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Logo of bmcsysbioBioMed Centralsearchsubmit a manuscriptregisterthis articleBMC Systems Biology
BMC Syst Biol. 2012; 6: 11.
Published online Feb 8, 2012. doi:  10.1186/1752-0509-6-11
PMCID: PMC3341200
Towards a quantitative understanding of the MITF-PIAS3-STAT3 connection
Josef Thingnes,corresponding author1 Timothy J Lavelle,3 Arne B Gjuvsland,1 Stig W Omholt,2 and Eivind Hovig3,4,5
1Centre for Integrative Genetics (CIGENE), Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, 1430 Ås, Norway
2Centre for Integrative Genetics (CIGENE), Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, 1430 Ås, Norway
3Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, PO Box 4950 Nydalen, 0424 Oslo, Norway
4Institute of Medical Informatics, The Norwegian Radium Hospital, Montebello, PO Box 4950 Nydalen, 0424 Oslo, Norway
5Institute of Informatics, The Faculty of Mathematics and Natural Sciences, University of Oslo, Postboks 1080, Blindern, 0316 OSLO, Norway
corresponding authorCorresponding author.
Josef Thingnes: joset/at/; Timothy J Lavelle: Timothy.J.Lavelle/at/; Arne B Gjuvsland: arne.gjuvsland/at/; Stig W Omholt: stig.omholt/at/; Eivind Hovig: ehovig/at/
Received October 23, 2011; Accepted February 8, 2012.
Expression of the two transcription factors microphthalmia-associated transcription factor (MITF) and signal transducer and activator of transcription 3 (STAT3) are tightly connected to cell proliferation and survival, and are important for melanocyte development. The co-regulation of MITF and STAT3 via their binding to a common inhibitor Protein Inhibitor of Activated STAT3 (PIAS3) is intriguing. A better quantitative understanding of this regulation is likely to be important for elucidation of the melanocyte biology.
We present a mathematical model describing the MITF-PIAS3-STAT3 signalling network. A default parameter set was developed, partly informed by the literature and partly by constraining the model to mimic reported behavioural features of the system. In addition, a set of experiment-specific parameters was derived for each of 28 experiments reported in the literature. The model seems capable of accounting for most of these experiments in terms of observed temporal development of protein amounts and phosphorylation states. Further, the results also suggest that this system possesses some regulatory features yet to be elucidated.
We find that the experimentally observed crosstalk between MITF and STAT3 via PIAS3 in melanocytes is faithfully reproduced in our model, offering mechanistic explanations for this behaviour, as well as providing a scaffold for further studies of MITF signalling in melanoma.
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