Molecular Mechanisms of Glial Abnormalities in Neurofibromatosis
Annual rept.19 sep 97-18 Sep 98
CALIFORNIA UNIV SAN DIEGO LA JOLLA
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Neurofibromatosis is a genetic disease in which the major pathology is due to abnormal proliferation of Schwann cells. One of the two tumor suppressor genes mutated in this disease is the neurofibromatosis 1 gene NF1. The product of this gene, neurofibromin, inhibits ras function. Based on several unique features of control of growth in Schwann cells, we believe that specific factors associated with CREB, and the CREB-binding protein, CBP, serve to specifically modulate cAMP and ras -dependent growth events in glia, and underly the NF1 mutation-induced Schwann cell proliferation. Our identification of CBP as an integral component of the activation complex for cAMP and Growth factors, and evidence that competition for limiting amounts of CBP can result in AP-1 inhibiting events, has led us to provide evidence for a molecular mechanism which integrates diverse signaling pathways, dictating differentiation and proliferation events. We hypothesize that this regulatory system can be exploited to discover novel approaches to the treatment of neurofibromatosis. We have proposed to generate various genetic models exhibiting altered cAMP and ras -dependent signaling pathways and utilize these model systems to identify and characterize factors which are responsible for the etiology of neurofibromatosis type 1.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research