Molecular Systems Biology 6 Article number: 446 doi:10.1038/msb.2010.102
Published online: 21 December 2010
Citation: Molecular Systems Biology 6:446
Design principles of nuclear receptor signaling: how complex networking improves signal transduction
Alexey N Kolodkin1, Frank J Bruggeman1,2,3, Nick Plant4, Martijn J Moné1, Barbara M Bakker1,5, Moray J Campbell6, Johannes P T M van Leeuwen7, Carsten Carlberg8, Jacky L Snoep1,9,10 & Hans V Westerhoff1,10
Molecular Cell Physiology, VU University Amsterdam, Amsterdam, The Netherlands
Regulatory Networks Group, Netherlands Institute of Systems Biology, Amsterdam, The Netherlands
Life Sciences, Centre for Mathematics and Computer Science (CWI), Amsterdam, The Netherlands
Centre for Toxicology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, USA
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg
Department of Biochemistry, Stellenbosch University, Matieland, South Africa
Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester, UK
Correspondence to: Hans V Westerhoff1,10 Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK. Tel.: +44 161 306 4407; Fax: +44 161 306 4556; Email: hans.westerhoff@manchester.ac.uk
Received 23 March 2010; Accepted 21 October 2010; Published online 21 December 2010
Article highlights
Nuclear receptors often function in the cytoplasm.
A triple conveyor belt pumps ligand (signal) into the nucleus and onto the DNA.
The active export of importins enhances signaling to the nucleus.
Sharing a single nuclear pore may reduce rather than increase crosstalk.
Synopsis
Nuclear receptors (NRs) derive their family name from the early observation that they are located in the nucleus, despite responding to extracellular signals such as hormones (e.g., cortisol) (Fanestil and Edelman, 1966). According to the ‘classical’ paradigm of NR signaling, the NR resides in the nucleus, attached to a DNA response element, waiting for its ligand to bind. The actual systems have multiple additional features (reviewed in Cutress et al, 2008; Cao et al, 2009;Levin, 2009a; Bunce and Campbell, 2010), such as that NRs shuttle between the nucleus and the cytoplasm (Von Knethen et al, 2010) and ligand addition changes receptor location dynamically (Pratt et al, 1989; Liu and DeFranco, 2000; Kumaret al, 2004, 2006; Tanaka et al, 2005; Heitzer et al, 2007; Prüfer and Boudreaux, 2007; Ricketson et al, 2007; Cutress et al, 2008): Figure 1 summarizes the current understanding of the topology of the reaction networks involved in NR signaling, in systems biological graphical notation (SBGN), with NR activation, importin-α and -β binding, nuclear pore complex (NPC)-mediated import, recycling of importins, NR binding to target promoter sequences, exportin-mediated nuclear export of the NR, exportin cycling and free energy-driven Ran recycling. This topology is surprisingly complex when compared with the ‘classical’ paradigm. To address to what extent this extra complexity is just detail or contributes essential functionality, we have simulated the dynamics of the NR transcriptional response in maximally realistic mathematical models of increasingly complex designs.
+++++
+++++
NOTA DESTE BLOGGER:
Embora os autores sejam evolucionistas (até onde sei), repare na linguagem teleológica empregada no Abstract! E ainda dizem que Darwin, de uma vez por todas, eliminou a linguagem teleológica da ciência. É muita bazófia para o homem que teve a maior ideia que toda a humanidade já teve, mas que nunca é corroborada no contexto de justificação teórica.
Fui, nem sei por que, pensando: a teleologia realmente é uma amante que os evolucionistas não gostam de aparecer tratando de amores publicamente, mas que eles não ignoram sua presença, ah, isso não. Design empiricamente detectado!!!
Basta ler a literatura especializada: quase que 100% teleológica!!! Darwin, sinto muito, mas você e os seus atuais discípulos não estão pra lá de Marrakesh em termos teleológicos. Queria ver a cara do Darwin...
