WO2004072110A1 - Procedes d'inhibition de la transduction de signaux - Google Patents

Procedes d'inhibition de la transduction de signaux Download PDF

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Publication number
WO2004072110A1
WO2004072110A1 PCT/AU2004/000191 AU2004000191W WO2004072110A1 WO 2004072110 A1 WO2004072110 A1 WO 2004072110A1 AU 2004000191 W AU2004000191 W AU 2004000191W WO 2004072110 A1 WO2004072110 A1 WO 2004072110A1
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WO
WIPO (PCT)
Prior art keywords
polypeptide
polynucleotide
sequence
seq
amino acid
Prior art date
Application number
PCT/AU2004/000191
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English (en)
Inventor
Christopher Martin Hovens
Nathan E. HALL
Peter LOCK
James Alexander John KING
Original Assignee
Ludwig Institute For Cancer Research
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 Ludwig Institute For Cancer Research filed Critical Ludwig Institute For Cancer Research
Publication of WO2004072110A1 publication Critical patent/WO2004072110A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity

Definitions

  • Ras/Raf/MAP kinase pathway The initial genetic studies in Drosophila placed the inhibition of mitogen-activated protein kinase (MAPK) upstream of Ras whilst in the context of wing development, inhibition of MAPK occurred downstream of
  • Yet a further aspect of the present invention provides an antagonist of a polypeptide of the present invention wherein the antagonist inhibits protein-protein interaction through the KBD of a polypeptide of the present invention.
  • Fig. 7 shows that SPRED1 and SPRED2 expression is brain restricted and induced by Ras/MAPK pathway activation.
  • A,B Northern blot analysis of SPRED1 and SPRED2 mRNA expression in rat tissues (A) and rat brain structures (B). 2 ⁇ g poly A+ RNA was isolated for each sample and loaded on the agarose gel. Northern blots were probed with the indicated human cDNA probes at low stringency. Predominant expression of both SPRED genes was observed in brain (A) then cerebral hemisphere, cerebellum and olfactory bulb (B).
  • Ethidium bromide (EthBr) staining of mRNA and glyceraldehyde-3- phosphate dehydrogenase (GAPDH) reprobing is depicted as a loading control. RNA size markers in kb are indicated.
  • C Western blot of SPRED1 and SPRED2 rat tissue protein expression.
  • SPRED3 is intended to include all forms of SPRED3, fragments of SPRED3, molecules having SPRED3 function and variants of SPRED3 resulting from alternate splicing of the primary transcript from the EVE3 gene.
  • SPRED3 function includes a function as described herein including but not limited to: inhibition of Ras/MAPK pathway, inhibition of c-Jun N-terminal kinase pathway, blocking cell cycle phase progression and preventing cell differentiation in response to growth factors.
  • SPRED3 and EVE3 are two distinct polypeptides encoded by the same gene (EVE3), with the larger SPRED3 polypeptide produced by translation of an alternatively spliced transcript.
  • SPRED3 shares a similar domain structure to SPREDs 1 and 2, but the KBD is only weakly conserved (28% identity).
  • EVE3, however, may include an N-terminal EVH1 domain and a unique C-terminal region encoded by exon 5, which possesses an in-frame stop codon.
  • EVE3 represents a new class of Ras/MAPK inhibitory protein.
  • bacteria employ an 11 amino acid C-terminal extension to direct degradation of incomplete polypeptides that result from ribosome stalling during translation.
  • the mechanism behind this process is unrelated to ubiquitiniation.
  • the bacterial sequence is highly hydrophobic and is recognised by a specific protease.
  • the present invention provides a first polypeptide sequence capable of destabilising a second polypeptide to which it is linked.
  • the sequence of the first polypeptide is at least 63%, 70%, 81% or 90%, identical to the 11 amino acids encoded by exon 5 of the EVE3 gene.
  • the first polypeptide sequence is LSQYFRHMLCP.
  • Yet another aspect of the present invention provides a method for identifying an agent capable of modulating the activity of a SPRED1 or SPRED2 polypeptide or a fragment or variant thereof.
  • the agent is an agonist or antagonist of the SPRED1 or SPRED2 polypeptide or fragment or variant thereof.
  • the method includes the steps of: (i) contacting the SPRED1 or SPRED2 polypeptide or fragment or variant thereof, with the agent under conditions permitting binding between the polypeptide and the agent; (ii) detecting specific binding of the agent to the polypeptide; and (iii) determining whether the agent binds to the polypeptide.
  • a further aspect of the present invention provides a method of using a SPRED3 or EVE3 polypeptide, or a fragment, variant, agonist or antagonist thereof, to modulate a cell function.
  • the cell function is cell proliferation and/or differentiation.
  • the cell function is signal transduction through the Ras/MAPK pathway.
  • a further aspect of the present invention provides a method of using a SPRED1 or SPRED2 polypeptide, or a fragment, variant, agonist or antagonist thereof, to modulate a cell function.
  • the cell function is cell proliferation and/or differentiation.
  • the cell function is signal transduction through the Ras/MAPK pathway.
  • Yet a further aspect of the present invention provides an antagonist of a polypeptide of the present invention wherein the antagonist inhibits protein-protein interaction through the KBD of a polypeptide of the present invention.
  • the surprising differential effects of SPRED3 and EVE3 on PDGF signal transduction imply a possible role in the regulation of fibrosis, angiogenesis, and sclerosis which suggests an important role in cell growth and differentiation, especially in association with conditions including, but not limited to, cancer and cirrhosis.
  • polypeptides of the present invention may be synthinated which directs expression of polypeptides or fragments thereof. These polypeptides or fragments may further include specific epitopes which facilitate purification. Polypeptides and fragments may also be synthesised by commercially available peptide synthesisers. This method is particularly useful for the generation of small peptides.
  • antibodies includes, but is not limited to, polyclonal antibodies, monoclonal antibodies (mAbs), phage display “antibodies”, chimeric antibodies, human antibodies, “humanised” antibodies, single chain antibodies, Fab fragments, F(ab')2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, domain antibodies, epitope-binding fragments of any of the above, and any other molecule that specifically binds a polypeptide of the present invention.
  • mAbs monoclonal antibodies
  • phage display “antibodies” chimeric antibodies
  • human antibodies “humanised” antibodies
  • single chain antibodies single chain antibodies
  • Fab fragments fragments
  • F(ab')2 fragments fragments produced by a Fab expression library
  • anti-Id anti-idiotypic antibodies
  • domain antibodies epitope-binding fragments of any of the above, and any other molecule that specifically binds a polypeptide of the present invention.
  • Example 3 EVE3 and SPRED3 polypeptides block Ras/MAPK signalling

