Aiolos gene

Details Aiolos gene Aiolos gene

1996-10-17

2003-03-04

Nolan, Patrick J. (Department: 1644)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C435S069100, C435S325000, C435S320100

Reexamination Certificate

active

06528634

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to the Aiolos gene, Aiolos polypeptide, Aiolos homodimers, Aiolos/Ikaros heterodimers and methods of using Aiolos nucleic acids and polypeptides.
SUMMARY OF THE INVENTION
In general, the invention features an Aiolos polypeptide, e.g., a polypeptide which includes all or part of the sequence shown in SEQ ID NO:2 or SEQ ID NO:8. The invention also features fragments and analogs of Aiolos polypeptides, preferably having at least one biological activity of an Aiolos polypeptide.
In preferred embodiments, the polypeptide is a recombinant or a substantially pure preparation of an Aiolos polypeptide.
In preferred embodiments, the polypeptide is a vertebrate, e.g., a mammalian, e.g., a human polypeptide.
In preferred embodiments, the Aiolos polypeptide includes additional Aiolos coding sequences 5′ to that of SEQ ID NO:8. In preferred embodiments: the additional sequence includes at least 1, 10, 20, 40, 60, 70, 80 or 100 amino acid residues; the additional sequence is equal to or less than 1, 10, 20, 40, 60, 70, 80 or 100 amino acid residues.
In preferred embodiments: the polypeptide has at least one biological activity, e.g., it reacts with an antibody, or antibody fragment, specific for an Aiolos polypeptide; the polypeptide includes an amino acid sequence at least 60%, 80%, 90%, 95%, 98%, or 99% homologous to an amino acid sequence from SEQ ID NO:2 or SEQ ID NO:8; the polypeptide includes an amino acid sequence essentially the same as an amino acid sequence in SEQ ID NO:2 or SEQ ID NO:8; the polypeptide is at least 5, 10, 20, 50, 100, 150, 200, or 250 amino acids in length; the polypeptide includes at least 5, preferably at least 10, more preferably at least 20, most preferably at least 50, 100, 150, 200, or 250 contiguous amino acids from SEQ ID NO:2 or SEQ ID NO:8; the polypeptide is preferably at least 10, but no more than 100, amino acids in length; the Aiolos polypeptide is either, an agonist or an antagonist, of a biological activity of a naturally occurring Aiolos polypeptide.
In preferred embodiments: the Aiolos polypeptide is encoded by the nucleic acid sequence of SEQ ID NO:1 or SEQ ID NO:7, or by a nucleic acid having at least 60%, 70%, 80%, 90%, 95%, 98%, or 99% homology with the nucleic acid of SEQ ID NO:1 or SEQ ID NO:7. For example, the Aiolos polypeptide can be encoded by a nucleic acid sequence which differs from a nucleic acid sequence of SEQ ID NO:1 or SEQ ID NO:7 due to degeneracy in the genetic code.
In a preferred embodiment, the Aiolos polypeptide encodes amino acid residues 1-507 of SEQ ID NO:2 or a functionally equivalent residue in the Aiolos sequence of another vertebrate or mammal, e.g., a human.
In a preferred embodiment, the Aiolos polypeptide encodes amino acid residues 58-507 of SEQ ID NO:2 or a functionally equivalent residue in the Aiolos sequence of another vertebrate or mammal, e.g., a human.
In a preferred embodiment, the Aiolos polypeptide encodes amino acid residues 72-507 of SEQ ID NO:2 or a functionally equivalent residue in the Aiolos sequence of another vertebrate or mammal, e.g., a human.
In a preferred embodiment, the Aiolos polypeptide encodes amino acid residues 76-507 of SEQ ID NO:2 or a functionally equivalent residue in the Aiolos sequence of another vertebrate or mammal, e.g., a human.
In a preferred embodiment, the Aiolos polypeptide encodes amino acid residues 1-206 of SEQ ID NO:8.
In a preferred embodiment the Aiolos polypeptide is an agonist of a naturally-occurring mutant or wild type Aiolos polypeptide (e.g., a polypeptide having an amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:8). In another preferred embodiment, the polypeptide is an antagonist which, for example, inhibits an undesired activity of a naturally-occurring Aiolos polypeptide (e.g., a mutant polypeptide).
