Karen Cichowski


Division of Genetics
Brigham & Women's Hospital
New Research Building, Room 458C
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 525-4722
Fax: (617) 525-4705
Email: kcichowski@rics.bwh.harvard.edu
6 postdoctoral fellows, 5 graduate students

 

The focus of my laboratory is to elucidate how deregulated cell signaling promotes tumorigenesis. To achieve this we have been taking a multi-faceted investigative approach; combining mouse modeling techniques with basic biochemical and cell biological studies. One of the most commonly deregulated signaling pathways in human cancer is the Ras pathway. Mutations can occur in Ras itself, upstream regulators, or downstream effectors. Therefore we have been focusing on how aberrant Ras signaling contributes to peripheral and central nervous system tumors, lung, and prostate cancer. Conversely, we have also been investigating how oncogene-induced senescence, in some settings, can function to limit the progression to malignancy.

 

One of the genes that we have been studying is the NF1 tumor suppressor. NF1 was first identified as the gene responsible for the familial cancer syndrome neurofibromatosis type I (NF1). 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 NF1-encoded protein, neurofibromin; however, it belongs to a family of proteins known as the Ras-GTPase activating proteins (GAPs), which negatively regulate Ras. It the last several years we have been 1) investigating how this protein is regulated by the proteasome and kinases 2) defining the critical downstream signals that drive tumorigenesis, 3) identifying novel functions of this enigmatic tumor suppressor and 4) delineating the signals that promote the progression to malignancy. Importantly, this work has led to insight that should impact the development of new therapies. As a result our goal is to test potential therapies on our genetically engineered mouse models for NF1 and investigate how these Ras-dependent signals contribute to other cancers. We are now using these approaches to extend our efforts toward understanding the pathogenesis of a variety of solid tumors.

 

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BBS webpage updated 12/02/2009