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WO1998000539A2 - Proteine d'interaction mkk3 (mip) - Google Patents

Proteine d'interaction mkk3 (mip) Download PDF

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Publication number
WO1998000539A2
WO1998000539A2 PCT/US1997/010866 US9710866W WO9800539A2 WO 1998000539 A2 WO1998000539 A2 WO 1998000539A2 US 9710866 W US9710866 W US 9710866W WO 9800539 A2 WO9800539 A2 WO 9800539A2
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WO
WIPO (PCT)
Prior art keywords
mip
protein
human
seq
mkk3
Prior art date
Application number
PCT/US1997/010866
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English (en)
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WO1998000539A3 (fr
Inventor
Venkatakrishna Shyamala
Michael W. Kavanaugh
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Chiron Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chiron Corporation filed Critical Chiron Corporation
Priority to AU43260/97A priority Critical patent/AU4326097A/en
Publication of WO1998000539A2 publication Critical patent/WO1998000539A2/fr
Publication of WO1998000539A3 publication Critical patent/WO1998000539A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the invention relates to the area of transduction of extracellular signals into the nucleus of human cells. More particularly, the invention relates to transduction of extracellular signals by means of the MKK3-p38 pathway.
  • the mitogen-activated protein kinase (MAPK) cascade is a major signaling system by which cells transduce extracellular cues into intracellular responses.
  • MAPKs phosphorylate substrates on serine or threonine adjacent to proline residues and are thus proline-directed protein kinases, as described in Cano and Mahadevan, ⁇ BS Reviews 20: 117-122 (1995). It is believed that multiple MAPK cascades exist, thus implicating many other molecules in the up and downstream events contributing to MAPK signal transduction events.
  • p38 MAPK signal transduction pathway is activated by proinflammatory cytokines and environmental stress (Xia et al, Science 270: 1326-1331 , 1995).
  • p38 MAPK is weakly activated by protein kinase C and receptor tyrosine kinases but is strongly activated by the treatment of cells with inflammatory cytokines (including tumor necrosis factor and interleukin- 1) and environmental stress (including osmotic shock and UV radiation), as described in Raingeaud et al, Mol. Cell Biol 16: 1247-1255 (1996).
  • MAPK kinase-3 is a protein kinase that phosphorylates and activates p38 MAP kinase specifically (Derijard et al, Science 267: 682-685, 1995). MKK3 is involved in transducing stress signals, for example in nerve growth factor (NGF)-mediated apoptosis in PC12 cells (Xia et al. Science 270: 1326-1331, 1995). MKK3 activity has also been correlated with changes in osmolarity.
  • NTF nerve growth factor
  • MIP human MKK3-interacting protein
  • the fusion protein comprises a first protein segment and a second protein segment fused to each other by means of a peptide bond.
  • the first protein segment consists of at least eight contiguous amino acids selected from the amino acid sequence shown in SEQ ID NO:l.
  • Yet another embodiment of the invention provides an isolated MIP polypeptide.
  • the polypeptide consists of at least eight contiguous amino acids of a human MIP protein having the amino acid sequence shown in SEQ ID NO: 1.
  • Still another embodiment of the invention provides a preparation of antibodies which specifically bind to a human MIP protein.
  • the human MIP protein has the amino acid sequence shown in SEQ ID NO: 1.
  • Even another embodiment of the invention provides a subgenomic polynucleotide which encodes all or a portion of a human MIP protein.
  • the MIP protein has the amino acid sequence shown in SEQ ID NO: 1.
  • Yet another embodiment of the invention provides a method of determining the tissue source of a body sample of a human.
  • the method comprises the step of assaying the body sample for the presence of a human MIP protein or a 2.0 kb MIP mRNA encoding the MIP protein.
  • the MIP protein has the amino acid sequence shown in SEQ ID NO: 1.
  • the presence of the human MIP protein or the 2.0 kb MIP mRNA encoding the MIP protein indicates that the body sample originates from a tissue selected from the group consisting of brain, kidney, liver, lung, pancreas, and spleen.
  • the present invention provides the art with the amino acid sequence and DNA coding sequence of MIP, a unique human protein that binds to a dominant interfering mutant of MKK3.
