Identification of sel-12 and uses thereof

Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C435S069100, C435S320100, C435S252300, C435S325000, C435S091500, C435S455000, C435S471000, C530S350000, C514S002600, C514S04400A, C424S093600, C424S093700

Reexamination Certificate

active

06787641

ABSTRACT:

BACKGROUND OF THE INVENTION
The lin-12 gene of
C. elegans
is the archetype of the, “lin-12/Notch” gene family found throughout the animal kingdom (reviewed in Greenwald and Rubin, 1992). Members of this family appear to function as receptors for intercellular signals that specify cell fates during development. Essentially, lin-12 activity controls binary decisions: if a cell has a choice between two fates, A and B, activation of lin-12 above a threshold value causes the cell to adopt fate A, whereas the failure to activate lin-12 above the threshold causes the cell to adopt fate B (Greenwald et al. 1983). Furthermore, inappropriate activation of mammalian lin-12/Notch genes have been implicated in oncogenesis (Ellisen et al., 1991; Robbins et al., 1993) and in normal development (e.g. Swiatek et al., 1993). Much of the work in applicants, laboratory is focused on understanding how lin-12 specifies cell fates. An important component of this endeavor is the identification of genes that influence lin-12 activity and the identification of potential “downstream” genes.
Applicants identified the sel-12 gene by screening for suppressors of the “Multivulva” phenotype caused by an allele of lin-12 that causes constitutive LIN-12 activation. Applicants performed a genetic and molecular characterization of sel-12, which established: (1) Reducing or eliminating sel-12 activity reduces the activity of lin-12 and of glp-1, another member of the lin-22/Notch family. In addition, reducing or eliminating sel-12 activity causes and egg-laying defective (Egl) phenotype. Applicants do not know if the Egl phenotype is a direct consequence of reducing lin-12 activity or an independent effect of reducing sel-12 activity. (2) sel-12 and lin-12 can functionally interact within the same cell. (3) sel-12 is predicted to encode a protein with multiple transmembrane domains that is highly similar to S182, which has been implicated in early-onset familial Alzheimer's disease (Sherrington et al., 1995). These findings have been described in a paper that has been accepted by
Nature
(Levitan and Greenwald, 1995). In addition, applicants have data indicating that sel-12 is more broadly expressed than lin-12, including a lot of expression in neurons.
The remarkable conservation of the SEL-12 and S182 predicted protein structure suggests that their functions are likely to be conserved as well. Recently, a second gene known as E5-1 or STM2 has been implicated in early-onset familial Alzheimer's disease (Levy-Lahad et al, 1995; Rogaev et al, 1995) E5-1/STM2 encodes a protein that is highly similar to S182 (Levy-Lahad et al, 1995b; Rogaev et al, 1995) and SEL-12. Furthermore, it is striking that four of the five changes in S182 or E5-1/STM2 associated with early-onset familial Alzheimer's disease alter amino acids that are absolutely conserved in the worm and the human proteins, and that the tenth alters an amino acid that has been changed very conservatively during evolution. Applicants hope to bring the powerful tools of classical and molecular genetic studies in
C. elegans
to bear on fundamental issues of SEL-12/S182/E5-1 structure and function. Thus, far, proteins similar to LIN-12 and SEL-12 have not been described in single-celled organisms, so
C. elegans
may be the simplest practical system for studying these issues in vivo.
SUMMARY OF THE INVENTION
This invention provides an isolated nucleic acid molecule encoding a SEL-12 protein. This invention further provides an isolated nucleic acid molecule which encodes a mutated SEL-12 protein. This invention also provides an isolated nucleic acid molecule which encodes a mutated SEL-12, wherein the mutated SEL-12 contains at least one of the following: position 115 is a leucine, position 132 is an arginine, position 215 is a glutamic acid, position 229 is a valine, position 254 is a valine, position 255 is a valine, position 371 is a valine, position 387 is tyrosine, position 104 is an isoleucine or position 204 is a valine. This invention further provides different uses of these nucleic acid molecules. This invention also provides different sel-12 mutants and transgenic animals which carry wild-type or mutated sel-12.


