NF1 protein and its role in activation of adenylyl cyclase...

Details NF1 protein and its role in activation of adenylyl cyclase... NF1 protein and its role in activation of adenylyl cyclase...

2000-04-04

2001-07-17

Schwartzman, Robert A. (Department: 1638)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Reexamination Certificate

active

06261761

ABSTRACT:

BACKGROUND OF THE INVENTION
Mutations in the ncurofibromatosis type 1 gene (NF1) lead to a common genetic disorder that is identified by benign tumors of the peripheral nerves, hyperpigmentation, white matter lesions in the brain, learning disabilities, and many other manifestations (D. Viskochil et al.,
Annu. Rev. Neurosci
. 16:183 (1993); F. McCormick,
Curr. Opinion Genet. Dev
. 5:51-55 (1995); K. North et al., Neurology 44:878 (1994)). The NF1 protein, which contains a fragment similar to the GTPase activating protein for Ras (Ras-GAP), stimulates the intrinsic activity of Ras-GTPase and therefore inhibits biological activation of Ras (G. F. Xu, et al.,
Cell
62:599 (1990);
Cell
63:835 (1990); A. M. Buchberg etal.,
Nature
347.291 (1990); R. Ballester etal.,
Cell
63.851 (1990); G. A. Martin et al.,
Cell
63:843 (1990)).
The gene responsible for human neurofibromatosis type 1 (NF1) encodes a large protein that contains a central domain related to RasGAPs (S. M. Huson, et al.,
Brain
111:1355-1381 (1988); F. McCormick,
Curr. Opin. Gen. Dev
. 5:51-55 (1995); A. Bernards, Biochem.
Biophys. Acta
1242:43-60 (1995)). Loss of NF1 expression correlates with increased Ras activity in several mammalian tumor cell types (T. N. Basu, et al.,
Nature
356:713-715 (1992); J. E. DeClue, et al.,
Cell
69:265-273 (1992); H. A. Kim et al.,
Oncogene
11:325-35 (1995); G. Bollag, et al.,
Nat. Genet
. 12:144-8 (1996); D. A. Largaespada et al.,
Nat. Genet
. 12:137-143 (1996)). However, the precise signaling pathways regulated by the NF1 protein remain poorly understood. Identification of such pathways would help to define molecular mechanisms underlying the extremely diverse symptoms observed in NF1 patients, which in addition to frequent benign and infrequent malignant tumors also include short stature and learning disabilities (S. M. Huson et al.,
Brain
111:1355-1381 (1988); F. McCormick,
Curr. Opin. Gen. Dev
. 5:51-55 (1995); A. Bernards,
Biochim. Biophys
. Acta 1242:43-60 (1995)).
SUMMARY OF THE INVENTION
In one aspect of the present invention, diseases associated with a defect in the NF1 protein are prevented. These diseases include neurofibromatosis type 1, benign tumors, malignant tumors, short stature, hyperpigmentation, white matter lesions in the brain and learning disabilities. The NF1 protein defect is either a diminution in the amount of NF1 protein produced, a diminution in the activity of the NF1 protein produced or both a diminution in amount and activity of NF1 protein. The diseases are prevented by the administration of the NF1 protein, or biologically active homolog, itself or an inducible gene which codes for either the NF1 protein or a biologically active homolog of the NF1 protein.
In another aspect of the present invention, an assessment can be made of whether diseases are associated with a defect in the NF1 protein by measuring the production of cAMP in tissue from an individual that exhibits one or more of the diseases. An NF1 protein defect is manifested by a loss of cAMP formation. This loss can be measured directly or, alternatively, by determining the lack of activity of protein kinase A (PKA) which is activated by cAMP.
In still another aspect of the present invention, the ability of a given compound to induce the production of cAMP can be determined by incubating the compound with two separate cellular preparations that differ from each other by the functional NF1 protein content. In one cellular preparation, functional NF1 protein is present; in the second preparation, NF1 protein is either absent or it is inactive. If a difference is noted in the amount of cAMP produced by the two preparations, with the preparation containing functional NF1 protein producing more cAMP than the preparation lacking functional NF1 protein, the compound can be categorized as having the property of inducing the production of cAMP.


REFERENCES:
patent: 5859195 (1999-01-01), Collins et al.
patent: WO 92/00387 (1992-01-01), None
Silva, A.J., et al. “A mouse model for the learning and memory deficits associated with neurofibromatosis type 1.”Nature Genetics.15:281-284 (1997).

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