IMP Research Report 2002

and JNP differentially regulate cell proliferation,
differentiation and apoptosis in diverse biological
processes.
JunB and Fos as tumour suppressors
JunB is a transcriptional activator of the cyclindependent
kinase inhibitor p16/INK4a and functions as
a negative regulator of cell proliferation. Using different
in vivo approaches including conditional inactivation we
Figure 2: Functional analysis of Fra-1.
an eye closure defect during embryonic development,
and skin tumour development. Chondrocyte-specific
inactivation resulted in severe scoliosis caused by
abnormal intervertebral disc formation suggesting that
Jun is a novel regulator of sklerotomal differentiation
(Figure 3).
An important mechanism regulating Jun activity is its
phosphorylation at serine 63 and 73 by Jun aminoterminal
kinases (JNKs). Null mutations in Jnk1 and
Jnk2 genes (collaboration with M. Karin, UCSD), as
well as a jun allele mutated in the JNK phosphoacceptor
sites (JunAA), were generated. Jnk1-/-, Jnk2-/- and
JunAA mice are healthy and fertile, however the
absence of Jnk1 and Jun-N-terminal phosphorylation
(JNP) results in growth retardation and in fibroblast
proliferation defects. Jnk1-/- Jnk2-/- double mutants
develop brain defects, and Jnk2-/- and JunAA
thymocytes are resistant to CD3-induced apoptosis.
Moreover, Jnk1 and Jun phosphorylation are required
for osteoclast differentiation. Therefore, JNK signalling
have shown that the absence of JunB expression in
the myeloid lineage results in a transplantable
myeloproliferative disease, which eventually progresses
to blast crisis resembling human chronic myeloid
leukemia. Thus, JunB was identified as a key
transcriptional regulator of myelopoiesis, which controls
the number of granulocyte progenitors through inhibition
of proliferation and promotion of apoptosis.
When the fos-/- osteopetrotic mice were crossed into
the p53 background, double mutant mice developed
rhabdomyosarcomas (Figure 1). Re-expressing Fos in
the double mutant muscle tumour-derived cell lines
induced apoptosis revealing a novel, totally unexpected
function of the proto-oncogene Fos as a potential
tumour suppressor in the muscle lineage.
Functional studies of VEGF, VEGF-R2/Flk-1
and EGF-R
The VEGF/Flk-1 signalling system is essential for the
development of endothelial and hematopoietic cells.
To test Flk-1’s role in adult mice and in tumour
angiogenesis a conditional allele of Flk-1 was
generated. In addition, a conditional allele of VEGF was
used to analyse the functional importance of VEGF-A
in developing chondrogenic tissues and to study the
role of VEGF-A in skin biology (collaboration with Erwin
Tschachler, General Hospital, Univ. Vienna). Finally,
conditional and mutated EGF receptor alleles are
employed to study the role of EGF-R in skin tumour
development (collaboration with Maria Sibilia, Dept. of
Dermatology, Univ. Vienna).
Figure 3: Functional analysis of Jun in development and disease.
Contact: wagner@imp.univie.ac.at
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