p38 MAPK and the C2C12 cell cycle : in vitro and in silico investigations.
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Date
2011
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Abstract
The mammalian cell cycle and its points-of-entry are well characterized pathways.
These points-of-entry are normally regulated via mitogens and include, amongst others,
the ERK, JNK and p38 mitogen-activated protein kinase (MAPK) pathways. However,
while the restriction point(R-point), the temporal switch-point at which a cell becomes
irrevocably committed to division irrespective of mitogenic stimulus, is known among other
cell types, its position within the murine myoblast line C2C12 is currently unknown.
Similarly, while MAPK pathways, such as JNK and ERK, have been modeled
computationally, no model yet exists of p38 MAPK as stimulated by mitogens. The aims of
this dissertation, then, were to determine the R-point within the C2C12 cell cycle and
construct a computational mitogen-stimulated p38 MAPK model.
It was found that a synchronous C2C12 population, when stimulated to divide, took 7 to
9 hours to reach S-phase from G0, consistent with data from the literature. The R-point
was determined to lie between 6 and 7 hours post G1-re-entry stimulation,which was
consistent with studies in other cell types. Core modeling of the p38 MAPK pathway
revealed that ultrasensitivitywas inherent within the pathway structure. Further, a
branching/re-converging structure within the pathway imparted greater responsiveness to
signal upon the pathway. A realistic p38 MAPK model demonstrated good responsiveness
to signal, its output matched that of several other MAPK models, and it was capable of
replicating previous in vitro data. This model can be used as a tool for further investigation
of the mammalian cell cycle by linking it to other cell cycle models. The predictions by an
expanded model may be better suited for understanding the effects of mitogen stimulus on
the cell cycle in situ.
Description
Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2011.
Keywords
Cell cycle--Physiology., Stem cells., Mitogen-activated protein kinases., Theses--Biochemistry.