In a preferred embodiment, the Aiolos polypeptide differs in amino acid sequence at 1, 2, 3, 5, 10 or more residues, from a sequence in SEQ ID NO:2 or SEQ ID NO:8. The differences, however, are such that the Aiolos polypeptide exhibits at least one biological activity of an Aiolos polypeptide, e.g., the Aiolos polypeptide retains a biological activity of a naturally occurring Aiolos polypeptide.
In preferred embodiments the Aiolos polypeptide includes an Aiolos polypeptide sequence, as described herein, as well as other N-terminal and/or C-terminal amino acid sequences.
In preferred embodiments, the polypeptide includes all or a fragment of an amino acid sequence from SEQ ID NO:2 or SEQ ID NO:8, fused, in reading frame, to additional amino acid residues, preferably to residues encoded by genomic DNA 5 to the genomic DNA which encodes a sequence from SEQ ID NO:2 or SEQ ID NO:8.
In yet other preferred embodiments, the Aiolos polypeptide is a recombinant fusion protein having a first Aiolos polypeptide portion and a second polypeptide portion having an amino acid sequence unrelated to an Aiolos polypeptide. The second polypeptide portion can be, e.g., any of glutathione-S-transferase, a DNA binding domain, or a polymerase activating domain. In preferred embodiment the fusion protein can be used in a two-hybrid assay.
In a preferred embodiment, the Aiolos polypeptide is a fragment or analog of a naturally occurring Aiolos polypeptide which inhibits reactivity with antibodies, or F(ab′)
2
fragments, specific for a naturally occurring Aiolos polypeptide.
In a preferred embodiment, the Aiolos polypeptide includes a sequence which is not present in the mature protein.
Polypeptides of the invention include those which arise as a result of the existence of multiple genes, alternative transcription events, alternative RNA splicing events, and alternative translational and postranslational events.
In preferred embodiments, the Aiolos polypeptide: is expressed in spleen and thymus; is expressed in mature T and/or B cells; is highly homologous, preferably at least 90% or 95% homologous, with the 50 most C-terminal amino acids of the Ikaros gene (e.g., the dimerization domain of exon 7 of the Ikaros gene); is highly homologous, preferably at least 90% or 95% homologous with the activation domain of exon 7 of the Ikaros gene; is capable of forming Aiolos dimers and/or Aiolos/Ikaros dimers; is involved in lymphocyte differentiation, e.g., T cell maturation.
In preferred embodiments, the Aiolos polypeptide includes: the YAS5 interaction domain; the YAS3 interaction domain; the YIZ Ikaros dimerization domain.
In preferred embodiments, an Aiolos polypeptide encodes: one, two, three, four, five exons, or more exons; exons 3, 4, 5 and 7; exons 3-7; exon 7 (the exons are shown in FIG.
4
).
In preferred embodiments, the Aiolos polypeptide has one or more of the following properties:
(a) it can form a dimer with an Aiolos or Ikaros polypeptide;
(b) it is expressed in committed lymphoid progenitors;
(c) it is expressed in committed T and B cells;
(d) it has a molecular weight of approximately 58 kD;
(e) it has at least one zinc finger domain;
(f) it is not expressed in stem cells; or
(g) it is a transcriptional activator of a lymphoid gene.
In other preferred embodiments, the Aiolos polypeptide has one or more of the following properties:
(a) it can form a dimer with an Aiolos or Ikaros polypeptide;
(b) it is expressed in committed lymphoid progenitors;
(c) it is expressed in committed T and B cells;
(d) it has a molecular weight of approximately 58 kD;
(e) it has an N-terminal zinc finger domain;
(f) it is not expressed in stem cells; or
(g) it is a transcriptional activator of a lymphoid gene.
In yet other preferred embodiments, the Aiolos polypeptide has one or more of the following properties:
(a) it can form a dimer with an Aiolos or Ikaros polypeptide;
(b) it is expressed in committed lymphoid progenitors;
(c) it is expressed in committed T and B cells;
(d) it has a molecular weight of approximately 58 kD;
(e) it has at least one or preferably two C-terminal zinc finger domains;
(f) it is not expressed in stem cells; or
(g) it is a transcriptional activator of a lymphoid gene.
The invention includes an immuno

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