Abstract
BackgroundExpression 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.ResultsWe 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.ConclusionsWe 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.
Highlights
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
We singled out a representative selection consisting of 28 well-reported experiments addressing various relevant aspects of the MITF-STAT3-Protein Inhibitor of Activated STAT3 (PIAS3) system (Table 2), and tested to what degree the model was able to account for the available experimental data
We observe that in the model, STAT3 is more affected by the activation of MITF than MITF is affected by the activation of STAT3
Summary
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. While knowledge about each single protein and gene involved in melanocyte development and regulation of homeostasis is important, developing an understanding of the signalling networks connecting the receptors on the surface to the regulating effect on gene transcription in the nucleus appears crucial in implementing efficient molecular. Expression of microphthalmia-associated transcription factor (MITF), the signal transducer and activator of transcription 3 (STAT3), and their co-regulation via protein inhibitor of activated STAT3 (PIAS3), are all tightly connected to cell differentiation, proliferation and survival. These sites are phosphorylated by different kinases in the MAPK pathway, the ERK and RSK, respectively [13,14]
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