP-activated protein kinase (AMPK). Although it is clear that this complex influences AMPK and other metabolic regulators, reports of its effects have been inconsistent. To address this issue, we created a recessive loss-of-function variant of Fnip1 Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells...
June 28, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26877139/mechanisms-of-pulmonary-cyst-pathogenesis-in-birt-hogg-dube-syndrome-the-stretch-hypothesis
#4
REVIEW
John C Kennedy, Damir Khabibullin, Elizabeth P Henske
Loss-of-function mutations in the folliculin gene (FLCN) on chromosome 17p cause Birt-Hogg-Dube syndrome (BHD), which is associated with cystic lung disease. The risk of lung collapse (pneumothorax) in BHD patients is 50-fold higher than in the general population. The cystic lung disease in BHD is distinctive because the cysts tend to be basilar, subpleural and lentiform, differentiating BHD from most other cystic lung diseases. Recently, major advances in elucidating the primary functions of the folliculin protein have been made, including roles in mTOR and AMPK signaling via the interaction of FLCN with FNIP1/2, and cell-cell adhesion via the physical interaction of FLCN with plakophilin 4 (PKP4), an armadillo-repeat containing protein that interacts with E-cadherin and is a component of the adherens junctions...
April 2016: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/26631379/lst4-the-yeast-fnip1-2-orthologue-is-a-denn-family-protein
#5
Angela Pacitto, David B Ascher, Louise H Wong, Beata K Blaszczyk, Ravi K Nookala, Nianshu Zhang, Svetlana Dokudovskaya, Tim P Levine, Tom L Blundell
The folliculin/Fnip complex has been demonstrated to play a crucial role in the mechanisms underlying Birt-Hogg-Dubé (BHD) syndrome, a rare inherited cancer syndrome. Lst4 has been previously proposed to be the Fnip1/2 orthologue in yeast and therefore a member of the DENN family. In order to confirm this, we solved the crystal structure of the N-terminal region of Lst4 from Kluyveromyces lactis and show it contains a longin domain, the first domain of the full DENN module. Furthermore, we demonstrate that Lst4 through its DENN domain interacts with Lst7, the yeast folliculin orthologue...
December 2015: Open Biology
https://www.readbyqxmd.com/read/26608100/birt-hogg-dub%C3%A3-syndrome-clinical-and-molecular-aspects-of-recently-identified-kidney-cancer-syndrome
#6
REVIEW
Hisashi Hasumi, Masaya Baba, Yukiko Hasumi, Mitsuko Furuya, Masahiro Yao
Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disease that predisposes patients to develop fibrofolliculoma, lung cysts and bilateral multifocal renal tumors, histologically hybrid oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, oncocytoma, papillary renal cell carcinoma and clear cell renal cell carcinoma. The predominant forms of Birt-Hogg-Dubé syndrome-associated renal tumors, hybrid oncocytic/chromophobe tumors and chromophobe renal cell carcinoma are typically less aggressive, and a therapeutic principle for these tumors is a surgical removal with nephron-sparing...
March 2016: International Journal of Urology: Official Journal of the Japanese Urological Association
https://www.readbyqxmd.com/read/26581862/clinical-features-genetics-and-potential-therapeutic-approaches-for-birt-hogg-dub%C3%A3-syndrome
#7
Laura S Schmidt, W Marston Linehan
INTRODUCTION: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder that predisposes to fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax and renal neoplasia. BHD is characterized by germline mutations in tumor suppressor FLCN. Inactivation of the remaining FLCN allele in kidney cells drives tumorigenesis. Novel FLCN-interacting proteins, FNIP1 and FNIP2, were identified. Studies with FLCN-deficient in vitro and in vivo models support a role for FLCN in modulating AKT-mTOR signaling...
2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/26334087/molecular-genetics-and-clinical-features-of-birt-hogg-dub%C3%A3-syndrome
#8
REVIEW
Laura S Schmidt, W Marston Linehan
Birt-Hogg-Dubé (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk of developing benign cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumours. Bilateral multifocal renal tumours that develop in BHD syndrome are most frequently hybrid oncocytic tumours and chromophobe renal carcinoma, but can present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome--BHD-associated renal tumours display inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumour suppressor gene that fits the classic two-hit model...