  • the present invention also provides the art with the information that MIP mRNA is differentially expressed in human tissues.
  • the invention can be used, inter alia, to determine the tissue source of human body samples.
  • MIP protein binds to and interacts with a dominant interfering mutant form of MKK3.
  • MIP is likely involved in transducing extracellular signals to wild-type MKK3.
  • MIP mRNA is differentially expressed in human tissues.
  • Human MIP protein has the sequence disclosed in SEQ ID NO:l and a molecular weight of approximately 40 kD. The protein is expressed in human brain, kidney, liver, lung, pancreas, and spleen, and not in heart or striated muscle. Any naturally occurring, biologically active variants of this sequence that occur in human tissues are within the scope of this invention. Naturally occurring, biologically active variants of MIP bind to a dominant interfering mutant of MKK3. MIP protein is useful, inter alia, for generating antibodies agaiast MIP protein sequences. Fragments (polypeptides) of a human MIP protein, comprising at least eight, ten, twelve, or fifteen consecutive amino acids selected from SEQ ID NO:l, may also be used as immunogens.
  • MIP protein may be isolated from MlP-producing human cells, such as brain, kidney, liver, lung, pancreas, or spleen cells. MIP may be obtained substantially free from other human proteins by standard protein purification methods, such as size exclusion chromatography, ion exchange chromatography, ammonium sulfate fractionation, affinity chromatography, or preparative gel electrophoresis. Alternatively, synthetic chemistry methods, such as solid-phase peptide synthesis, can be used to synthesize MIP protein or polypeptides.
  • MIP protein or polypeptides may also be produced recombinantly, by expressing MIP coding sequences selected from SEQ ID NO: 2 in prokaryotic or eukaryotic host cells, such as bacteria, yeast, insect, or mammalian cells, using expression vectors known in the art. Enzymes may be used to generate MIP polypeptides by enzymatic proteolysis of full-length MIP protein.
  • MIP protein or polypeptides may also be used in a fusion protein, for example as an immunogen.
  • the fusion protein comprises two protein segments.
  • the first protein segment consists of at least 8, 10, 12, or 15 contiguous amino acids of MIP selected from the amino acid sequence shown in SEQ ID NO: 1.
  • the first protein segment is fused to a second protein segment by means of a peptide bond.
  • the second protein segment may be a full-length protein or a fragment of a protein. Techniques for making fusion proteins, either recombinantly or by covalently linking two protein segments, are well known in the art.
  • the second protein or protein fragment may be, for example, a ligand for yet a diird molecule.
  • the second protein or protein fragment may be labeled with a detectable marker, such as a radioactive or fluorescent tag, or may be an enzyme that will generate a detectable product. Enzymes suitable for this purpose, such as ⁇ -galactosidase, are well-known in the art.
  • a fusion protein may be used, for example, to target MIP protein or MIP polypeptides to a particular location in a cell or tissue, to use MIP protein or polypeptides in various assays, such as the yeast two-hybrid technique, or as an immunogen.
  • MIP proteins, fusion proteins, or polypeptides may be used to obtain a preparation of antibodies that specifically bind to a human MIP protein.
  • the antibodies may be polyclonal or monoclonal. Techniques for raising both polyclonal and monoclonal antibodies are well known in the art.
  • the antibodies bind specifically to MIP epitopes.
  • the MIP epitopes are not present on other human proteins.
  • a minimum number of contiguous amino acids to encode an epitope is 6, 8, or 10. However, more may be used, for example, at least 15, 25, or 50, especially to form epitopes which involve non-contiguous residues.
  • Antibodies that bind specifically to MIP proteins include those that bind to full-length MIP protein, MIP polypeptides, or MIP fusion proteins. Specific binding antibodies do not detect other proteins on Western blots of human cells, or provide a signal at least ten-fold lower than the signal provided with MIP. Most preferably the antibodies bind to neither GMP reductase nor glucose-6-phosphate dehydrogenase. Antibodies which have such specificity can be obtained by routine screening. In a preferred embodiment of the invention, the antibodies prevent MIP binding to a dominant interfering mutant of MKK3, immunoprecipitate MIP bound to the mutant MKK3 from a cell lysate, or react with MIP protein in tissue sections or on Western blots of polyacrylamide gels.
