[Federal Register Volume 64, Number 49 (Monday, March 15, 1999)]
[Notices]
[Pages 12815-12816]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-6205]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions; Availability for Licensing
AGENCY: National Institutes of Health, Public Health Service, DHHS.
ACTION: Notice.
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SUMMARY: The invention listed below is owned by an agency of the U.S.
Government and is available for licensing in the U.S. in accordance
with 35 U.S.C. 207 to achieve expeditious commercialization of results
of federally funded research and development.
ADDRESSES: Licensing information and a copy of the U.S. patent
application referenced below may be obtained by contacting J.R. Dixon,
Ph.D., at the Office of Technology Transfer, National Institutes of
Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-
3804 (telephone 301/496-7056 ext 206; fax 301/402-0220). A signed
Confidential Disclosure Agreement is required to receive a copy of any
patent application.
Title: ``Anthrax Lethal Factor is a MAPK Kinase Protease''
Inventors: Drs. Nicholas S. Duesbery (NCI-FCRDC), Craig Webb (NCI-
FCRDC), Stephen H. Leppla (NIDCR), and Dr. George Vande Woude (NCI-
FCRDC)
DHHS Ref. No. E-066-98/0--Filed April 1, 1998
Anthrax toxin, produced by Bacillus anthracis, is composed of three
proteins; protective antigen (PA), edema factor (EF), and lethal factor
(LF). PA by itself has little or no toxic effect upon cells, but serves
to bind cell surface receptors and mediate the entry of EF and LF into
the cell. EF has been identified as an adenylate cyclase and together
with PA forms a toxin (edema toxin; EdTx) which can induce edema
formation when injected subcutaneously. LF and PA together form a toxin
(lethal toxin; LeTx) which can cause rapid lysis of certain
[[Page 12816]]
macrophage-derived cell lines in vitro as well as death when injected
intravenously.
Indirect evidence had suggested that LF was a metalloprotease.
However, the intracellular target of LF remained unknown until recently
when NIH scientists discovered that LF proteolytically inactivates
mitogen activated protein kinase kinase 1 and 2 (MAPKK1, 2). Using
oocytes of the frog Xenopus laevis as well as tumor derived NIH3T3
(490) cell expressing an effector domain mutant form of the human
V12HaRas oncogene these scientists demonstrated that LF induced
proteolysis of MAPKK 1 and 2, resulting in their irreversible
inactivation. MAPKK 1 and 2 are components of the mitogen activated
protein kinase (MAPK) signal transduction pathway, an evolutionarily
conserved pathway that controls cell proliferation and differentiation
in response to extracellular signal and also plays a crucial role in
regulating oocyte meiotic maturation. Further, the MAPK pathway has
been shown to be constitutively activated in many primary human as well
as in tumor-derived cell lines. Consistent with this, treatment of
V12Ha-Ras transformed NIH 3T3 cells with LeTx inhibits cell
proliferation and causes their reversion to a non-transformed
phenotype.
This invention specifically relates to in vitro and ex vivo methods
of screening for modulators, homologues, and mimetics of LF mitogen
activated protein kinase kinase (MAPKK) protease activity. Applications
for this technology could be:
1. A novel tool (LF) for the study of the cellular role of the MAPK
pathway in normal or tumor cells.
2. Investigation of LF for developing inhibitors for cancer
therapy. By analyzing structural-functional relationships, additional
compounds with improved specificity, increased potency, and reduced
toxicity can be generated. Mimetics which block MAPKK activity or the
determination of mechanisms of regulation of proteases that target
MAPKK at or near the same site targeted by LF could be developed.
3. A protease-based assay for LF by using a peptide to test for LF
cleavage. There is no commercial test for anthrax. This assay could be
used for testing soldiers for anthrax exposure. Characterization of the
interaction between LT and MAPKK at the amino acid level may lead to
the generation of inhibitors which may prove useful in treating
anthrax.
The above mentioned invention is available for licensing on an
exclusive or non-exclusive basis.
Dated: March 5, 1999.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer.
[FR Doc. 99-6205 Filed 3-12-99; 8:45 am]
BILLING CODE 4140-01-M