Master´s thesis defense by Leevi Kerkelä – Niels Bohr Institute - University of Copenhagen

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Niels Bohr Institute > Calendar > NBI Calendar 2017 > Master´s thesis defens...

Master´s thesis defense by Leevi Kerkelä

Title: Dynamics of p53 protein expression in response to a heat shock and hyperosmotic shock

p53 is an important tumour suppressing protein that functions as a sequence
speci c transcriptional factor inhibiting and activating a large number of
downstream genes. It regulates the cell's response to DNA damaging cellular
stress, and recently it was shown that important signals about cell fate can
be encoded in the temporal pattern of p53 expression. Information about the
time evolution of p53 expression in response to diff erent cellular stresses can
be used to infer the structure of the p53 network. Currently it is unknown
how the p53 network responds to diff erent types of cellular stress, and if the
same motifs of the p53 network are responsible for generating all responses.

In this thesis, I present the experimental results of a series of fluorescent
time lapse experiments showing the temporal pattern of the p53 protein
expression in breast cancer cells in response to heat shock and hyperosmotic
shock. Cells respond to a heat shock at 43 degrees C by increasing the production
of p53 over a time scale of multiple hours. On average, the p53 production
of a population of cells increases as long as the heat shock continues. Two
distinct stress responses to hyperosmotic shock were obeserved; a pulse of
p53 or a permanent increase in p53 levels. The fraction of cells expressing
permanently increased p53 levels increases as the magnitude of the osmotic
shock is increased. A mathematical model describing the structure of the
core of the p53 protein network is also presented and used to recreate the
experimentally observed results by simulations. The results show that there
is signi cant heterogeneity in the way cells experience the same environment,
and that the same core motifs of the p53 network are able to generate di fferent
dynamical patterns of p53 expression in response to di fferent stresses.