  • the antibodies do not exhibit nonspecific cross-reactivity with other human proteins on Western blots or in immunocytochemical assays.
  • Techniques for purifying MIP antibodies are available in the art.
  • antibodies are affinity purified by passing antiserum over a column to which a MIP protein, polypeptide, or fusion protein is bound and then eluting the bound antibody, for example with a buffer having a high salt concentration.
  • Subgenomic polynucleotides may encode all or a contiguous portion of MIP selected from the amino acid sequence of SEQ ID NO: 1.
  • the MIP coding sequence (cDNA) has the nucleotide sequence shown in SEQ ID NO:2.
  • polynucleotides may be used to produce MIP protein, polypeptides, or fusion proteins, and may be used as probes for the detection of MIP mRNA in samples or extracts of human cells.
  • MIP subgenomic polynucleotides contain less than a whole chromosome and are preferably intron-free. MIP polynucleotides may be isolated and purified free from other nucleotide sequences by standard nucleic acid purification techniques, using restriction enzymes and probes to isolate fragments comprising the MIP encoding sequences. In a preferred embodiment, the polynucleotide molecules comprise a contiguous sequence of 12, 15, 20, 25, or 30 nucleotides selected from SEQ ID NO:2. MIP cDNA can be made using reverse transcriptase with MIP mRNA as a template. Amplification by PCR may also be used to obtain the polynucleotides, using either genomic DNA or cDNA as a template.
  • the polynucleotide molecules can also be made using the techniques of synthetic chemistry.
  • the degeneracy of the genetic code permits alternate nucleotide sequences to be synthesized that will encode the MIP amino acid sequence shown in SEQ ID NO: 1. All such nucleotide sequences are within the scope of the present invention.
  • the MIP polynucleotides can be propagated in vectors and cell lines using techniques well known in the art.
  • Expression systems in bacteria include those described in Chang et al., Nature (1978) 275: 615, Goeddel et al., Nature (1979) 281: 544, Goeddel et al., Nucleic Acids Res. (1980) 8: 4057, EP 36,776, U.S. 4,551,433, deBoer et al., Proc. Natl. Acad. Sci. USA (1983) 80: 21-25, and Siebenlist et al., Cell (1980) 20: 269.
  • Expression systems in yeast include those described in Hinnen et al., Proc. Natl. Acad. Sci.
  • the MIP polynucleotides may be on linear or circular molecules. They may be on autonomously replicating molecules or on molecules without replication sequences. They can be regulated by their own or by other regulatory sequences as are known in the art. MIP polynucleotides may be introduced into suitable host cells using a variety of techniques which are available in the art, such as transferrin-polycation-mediated DNA transfer, transfection with naked or encapsulated nucleic acids, liposome-mediated DNA transfer, intracellular transportation of DNA-coated latex beads, protoplast fusion, viral infection, electroporation, and calcium phosphate-mediated transfection.
  • the present invention also provides a method of determining the tissue source of a human body sample.
  • the basis for this method is the discovery that MIP mRNA is expressed in some human tissues, such as brain, kidney, liver, lung, pancreas, and spleen, but not in others, such as heart or striated muscle.
  • the body sample is assayed for the presence of a human MIP protein.
  • the MIP protein has the sequence shown in SEQ ID NO:l and may be detected using the MlP-specific antibodies of die present invention.
  • the antibodies may be labeled, for example, with a radioactive, fluorescent, biotinylated, or enzymatic tag and detected directly, or may be detected using indirect immunochemical methods, using a labeled secondary antibody.
  • MIP protein may be assayed in tissue sections by immunocytochemistry, or in
  • the body sample is assayed for the presence of MIP mRNA.
  • MIP mRNA is 2.0 kb in length and may be detected by in situ hybridization in tissue sections or in Northern blots containing poly A-f mRNA. MlP-specific probes may be generated using the
  • the probes are preferably 15 to 50 nucleotides in length, although they may be 8, 10, 20, 25, 30, 35, 40, 45, 60, 75, or 100 nucleotides in length.
  • the probes may be synthesized chemically or may be generated from longer polynucleotides using restriction enzymes.
  • the probes may be labeled, for example, with a radioactive, biotinylated, or fluorescent tag.
  • the body sample which is assayed may be normal or may be diseased.