October 2015: Nature Reviews. Urology
https://www.readbyqxmd.com/read/26261209/tdp-43-affects-splicing-profiles-and-isoform-production-of-genes-involved-in-the-apoptotic-and-mitotic-cellular-pathways
#9
Laura De Conti, Maureen V Akinyi, Ramiro Mendoza-Maldonado, Maurizio Romano, Marco Baralle, Emanuele Buratti
In recent times, high-throughput screening analyses have broadly defined the RNA cellular targets of TDP-43, a nuclear factor involved in neurodegeneration. A common outcome of all these studies is that changing the expression levels of this protein can alter the expression of several hundred RNAs within cells. What still remains to be clarified is which changes represent direct cellular targets of TDP-43 or just secondary variations due to the general role played by this protein in RNA metabolism. Using an HTS-based splicing junction analysis we identified at least six bona fide splicing events that are consistent with being controlled by TDP-43...
October 15, 2015: Nucleic Acids Research
https://www.readbyqxmd.com/read/25775561/folliculin-interacting-proteins-fnip1-and-fnip2-play-critical-roles-in-kidney-tumor-suppression-in-cooperation-with-flcn
#10
Hisashi Hasumi, Masaya Baba, Yukiko Hasumi, Martin Lang, Ying Huang, HyoungBin F Oh, Masayuki Matsuo, Maria J Merino, Masahiro Yao, Yusuke Ito, Mitsuko Furuya, Yasuhiro Iribe, Tatsuhiko Kodama, Eileen Southon, Lino Tessarollo, Kunio Nagashima, Diana C Haines, W Marston Linehan, Laura S Schmidt
Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes similar to those seen in Flcn-deficient mice in multiple organs, but not in kidneys...
March 31, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25548157/fnip1-regulates-skeletal-muscle-fiber-type-specification-fatigue-resistance-and-susceptibility-to-muscular-dystrophy
#11
Nicholas L Reyes, Glen B Banks, Mark Tsang, Daciana Margineantu, Haiwei Gu, Danijel Djukovic, Jacky Chan, Michelle Torres, H Denny Liggitt, Dinesh K Hirenallur-S, David M Hockenbery, Daniel Raftery, Brian M Iritani
Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I "red" slow twitch and type II "white" fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined...
January 13, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/24785297/metabolic-regulator-fnip1-is-crucial-for-inkt-lymphocyte-development
#12
Heon Park, Mark Tsang, Brian M Iritani, Michael J Bevan
Folliculin-interacting protein 1 (Fnip1) is an adaptor protein that physically interacts with AMPK, an energy-sensing kinase that stimulates mitochondrial biogenesis and autophagy in response to low ATP, while turning off energy consumption mediated by mammalian target of rapamycin. Previous studies with Fnip1-null mice revealed that Fnip1 is essential for pre-B-cell development. Here we report a critical role of Fnip1 in invariant natural killer T (iNKT) cell development. Thymic iNKT development in Fnip1(-/-) mice was arrested at stage 2 (NK1...
May 13, 2014: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/24095279/the-folliculin-tumor-suppressor-is-a-gap-for-the-ragc-d-gtpases-that-signal-amino-acid-levels-to-mtorc1
#13
Zhi-Yang Tsun, Liron Bar-Peled, Lynne Chantranupong, Roberto Zoncu, Tim Wang, Choah Kim, Eric Spooner, David M Sabatini
The mTORC1 kinase is a master growth regulator that senses numerous environmental cues, including amino acids. The Rag GTPases interact with mTORC1 and signal amino acid sufficiency by promoting the translocation of mTORC1 to the lysosomal surface, its site of activation. The Rags are unusual GTPases in that they function as obligate heterodimers, which consist of RagA or B bound to RagC or D. While the loading of RagA/B with GTP initiates amino acid signaling to mTORC1, the role of RagC/D is unknown. Here, we show that RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP bound for the interaction to occur...
November 21, 2013: Molecular Cell
https://www.readbyqxmd.com/read/24081491/recruitment-of-folliculin-to-lysosomes-supports-the-amino-acid-dependent-activation-of-rag-gtpases
#14
Constance S Petit, Agnes Roczniak-Ferguson, Shawn M Ferguson
Birt-Hogg-Dubé syndrome, a human disease characterized by fibrofolliculomas (hair follicle tumors) as well as a strong predisposition toward the development of pneumothorax, pulmonary cysts, and renal carcinoma, arises from loss-of-function mutations in the folliculin (FLCN) gene. In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). Our results indicate that FLCN is specifically required for the amino acid-stimulated recruitment of mTORC1 to lysosomes by Rag GTPases...