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Toxicology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

L'invention concerne des polynucléotides codant un polypeptide SPRED ou un polypeptide EVE. L'invention concerne également des polypeptides codés par lesdits polynucléotides, de même que des anticorps desdits polypeptides et des antagonistes et des agonistes de la fonction peptidique.
PCT/AU2004/000191 2003-02-17 2004-02-17 Procedes d'inhibition de la transduction de signaux WO2004072110A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2003901055 2003-02-17
AU2003901055A AU2003901055A0 (en) 2003-02-17 2003-02-17 Methods for inhibiting signal transduction

Publications (1)

Publication Number Publication Date
WO2004072110A1 true WO2004072110A1 (fr) 2004-08-26

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Application Number Title Priority Date Filing Date
PCT/AU2004/000191 WO2004072110A1 (fr) 2003-02-17 2004-02-17 Procedes d'inhibition de la transduction de signaux

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AU (1) AU2003901055A0 (fr)
WO (1) WO2004072110A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114045335B (zh) * 2021-11-16 2023-05-02 四川大学华西医院 circSpred1基因作为标志物在纤维化肝脏、肝癌的诊断和药物制备中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002031111A2 (fr) * 2000-10-12 2002-04-18 Hyseq, Inc. Acides nucleiques et polypeptides
WO2002070539A2 (fr) * 2001-03-05 2002-09-12 Hyseq, Inc. Nouveaux acides nucleiques et polypeptides
EP1293569A2 (fr) * 2001-09-14 2003-03-19 Helix Research Institute Clones d'ADNc complets
JP2003219889A (ja) * 2002-02-01 2003-08-05 Akihiko Yoshimura 新規ｍａｐキナーゼ活性抑制因子
WO2003072723A2 (fr) * 2002-02-22 2003-09-04 Incyte Corporation Molecules de signalisation intracellulaire

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002031111A2 (fr) * 2000-10-12 2002-04-18 Hyseq, Inc. Acides nucleiques et polypeptides
WO2002070539A2 (fr) * 2001-03-05 2002-09-12 Hyseq, Inc. Nouveaux acides nucleiques et polypeptides
EP1293569A2 (fr) * 2001-09-14 2003-03-19 Helix Research Institute Clones d'ADNc complets
JP2003219889A (ja) * 2002-02-01 2003-08-05 Akihiko Yoshimura 新規ｍａｐキナーゼ活性抑制因子
WO2003072723A2 (fr) * 2002-02-22 2003-09-04 Incyte Corporation Molecules de signalisation intracellulaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WAKIOKA ET AL.: "Spred is a sprouty-related supressor of Ras signalling", NATURE, vol. 412, 2001, pages 647 - 651, XP002980582, DOI: doi:10.1038/35088082 *

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