The general focus of our laboratory is to investigate signaling
mechanisms underlying cancer and related developmental processes. To
achieve this we are taking a multi-faceted investigative approach;
combining mouse modeling techniques with basic biochemical and cell
biological studies. This approach provides a powerful means of
dissecting gene function on a molecular and cellular level, as well
as in the context of tumorigenesis and development. We have begun by
studying the NF1 tumor suppressor gene. NF1 was first identified as
the gene responsible for the familial cancer syndrome
neurofibromatosis type I (NF1). Unlike most inherited cancer
syndromes NF1 is strikingly common, affecting 1 in 3500 individuals
worldwide. The hallmark feature of the disease is the development of
numerous benign and malignant tumors of the peripheral nervous
system. However, NF1 patients are also predisposed to developing
brain tumors, myeloid malignancies, and may exhibit cognitive
deficits and bone deformities, implicating a role for NF1 in a wide
variety of tissues and disease processes.
Little is known about the NFI-encoded protein, neurofibromin;
however, it does exhibit similarity to Ras-GTPase activating proteins
(GAPs), a family of proteins that serve to negatively regulate Ras.
Furthermore, while the gene was cloned over 15 years ago, until
recently, nothing was known about how its activity is regulated or in
what contexts it affects Ras signaling pathways. We have shown that
neurofibromin is dynamically regulated by the proteasome and serves as a
critical attenuator of the MAP kinase
pathway. We are currently focusing on 1) understanding how NF1
functions throughout the cell cycle and how the proteasome regulates
this function 2) investigating the role of protein kinases in this
process and 3) identifying interacting proteins as a means of
elucidating additional cellular functions of neurofibromin (e.g.
apoptosis). The information gained from these studies will also be
examined in the context of tumorigenesis and neural crest development
as described below. Currently there is no treatment for NF1.
Ultimately, this approach may play a critical role in identifying
appropriate therapeutic targets.
In addition to elucidating the normal cellular function of NF1 we are
also interested in utilizing animal models to understand how NF1
mutations affect tumor development. To this end we have generated
mouse models that develop both the benign and malignant peripheral
nerve tumors similar to those observed in NF1 patients. This was
achieved by generating mice with a targeted disruption in the Nf1
gene alone or in combination with germline mutations in the p53 and
INK4 tumor suppressor genes. We have been utilizing these models to
understand the molecular changes required for the progression to
malignancy and have been testing the involvement of candidate effector
pathways (and therapeutics) in vivo. In addition, because a defect in neural
crest
and/or Schwann cell development is thought to underlie the
development of these tumors, we are able to utilize these animal
models to investigate the earliest developmental defects that
contribute to tumorigenesis.