September 30, 2013: Journal of Cell Biology
https://www.readbyqxmd.com/read/24048253/mbnl1-and-rbfox2-cooperate-to-establish-a-splicing-programme-involved-in-pluripotent-stem-cell-differentiation
#15
Julian P Venables, Laure Lapasset, Gilles Gadea, Philippe Fort, Roscoe Klinck, Manuel Irimia, Emmanuel Vignal, Philippe Thibault, Panagiotis Prinos, Benoit Chabot, Sherif Abou Elela, Pierre Roux, Jean-Marc Lemaitre, Jamal Tazi
Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) has provided huge insight into the pathways, mechanisms and transcription factors that control differentiation. Here we use high-throughput RT-PCR technology to take a snapshot of splicing changes in the full spectrum of high- and low-expressed genes during induction of fibroblasts, from several donors, into iPSCs and their subsequent redifferentiation. We uncover a programme of concerted alternative splicing changes involved in late mesoderm differentiation and controlled by key splicing regulators MBNL1 and RBFOX2...
2013: Nature Communications
https://www.readbyqxmd.com/read/23582324/exit-from-pluripotency-is-gated-by-intracellular-redistribution-of-the-bhlh-transcription-factor-tfe3
#16
Joerg Betschinger, Jennifer Nichols, Sabine Dietmann, Philip D Corrin, Patrick J Paddison, Austin Smith
Factors that sustain self-renewal of mouse embryonic stem cells (ESCs) are well described. In contrast, the machinery regulating exit from pluripotency is ill defined. In a large-scale small interfering RNA (siRNA) screen, we found that knockdown of the tumor suppressors Folliculin (Flcn) and Tsc2 prevent ESC commitment. Tsc2 lies upstream of mammalian target of rapamycin (mTOR), whereas Flcn acts downstream and in parallel. Flcn with its interaction partners Fnip1 and Fnip2 drives differentiation by restricting nuclear localization and activity of the bHLH transcription factor Tfe3...
April 11, 2013: Cell
https://www.readbyqxmd.com/read/23248642/discovery-of-novel-denn-proteins-implications-for-the-evolution-of-eukaryotic-intracellular-membrane-structures-and-human-disease
#17
Dapeng Zhang, Lakshminarayan M Iyer, Fang He, L Aravind
The tripartite DENN module, comprised of a N-terminal longin domain, followed by DENN, and d-DENN domains, is a GDP-GTP exchange factor (GEFs) for Rab GTPases, which are regulators of practically all membrane trafficking events in eukaryotes. Using sequence and structure analysis we identify multiple novel homologs of the DENN module, many of which can be traced back to the ancestral eukaryote. These findings provide unexpected leads regarding key cellular processes such as autophagy, vesicle-vacuole interactions, chromosome segregation, and human disease...
2012: Frontiers in Genetics
https://www.readbyqxmd.com/read/23223565/birt-hogg-dube-syndrome-clinicopathological-features-of-the-lung
#18
REVIEW
Mitsuko Furuya, Yukio Nakatani
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant inherited disorder characterised by fibrofolliculomas, renal tumours, pulmonary cysts and pneumothorax. The pulmonary cysts and repeated episodes of pneumothorax are the clinical hallmarks for discovering families affected by the syndrome. This disorder is caused by mutations in the gene coding for folliculin (FLCN). FLCN forms a complex with FLCN-interacting protein 1 (FNIP1) and FNIP2 (also known as FNIPL), and the complex cross-talks with signalling molecules such as 5'-AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR)...
March 2013: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/23108783/birt-hogg-dub%C3%A3-syndrome-from-gene-discovery-to-molecularly-targeted-therapies
#19
Laura S Schmidt
Since the hallmark dermatologic features of Birt-Hogg-Dubé (BHD) syndrome were first described by three Canadian physicians in 1977, the clinical manifestations of BHD have been expanded to include hamartomas of the hair follicle, lung cysts, increased risk for spontaneous pneumothorax and kidney neoplasia. Twenty-five years later the causative gene FLCN was identified, and the mutation spectrum has now been defined to include mainly protein truncating mutations, but also rare missense mutations and large gene deletions/duplication...
September 2013: Familial Cancer
https://www.readbyqxmd.com/read/22709692/the-folliculin-fnip1-pathway-deleted-in-human-birt-hogg-dub%C3%A3-syndrome-is-required-for-murine-b-cell-development
#20
Masaya Baba, Jonathan R Keller, Hong-Wei Sun, Wolfgang Resch, Stefan Kuchen, Hyung Chan Suh, Hisashi Hasumi, Yukiko Hasumi, Kyong-Rim Kieffer-Kwon, Carme Gallego Gonzalez, Robert M Hughes, Mara E Klein, Hyoungbin F Oh, Paul Bible, Eileen Southon, Lino Tessarollo, Laura S Schmidt, W Marston Linehan, Rafael Casellas
Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models...
August 9, 2012: Blood
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