Human LEA-motif developmental protein

Details Human LEA-motif developmental protein Human LEA-motif developmental protein

1998-12-15

2001-08-28

Carlson, Karen Cochrane (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S350000

Reexamination Certificate

active

06281190

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of a novel human LEA motif protein and to the use of these sequences in the diagnosis, prevention, and treatment of disorders associated with aberrant cell growth and differentiation including cancer.
BACKGROUND OF THE INVENTION
Bromodeoxyuridine (BrdU) suppresses the appearance of proteins associated with the differentiated state of various embryonic tissues without significantly affecting cell viability. Low doses of BrdU are proposed to inhibit “switching loci” for differentiation (Weintraub, H. et al. (1973) Nature New Biol. 244:142-143). For instance, BrdU blocks myogenic differentiation and decreases the expression of the MyoD1 regulatory protein (Tapscott, S. J. et al. (1989) Science 245:532-536). forced expression of MyoD1 from an expression vector in BrdU-treated myoblasts overcomes the differentiation block. BrdU thus appears to selectively block regulatory genes important for cellular development (Tapscott et al., supra).
The immortalized myc embryonic quail cardiomyocyte (MEQC) cell line is induced to differentiate by coculturing with NIH 3T3 cells in a defined synthetic medium (Jaffredo, T. et al. (1991) Exp. Cell Res. 192:481-491). Muscle-specific markers are expressed in cardiac cells as soon as one day after coculture. Treatment with low concentrations of BrdU before coculture prevents phenotypic marker expression, presumably by blocking the expression of genes responsible for differentiation (Niu, S. et al. (1996) Gene 175:187-191).
In an attempt to identify genes involved in avian development, MEQC transcripts attenuated by BrdU treatment were identified by a subtraction hybridization procedure. One corresponding transcript subsequently cloned from an embryonic chick heart cDNA library encodes a putative 215 amino acid protein designated px19 (Niu et al., supra). In five-day chick embryos, px19 mRNA is expressed in hematopoietic cells in liver. In earlier embryos, px19 is strongly expressed in the blood islands of area opaca, which is the location of hematopoiesis in early avian development. Niu et al., suggest that the px19 protein may therefore be associated with hematopoiesis in early chick development.
The px19 amino acid sequence contains two predicted &agr;-helices with oppositely oriented amphipathic surfaces. Each helix contains an LEA (late embryogenesis abundant) consensus sequence, which had previously been described only in plant seed-specific proteins (Puupponen-Pimia, R. et al. (1993) Plant Mol. Biol. 23:423-428). In certain plants, LEA proteins accumulate in embryo tissues as the tissues approach maturity and begin to desiccate. LEA proteins can also be induced by desiccation stress as other plant developmental stages. LEA plant proteins may thus play a role in the protection of plant cells during water loss (Puupponen-Pimia, et al., supra).
The discovery of polynucleotides encoding a human LEA motif protein, and the molecules themselves, provides a means to investigate cellular development and differentiation under normal and disease conditions. Discovery of a human LEA motif protein satisfies a need in the art by providing new compositions useful in diagnosing and treating disorders relating to aberrant cell growth and differentiation including cancer.
SUMMARY OF THE INVENTION
The present invention features a novel human LEA motif protein hereinafter designated HuLEAP and characterized as having similarity to px19 protein from chick embryo.
Accordingly, the invention features a substantially purified HuLEAP having the amino acid sequence shown in SEQ ID NO:1.
One aspect of the invention features isolated and substantially purified polynucleotides that encode HuLEAP. In a particular aspect, the polynucleotide is the nucleotide sequence of SEQ ID NO:2.
The invention also relates to a polynucleotide sequence comprising the complement of SEQ ID NO:2 or variants thereof. In addition, the invention features polynucleotide sequences which hybridize under stringent conditions to SEQ ID NO:2.
The invention additionally features nucleic acid sequences encoding polypeptides, oligonucleotides, peptide nucleic acids (PNA), fragments, portions or antisense molecules thereof, and expression vectors and host cells comprising polynucleotides that encode HuLEAP. The present invention also features antibodies which bind specifically to HuLEAP, and pharmaceutical compositions comprising substantially purified HuLEAP. The invention also features the use of agonists and antagonists of HuLEAP. The invention also features methods for treating disorders which are associated with HuLEAP and for detecting a polynucleotide which encodes HuLEAP.


REFERENCES:
Shi et al. Jul., 1995. EMBL U31977.*
Weintraub, H, “Size of the BudR sensitive targets for differentiation”Nature New Biol.244 (135) : 142-143 (1973).
Tapscott, SJ et al., “5-bromo-2′-deoxyuridine blocks myogenesis by extinguishing expression of MyoD1”Science245 (4917) : 532-536 (1989).
Jaffredo, T et al., “MC29-immortalized clonal avian heart cell lines can partially differentiate in vitro”Exp Cell Res192 (2) : 481-491 (1991).
Niu, S et al., “Cloning and sequencing of a developmentally regulated avian mRNA containing the LEA motif found in plant seed proteins”Gene175:187-191 (1996) (GI 969170).
Puupponen-Pimia, R et al., “Characterization of a birch (Betula pendulaRoth.) embryogenic gene, BP8”Plant Mol. Biol.23:423-428 (1993).
Niu, S et al. (GI 969170), GenBank Sequence Database (Accession 969170), National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland 20894.
Niu, S et al. (GI 969170), GenBank Sequence Database (Accession U31977), National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland 20894.
S. P. Hehner et al., EMBL Database entry HSU779, Accession No. U94779, May 25, 1997.
M. Marra et al., EMBL Database entry AA689906, Accession No. AA689906, Dec. 19, 1997.
L. Hillier et al., EMBL Database entry HSAA13056, Accession No. AA113056, Jan. 1, 1998.
M. Marra et al., EMBL Database entry AA770799, Accession No. AA770799, Jan. 31, 1998.
Ngo et al.,The Protein Folding Problem and Tertiary Structure Prediction, Merz et al. (eds) Birkhauser Boston, pp. 433, 49-295, (1994).
Niu et al., Gene 175:187-191, (1996).

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