Mnk kinase homologous proteins involved in the regulation of energy homeostasis and organelle metabolism

Abstract

The present invention discloses Mnk homologous proteins regulating the energy homeostasis, the metabolism of triglycerides, and/or is contributing to membrane stability and/or function of organelles, and polynucleotides, which identify and encode the proteins disclosed in this invention. The invention also relates to the use of these sequences in the diagnosis, study, prevention, and treatment of diseases and disorders related to body-weight regulation and thermogenesis, for example, but not limited to, metabolic diseases such as obesity, as well as related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, osteoarthritis, gallstones, and sleep apnea, and disorders related to ROS defence, such as diabetes mellitus, neurodegenerative disorders, and cancer, e.g. cancers of the reproductive organs, and others.

1 . A pharmaceutical composition comprising a nucleic acid molecule of the MAP kinase interacting kinase (Mnk) gene family or a polypeptide encoded thereby or a fragment or a variant of said nucleic acid molecule or said polypeptide or an antibody, an aptamer or another receptor recognizing a nucleic acid molecule of the Mnk gene family or a polypeptide encoded thereby together with pharmaceutically acceptable carriers, diluents and/or adjuvants.  
     
     
         2 . The composition of  claim 1 , wherein the nucleic acid molecule is a vertebrate or insect Mnk nucleic acid, particularly a human Mnk homologous nucleic acid, particularly a nucleic acid encoding a Mnk homologous nucleic acid encloding a Mnk homologous gene on human chromosome 19 (Mnk2)(Genbank Accession No. XM — 030637, identical to Genbank Accession No. AF237775.1, and or/Genbank Accession Number NM — 017572.1) or a human Mnk protein on chromosome 1 (Mnk1) (Genbank Accession No. XM — 001600, identical to Genbank Accession No. AB00409.1, and/or Genbank Accession Number NM, 003684.2) or a fragment thereof or a variant thereof.  
     
     
         3 . The composition of  claim 1  or2, wherein said nucleic acid molecule 
 (a) hybridizes at 50° C. in a solution containing 1×SSG and 0.1% SDS to a Mnk nucleic acid or the complementary strand thereof, particularly a nucleic acid molecule encoding the amino acid sequences shown in  FIG. 3 ;    (b) it is degenerate with respect to the nucleic acid molecule of (a)    (c) encodes a polypeptide which is at least 85%, preferably at least 90%, more preferably at least 95%, more preferably at least 98% and up to 99,6% identical to polypeptides shown in  FIG. 3 ;    (d) differs from the nucleic acid molecule of (a) to (c) by mutation and wherein said mutation causes an alteration, deletion, duplication or premature stop in the encoded polypeptide.    
     
     
         4 . The composition of  claim 1 , wherein the nucleic acid molecule is a DNA molecule, particularly a cDNA or a genomic DNA.  
     
     
         5 . The composition of  claim 1 , wherein said nucleic acid encodes a polypeptide contributing to regulating the energy homeostasis and/or the metabolism of triglycerides and/or to membrane stability and/or function in organelles such as mitochondria.  
     
     
         6 . The composition of  claim 1 , wherein said nucleic acid molecule is a recombinant nucleic acid molecule.  
     
     
         7 . The composition of  claim 1 , wherein the nucleic acid molecule is a vector, particularly an expression vector.  
     
     
         8 . The composition of  claim 1 , wherein the polypeptide is a recombinant polypeptide.  
     
     
         9 . The composition of  claim 8 , wherein said recombinant polypeptide is a fusion polypeptide.  
     
     
         10 . The composition of  claim 1 , wherein said nucleic acid molecule is selected from hybridization probes, primers and anti-sense oligonucleotides.  
     
     
         11 . The composition of  claim 1  which is a diagnostic composition.  
     
     
         12 . The composition of  claim 1  which is a pharmaceutical composition.  
     
     
         13 . The composition of  claim 1  for the manufacture of an agent for detecting and/or verifying, for the treatment, alleviation and/or prevention of diseases and disorders related to body-weight regulation and thermogenesis, for example, but not limited to, metabolic diseases such as obesity, as well as related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, osteoarthritis, gallstones, and sleep apnea, and disorders related to ROS defence, such as diabetes mellitus, neurodegenerative disorders, and cancer, e.g, cancers of the reproductive organs, and others, in cells, cell masses, organs and/or subjects.  
     
     
         14 . Use of a nucleic acid molecule of the Mnk gene family or a polynucleotide encoded thereby or a fragment or a variant of said nucleic acid molecule or said polypeptide or an antibody, an aptamer or another receptor recognizing a nucleic acid molecule of the Mnk gene family or a polypeptide encoded thereby for controlling the function of a gene and/or a gene product which is influenced and/or modified by an Mnk homologous polypeptide.  
     
     
         15 . Use of the nucleic acid molecule of the Mnk gene family or a polynucleotide encoded thereby or a fragment or a variant of said I nucleic acid molecule or said polypeptide or an antibody, an aptamer or another receptor recognizing a nucleic acid molecule of the Mnk gene family or a polypeptide encoded thereby for identifying substances capable of interacting with an Mnk homologous polypeptide.  
     
