Towards a quantitative understanding of the MITF-PIAS3-STAT3 connection.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Centre for Integrative Genetics, Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, 1430 Ås, Norway. joset@umb.no
Josef
J
Thingnes
Timothy J
TJ
Lavelle
Arne B
AB
Gjuvsland
Stig W
SW
Omholt
Eivind
E
Hovig
D049109:Cell Proliferation; D003198:Computer Simulation; D008544:Melanocytes / Q000378:metabolism / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human