DF/HCC Program Affiliation

Neuro-Oncology
Cancer Cell Biology, Co-Leader

DF/HCC Associations

Member, Center Scientific Council

Research Abstract

The general focus of my 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 10 years ago, until recently, nothing was known about how its activity is regulated or in what contexts it affects Ras signaling pathways. We have recently demonstrated that neurofibromin is dynamically regulated by the proteasome and serves as a critical attenuator of the ERK 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. 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 are utilizing these models to understand the molecular changes required for the progression to malignancy as well as test the involvement of candidate effector pathways 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.

Publications

• Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K.The NF1 tumor suppressor critically regulates TSC2 and mTOR.Proc Natl Acad Sci U S A 2005 Jun 14;102(24):8573-8.
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• Cichowski K, Santiago S, Jardim M, Johnson BW, Jacks T.Dynamic regulation of the Ras pathway via proteolysis of the NF1 tumor suppressor.Genes Dev 2003 Feb 15;17(4):449-54.
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• Cichowski K, Jacks T.NF1 tumor suppressor gene function: narrowing the GAP.Cell 2001 Feb 23;104(4):593-604.
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• Cichowski K, Shih TS, Schmitt E, Santiago S, Reilly K, McLaughlin ME, Bronson RT, Jacks T.Mouse models of tumor development in neurofibromatosis type 1.Science 1999 Dec 10;286(5447):2172-6.
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