     
         16 . A non-human transgenic animal exhibiting a modified expression of an Mnk homologous polypeptide.  
     
     
         17 . The animal of  claim 16 , wherein the expression of the Mnk homologous polypeptide is increased and/or reduced.  
     
     
         18 . A recombinant host cell exhibiting a modified expression of an Mnk I homologous polypeptide.  
     
     
         19 . The cell of  claim 18  which is a human cell.  
     
     
         20 . A method of identifying a (poly)peptide involved in the regulation of energy homeostasis and/or metabolism of triglycerides in a mammal comprising the steps of 
 (a) contacting a collection of (poly)peptides with an Mnk homologous polypeptide or a fragment thereof under conditions that allow binding of said (poly)peptides;    (b) removing (poly)peptides which do not bind and    (c) identifying (poly)peptides that bind to said Mnk homologous polypeptide.    
     
     
         21 . A method of screening for an agent which modulates the interaction of an Mnk homologous polypeptide with a binding target/agent, comprising the steps of 
 (a) incubating a mixture comprising 
 (aa) an Mnk homologous polypeptide, or a fragment thereof;  
 (ab) a binding target/agent of said Mnk homologous polypeptide or fragment thereof; and  
 (ac) a candidate agent  
 under conditions whereby said Mnk polypeptide or fragment thereof specifically binds to said binding target/agent at reference affinity;  
   (b) detecting the binding affinity of said Mnk polypeptide or fragment thereof to said binding target to determine an (candidate) agent-based affinity; and    (c) determining a difference between (candidate) agent-biased affinity and the reference affinity.    
     
     
         22 . A method of screening for an agent which modulates the activity of an Mnk homologous polypeptide, comprising the steps of 
 (a) incubating a mixture comprising 
 (aa) an Mnk homologous polypeptide, or a fragment thereof;  
 (ab) a candidate agent,  
 under conditions whereby said Mnk polypeptide or fragment thereof exhibits a reference activity;  
   (b) detecting the activity of said Mnk polypeptide or fragment thereof to determine an (candidate) agent-biased activity, and    (c) determining a difference between a (candidate) agent-biased activity and the reference activity.    
     
     
         23 . The method of  claim 21 , wherein the candidate agent is selected from peptides and low-molecular weight organic compounds.  
     
     
         24 . The method of  claim 20  wherein a known Mnk effector is used as a positive control for assay development and/or validation of candidate agents.  
     
     
         25 . A method of producing a composition comprising mixing the (poly)peptide identified by the method of  claim 20  with a pharmaceutically acceptable carrier, diluent and/or adjuvant.  
     
     
         26 . The method of  claim 25  wherein said composition is a pharmaceutical composition for preventing, alleviating or treating diseases and disorders related to body-weight regulation and thermogenesis, for example, but not limited to, metabolic diseases such as obesity, as well as related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, osteoarthritis, gallstones, and sleep apnea, and disorders related to ROS defence, such as diabetes mellitus, neurodegenerative disorders, and cancer, e.g. cancers of the reproductive organs, and others, in cells, cell masses, organs and/or subjects.  
     
     
         27 . Use of a polypeptide as identified by the method of  claim 20  for the preparation of a pharmaceutical composition for the treatment, alleviation and/or prevention of diseases and disorders related to body-weight regulation and thermogenesis, for example, but not limited to, metabolic diseases such as obesity, as well as related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, osteoarthritis, gallstones, and sleep apnea, and disorders related to ROS defence, such as diabetes mellitus, neurodegenerative disorders, and cancer, e.g. cancers of the reproductive organs, and others, in cells, cell masses, organs and/or subjects.  
     
     
         28 . Use of a nucleic acid molecule of the Mnk family or of a fragment thereof for the preparation of a non-human animal which over or under-expresses the Mnk gene product.  
     
     
         29 . Kit comprising at least one of 
 (a) an Mnk nucleic acid molecule or a fragment thereof;    (b) a vector comprising the nucleic acid of (a);    (c) a host cell comprising the nucleic acid of (a) or the vector of    (d) a polypeptide encoded by the nucleic acid of (a);    (e) a fusion polypeptide encoded by the nucleic acid of (a)    (f) an antibody, an aptamer or another receptor against the nucleic acid of (a) or the polypeptide of (d) or (e) and    (g) an anti-sense oligonucleotide of the nucleic acid of (a).    
     
     
         30 . Use of an effector of an Mnk polypeptide for the manufacture of an agent for the prophylaxis, treatment or diagnosis of diseases and disorders related to body-weight regulation and thermogenesis, for example, but not limited to, metabolic diseases such as obesity, as well as related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, osteoarthritis, gallstones, and sleep ) apnea, and disorders related to ROS defence, such as diabetes mellitus, neurodegenerative disorders, and cancer, e.g. cancers of the reproductive organs.  
     
     
         31 . The use of  claim 30 , wherein the effector is of an Mnk2 or Mnk1 polypeptide.  
     
     
         32 . The use of  claim 30  wherein the effector is selected from staurosporine or pyrazole derivatives.  
     
     
         33 . The use of  claim 30  wherein the effector is CGP57380 or a derivative thereof.