  • the body sample is a primary tumor or a metastatic lesion. Metastatic lesions originating from tumors of the brain, kidney, liver, lung, pancreas, and spleen may be identified using this method. Other tissues can also be tested for the presence or absence of
  • MIP protein or mRNA MIP protein or mRNA
  • This example demonstrates the identification of MIP cDNA.
  • yeast 2-hybrid system as described in U.S. Patent No. 5,283,173 and Chien et al, Proc. Nat'l Acad Sci USA 58:9578-9582 (1991), was used to identify a protein which interacts with a dominant interfering mutant of MKK3.
  • MKK3 wild type was obtained by RT-PCR from human brain poly A 4- RNA.
  • a dominant interfering mutant of MKK3 (K-R) was constructed using overlap PCR, as described in Shyamala and Asmes, Gene 97: 1-6 (1991). Fragments which contained a sequence differing from the wild-type sequence by amino acid K64R were cloned into a pAS vector and used as bait DNA.
  • the pAS vector is yeast expression vector with a Gal4 binding domain and other required features.
  • the bait DNA along with a human fetal brain cDNA library in a pAD-Gal4 vector (Stratagene, La Jolla, CA) was used for transformation.
  • the pAD-Gal4 vector has the Gal4 activation domain and other required features.
  • a total of 1 x 10 6 transformants were obtained for both wild type and mutant MKK3 using the library DNA.
  • 5 x 10 4 and 5 x 10 5 colonies were obtained for the MKK3 wild type and mutant, respectively.
  • MKK3 and ten colonies were positive using the dominant interfering mutant bait. All positive colonies were recultured on selection plates. Upon sufficient growth of the yeast colony, DNA was isolated as described by Stratagene, La Jolla, CA. An aliquot was used to perform PCR with (a) MKK3 DNA specific primers to confirm the presence of the bait plasmid and (b) pAD vector specific primers bracketing the insert to confirm presence of the insert. All of the clones were positive for both plasmids. Another aliquot was used for transforming bacterial cells. Plasmid DNA was then isolated and sequenced.
  • MIP MKK3-interacting protein
  • This example demonstrates die isolation and cloning of the 5' end of the human MIP cDNA.
  • MIP MKK3 interacting protein
  • MIP is localized to chromosome 14. Chromosome localization of MIP was determined by performing PCR with MIP- specific primers on DNA from mouse human hybrids (BIOS Labs, New Haven, CT). The MIP gene was localized to chromosome 14.
  • This example demonstrates the molecular weight of MIP protein.
  • a flag epitope tagged MIP was constructed in a pCMV-flag vector (cytomegalovirus vector with a sequence coding the 8 amino acid flag polypeptide tag; Chubet and Brizzard,
  • MIP protein has a molecular weight of about 40 kD.
  • This example demonstrates the tissue-specific expression of MIP mRNA.
  • MIP mRNA was detected in a blot of poly A+ mRNA from various normal adult human tissues using a MIP cDNA probe.
  • a hybridization signal corresponding to a 2.0 kb mRNA was visualized in the brain (moderately strong), kidney (moderately strong), liver (moderate), lung (weak), pancreas (moderate), and spleen (very strong). No hybridization was detected in heart or striated muscle.
  • MIP mRNA is differentially expressed in adult human tissues.
  • pFLAG-MIP is a DNA plasmid that is transformed into DH5 ⁇ cells.
  • the vector contains an ampicillin marker, and the insert can be excised with EcoRl and Smal restriction enzymes.
  • the plasmid is 6130 base pairs, and the insert containing the coding region for MIP is 1053 base pairs.
  • a MIP fusion protein which comprises a first protein segment and a second protein segment fused to each other by means of a peptide bond, wherein the first protein segment consists of at least eight contiguous amino acids selected from the amino acid sequence shown in SEQ ID NO:l.
  • An isolated MIP polypeptide which consists of at least eight contiguous amino acids of a human MIP protein having the amino acid sequence shown in SEQ ID NO: 1.
  • the subgenomic polynucleotide of item 8 having the nucleotide sequence shown in SEQ ID NO:2. 10. The subgenomic polynucleotide of item 8 which is intron-free.
  • a method of determining the tissue source of a body sample of a human comprising the step of: assaying the body sample for the presence of a human MIP protein having the amino acid sequence shown in SEQ ID NO: 1 or a 2.0 MIP mRNA encoding said human MIP protein, the presence of said human MIP protein or said 2.0 kb MIP mRNA encoding said human MIP protein indicating that the body sample originates from a tissue selected from the group consisting of brain, kidney, liver, lung, pancreas, and spleen.

