Læknaneminn - 01.10.1996, Page 118

Rannsóknarverkefni 4. árs læknanema, útdrættir
the years 1989 and 1994. Patient characteristics including
sex, height, weight and body surface area were similar to the
age-matched control group (p=NS). Our results show no
significant difference between the patient group and control
group with respect to systolic left ventricular function
(p=NS). Of the diastolic function indices considered in this
study, isovolumic relaxation time was shorter in the patient
group, but did'nt achieve statistical significance (p=0.0793).
All other diastolic function indices were similar between the
two groups (p=0.009). Öur follow-up results of children who
have undergone the successful surgical repair of an ASD
imply prolonged isovolumic relaxation time consistent with
left ventricular hypertrophy. We suggest that further studies
be undertaken to demonstrate the clinical significance of our
findings.
A theoretical mechanism for regulation of the
tyrosine kinase pathway
Þorbergur Hognason1.
Amyn Habib M.D2, Anne Lane, Ph.D2.,
Kári Stefánsson, M.D.2
‘LHl, 2Department of Neurology and Neuropathology,
Harvard Institutes of Medicine, Boston, MA.
Introduction: Activation of receptor tyrosine kinases
results in the phosphorylation and activation of intracellular
kinases, that ultimately converge on the Mitogen Activating
Protein Kinases (MAPKs). Activation of MAPKs leads to ex-
pression of immediate early genes by transcription factor
phosphorylation, resulting in cell division or cell differenti-
ation.
MAPK can be activated through several different pathwa-
ys; in response to Iigands that signal via transmembrane tyro-
sine kinase receptors, receptors coupled to heterotrimeric G-
proteins and in response to direct activators of Protein Kinase C.
It has been shown that while phosphorylation and acti-
vation of the Ras(Raf pathway results in increased MAPK
activity, activation of Protein Kinase A (PKA) causes decrea-
sed MAPK activity. The stimulus resulting in PKA activation
is thought to be extracellular.
P35 is important in the G1 arrest induced by certain gen-
otoxic stimuli, such as ionizing radiation. DNA damage in
some cell types leads to Gl cell cycle arrest and a correspond-
ing increase in the levels of p53, which is the product of the
tumor suppressor gene p53. P53 in turn is thought to ind-
uce transcription of genes that may contribute to the
mechanism of action of G1 arrest, such as p21.
Thus the mechanism of action of p53 in inducing cell
cycle arrest in response to DNA damage is to inhibit activity
of cell cycle components.
We propose to examine, if in addition to this, p53 also has
an effect on mitogenic signaling, which would further ensure
that a ceil with DNA damage does not proliferate.
Materials and methods: Cells which express PDGF
receptors and have a normal p53 genotype were used in our
preliminary experiments. In our initial trials, mouse fibrob-
lasts with normal p53 genes (BALB 3T3 cells) were subject-
ed to ionizing radiation and stimulated with PDGF-BB to
activate MAPK. MAP Kinase assays were then performed to
determine the activity of MAPK in cells that had been expos-
ed to ionizing radiation, PDGF-BB or both.
We have also conducted experiments on cells transfected
with a tempereature sensitive p53 mutant (10/Val-5 cells,
mouse fibroblasts). The active form behaves as wild type p53
at 32°C, but the mutant activity is induced at 37°C. We have
examined the ability of these cells to increase MAPK activity
in response to PDGF-BB stimulation, at both the restricitive
and permissive temperatures, concomitantly examining the
effect of elevated p53 levels, induced by ionizing radiation.
Results: We have conducted a series of experiments on
various cell types. We were able to demonstrate a significant
decrease in PDGF-BB dependent MAPK activation in
BALB-3T3 cells, by exposing them to ionizing radiation.
In 10/Val-5 cells, we were able to demonstrate a significant
decrease in PDGF-BB dependent MAPK activation in the wt
p53 cells, by elevating p53 levels with ionizing radiation,
while MAPK activation in the mutant p53 cells was unalter-
ed.
Discussion: Preliminary results suggest that ionizing radi-
ation blocks mitogenic signaling in BALB 3T3 cells, as evi-
dence as a block in PDGF-BB induced MAPK activation.
Our preliminary data with the 10/Val-5 cell line suggest that
this mitogenic block is p53 dependent.
If further experiments give similar results, we will attempt
to elucidate the mechanism.
The screening for mutations in the OMgp
gene in brain tumour DNA
Þorbergur Högnason1.
Amyn Habib M.D.2, Anne Lane, Ph.D.2,
Kári Stefánsson, M.D.2
’LHl, 2Department of Neurology and Neuropathology,
Harvard Institutes of Medicine, Boston, MA.
Introduction: OMgp is a plasma membrane glycoprotein
expressed primarily in the CNS, in the paranodal region of
the myelin sheath. In addition to white matter it is expressed
in groups of neurons, such as the Purkinje cells of the
cerebellum, pyramidal cells of the hippocampus and in
groups of neurons in the neocortex. Thus OMgp has a distru-
btion pattern similar to that of neurofibromin.
The gene encoding Omgp is located within an intron of
the neurofibromin gene on chromosome 17, bands qll-12.
LÆKNANEMINN
108 2. tbl. 1996, 49. árg.