REFERENCES:
patent: 5840540 (1998-11-01), St. George-Hyslop et al.
patent: 5986054 (1999-11-01), St. George-Hyslop et al.
patent: 6087153 (2000-07-01), Greenwald et al.
patent: 6376239 (2002-04-01), Baumeister
Daigle I., and Li C., “apl-1, aCaenorhabditis elegansgene encoding a protein related to the human beta-amyloid protein precursor” Proc. Natl. Acad. Sci. U.S.A. (1993) 90(24):12045-9 (Exhibit 4).
Database dbEST, National Center for Biotechnology Information, National Library of Medicine, GenBank Accession No. H19012 (1995) (Exhibit 5).
Database EMBL Accession No. U35660 (1995) Levitan D., Greenwald I., “Caenorhabditis elegansmembrane protein (sel-12) mRNA ” XPoo2176178 (Exhibit 6).
Fire A., et al., “A modular set of lacz fusion vectors for studying gene expression in Caenorhabditis elegans” Gene (1990) 93(2):189-98 (Exhibit 7).
Fitgerald K., and Greenwald I., “Interchangeability of Caenorhabditis elegans DSL proteins and intrinsic signalling activity of their extracellular domains in vivo” Development (1995) 121(12):4275-82 (Exhibit 8).
Greenwald I., “Structure/function studies of lin-12/Notch proteins” Curr. Opin. Genet. Dev. (1994) 4(4):556-62 (Exhibit 9).
Hedegecock E. M. and Herman R. K., “The ncl-1 gene and genetic mosaics of Caenorhabditis elegans” Genetics (1995) 141 (3):989-1006 (Exhibit 10).
Hedgecock E. M., et al., “Genetics of cell and axon migrations in Caenorhabditis elegans” Development (1987) 100 (3): 365-82 (Exhibit 11).
Levitan D. and Greenwald I., “Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene” Nature (1995) 377 (6547): 351-4 (Exhibit 12).
Levy-Lahad E., et al., “Genomic structure and expression of SSTM2, the chromosome 1 familial Alzheimer disease gene” Genomics (1996) 34(2):198-204 (Exhibit 13).
Li X. and Greenwald I., “HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling ” Proc. Natl. Acad. Sci. U.S.A. (1997) 94(22):12204-9 (Exhibit 14).
Rogaev E. I., et al., “Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene” Nature (1995) 376(6543):775-8 (Exhibit 15).
Sherrington R., et al., “Cloning of a gene bearing missense mutations in early-onset familial alzheimer's disease” Nature (1995) 375(6534):754-60 (Exhibit 16).
Stratagene Cloning Systems Catalog, 1993 pp. 27, 31, 32, and 313 (Exhibit 17).
Sundaram M. and Greenwald I., “Genetic and phenotypic studies of hypomorphic lin-12 mutants in Caenorhabditis elegans” Genetics (1993) 135(3):755-63 (Exhibit 18).
Sundaram M. and Greenwald I., “Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans” Genetics (1993) 135(3):765-83 (Exhibit 19).
Wen C., et al., “spr-2, a suppressor of the egg-laying defect caused by loss of sel-12 presenilin in Caenorhabditis elegans, is a member of the SET protein subfamily” Proc. Natl. Acad. Sci. U.S.A. (2000) 97(26):14524-9 (Exhibit 20).
Wilkinson H. A. and Greenwald I., “Spatial and temporal patterns of lin-12 expression during C. elegans hermaphrodite development” Genetics 1995 141(2):513-26 (Exhibit 21); and.
Wilkinson H. A., et al., “Reciprocal changes in expresssion of the receptro lin-12 and its ligand lag-2 prior to commitment in a C. elegans cell fate decsion” Cell (1994) 79(7):1187-98 (Exhibit 22).
Brenner S., “The genetics of Caenorhabditis elegans”, Genetics. (1974) 77(1):71-94 (Exhibit 1).
Levy-Lahad E., et al., “Candidate gene for the chromosome 1 familial Alzheimer's disease locus” Science (1995) 269 (5226):973-7 (Exhibit 2).
L'Hernault S. W. and Arduengo P. M., “Mutation of a putative sperm membrane protein in Caenorhabditis elegans prevents sperm differentiation but not its associated me

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Identification of sel-12 and uses thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Identification of sel-12 and uses thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Identification of sel-12 and uses thereof will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-3247723

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.