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Abstract

L'invention porte sur un nouveau gène humain codant une protéine appelée protéine d'interaction MKK3 (MIP) dont l'expression est propre à un tissu sélectionné dans un groupe comprenant le cerveau, les reins, le foie, le pancréas et la rate. La MIP, qui se fixe à un mutant interférant dominant de la MAPK kinase-3 (MKK3) peut jouer un rôle dans la transduction de signaux extracellulaires à l'intérieur du noyau, ce qui entraîne l'activation de la p38 kinase.
PCT/US1997/010866 1996-07-03 1997-07-02 Proteine d'interaction mkk3 (mip) WO1998000539A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43260/97A AU4326097A (en) 1996-07-03 1997-07-02 (mitogen-activated protein kinase) kinase-3 (mkk3) interacting protein (mip)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US2122496P 1996-07-03 1996-07-03
US60/021,224 1996-07-03
US2164196P 1996-07-12 1996-07-12
US60/021,641 1996-07-12
US88657297A 1997-07-01 1997-07-01
US08/886,572 1997-07-01

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WO1998000539A2 true WO1998000539A2 (fr) 1998-01-08
WO1998000539A3 WO1998000539A3 (fr) 1998-03-26

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029553A1 (fr) * 1996-12-26 1998-07-09 Incyte Pharmaceuticals, Inc. Nouvelle reductase de l'acide guanylique
WO1999053076A1 (fr) * 1998-04-14 1999-10-21 Board Of Regents, The University Of Texas System Proteine kinases tao et leurs methodes d'utilisation
US6372473B1 (en) 1997-05-28 2002-04-16 Human Genome Sciences, Inc. Tissue plasminogen activator-like protease
US6809199B2 (en) 2000-12-20 2004-10-26 Merck & Co., Inc. (Halo-benzo carbonyl)heterocyclo fused phenyl p38 kinase inhibiting agents

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
B. DÉRIJARD ET AL.: "Independent Human MAP kinase signal transduction pathways defined by MEK and MKK isoforms." SCIENCE, vol. 267, 3 February 1995, pages 682-685, XP002054336 cited in the application *
H. KANNO ET AL.: "Two structural genes on different chromosomes are required for encoding the major subunit of human cell glucose-6-phosphate dehydrogenase." CELL, vol. 58, 11 August 1989, pages 595-606, XP002054262 *
S. HENIKOFF ET AL.: "The human mRNA that provides the N-terminus of chimeric G6PD encodes GMP reductase." CELL, vol. 58, 22 September 1989, pages 1021-1022, XP002054263 *
T. KONDOH ET AL.: "Genomic structure and expression of human guanosine monophosphate reductase." HUMAN GENETICS, vol. 88, 1991, pages 219-224, XP002054264 *
Z. XIA ET AL.: "Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis." SCIENCE, vol. 270, 24 November 1995, pages 1326-1331, XP002054337 cited in the application *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029553A1 (fr) * 1996-12-26 1998-07-09 Incyte Pharmaceuticals, Inc. Nouvelle reductase de l'acide guanylique
US6372473B1 (en) 1997-05-28 2002-04-16 Human Genome Sciences, Inc. Tissue plasminogen activator-like protease
US6815534B2 (en) 1997-05-28 2004-11-09 Human Genome Sciences, Inc. Tissue plasminogen activator-like protease
US7205139B2 (en) 1997-05-28 2007-04-17 Human Genome Sciences, Inc. Tissue plasminogen activator-like protease
WO1999053076A1 (fr) * 1998-04-14 1999-10-21 Board Of Regents, The University Of Texas System Proteine kinases tao et leurs methodes d'utilisation
CN100374568C (zh) * 1998-04-14 2008-03-12 德克萨斯大学董事会 Tao蛋白激酶及其使用方法
US6809199B2 (en) 2000-12-20 2004-10-26 Merck & Co., Inc. (Halo-benzo carbonyl)heterocyclo fused phenyl p38 kinase inhibiting agents

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Publication number Publication date
AU4326097A (en) 1998-01-21
WO1998000539A3 (fr) 1998-03-26

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