Mammalian grainyhead transcription factors

Abstract

The present invention relates generally to diagnostic and therapeutic agents. More particularly, the present invention provides mammalian transcription factors which function in the modulation of expression of genetic sequences. The present invention further provides nucleic acid molecules encoding the transcription factors as well as nucleic acid and/or proteinaceous molecules with which the transcription factors interact. The transcription factors of the present invention or molecules interacting with same may be used inter alia in the generation of a range of diagnostic and therapeutic agents for a range of conditions.

1 . An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a mammalian transcription factor comprising an amino acid sequence having at least 75% identity to SEQ ID NO:8 (human SOM) or SEQ ID NO: 16 (murine SOM) after optimal alignment. 
     
     
         2 . The isolated nucleic acid molecule of  claim 1  wherein the molecule has a nucleotide sequence selected from the group consisting of: SEQ ID NO: 7 (human som), SEQ ID NO: 15 (murine som), and a nucleotide sequence capable of hybridizing to SEQ ID NO: 7, SEQ ID NO:15 or a complementary form of any of the foregoing under high stringency conditions (0.1×SSC, 0.1% w/v SDS at 65° C.). 
     
     
         3 . The isolated nucleic acid molecule of  claim 1  encoding a polypeptide comprising an amino acid sequence selected from SEQ ID NO: 8 or SEQ ID NO: 16. 
     
     
         4 . The isolated nucleic acid molecule of  claim 1  comprising a nucleotide sequence selected from SEQ ID NO: 7 and SEQ ID NO: 15. 
     
     
         5 . The isolated nucleic acid molecule of  claim 1  comprising the nucleotide sequence set forth in SEQ ID NO: 7. 
     
     
         6 . The isolated nucleic acid molecule of  claim 1  comprising the nucleotide sequence set forth in SEQ ID NO: 15. 
     
     
         7 . A pharmaceutical composition for the treatment of a genetic or physiological disorder, comprising: an isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a mammalian homolog of  Drosophila  grh wherein the nucleic acid molecule encodes a transcription factor selected from the group consisting of: human SEQ ID NO: 2 (MGR p49), SEQ ID NO: 4 (human MGR p70), SEQ ID NO: 6 (human BOM), SEQ ID NO: 7 (human SOM), SEQ ID NO: 10 (murine MGR p61), SEQ ID NO: 12 (murine MGR p70), SEQ ID NO: 14 (murine BOM) and SEQ ID NO: 16) murine SOM), a transcription factor having at least 65% identity to SEQ ID NO: 2, a transcription factor having at least 65% identity to SEQ ID NO: 4, a transcription factor having at least 65% identity to SEQ ID NO: 6, a transcription factor having at least 65% identity to SEQ ID NO: 7, a transcription factor having at least 65% identity to SEQ ID NO: 10, a transcription factor having at least 65% identity to SEQ ID NO: 12, a transcription factor having at least 65% identity to SEQ ID NO: 14, and a transcription factor having at least 65% identity to SEQ ID NO: 16 after optimal alignment in an amount effective to treat said genetic or physiological disorder. 
     
     
         8 . The pharmaceutical composition of  claim 7  wherein the mammalian homolog comprises a nucleotide sequence having at least 75% identity after optimal alignment to one or more of the sequences selected from the group consisting of: SEQ ID NO: 17, SEQ ID NO: 34, SEQ ID NO: 36 and SEQ ID NO: 38 or comprises a nucleotide sequence capable of hybridizing to a sequence selected from the group consisting of: SEQ ID NO: 17, SEQ ID NO: 34, SEQ ID NO: 36 SEQ ID NO: 38, and a complementary form thereof under stringent conditions. 
     
     
         9 . The pharmaceutical composition of  claim 7  wherein the nucleic acid molecule comprises a sequence of nucleotides encoding a polypeptide having transcription factor activity and comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14 and SEQ ID NO: 16. 
     
     
         10 . The pharmaceutical composition of  claim 7  wherein the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13 and SEQ ID NO: 15. 
     
     
         11 . A method of identifying a nucleotide sequence likely to encode a M-GRH transcription factor, said method comprising:
 interrogating a mammalian genome database conceptually translated into different reading frames with an amino acid sequence defining  Drosophila  GRH or any one of the sequences selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14 AND SEQ ID NO: 16; and   identifying a nucleotide sequence corresponding to an amino acid sequence having at least about 70% similarity to  Drosophila  GRH or to any one of the sequences selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12 SEQ ID NO: 14 and SEQ ID NO: 16; and   determining that the nucleotide sequence exhibits a restricted pattern of expression.   
     
     
         12 . A method for treating spinabifida or other physiological or genetic disorders in a patient, comprising administering to said patient an isolated mammalian transcription factor which is a homolog of Drosophilia grainyhead (GRH) selected from the group consisting of: human SEQ ID NO: 2 (MGR p49), SEQ ID NO: 4 (human MGR p70), SEQ ID NO: 6 (human BOM), SEQ ID NO: 8 (human SOM), SEQ ID NO: 10 (murine MGR p61), SEQ ID NO: 12 (murine MGR p70), SEQ ID NO: 14 (murine BOM) and SEQ ID NO:16 (murine SOM), a molecule having at least 75% identity to SEQ ID NO: 2, a molecule having at least 75% identity to SEQ ID NO: 4, a molecule having at least 75% identity to SEQ ID NO: 6, a molecule having at least 75% identity to SEQ ID NO: 8, a molecule having at least 75% identity to SEQ ID NO: 10, a molecule having at least 75% identity to SEQ ID NO: 12, a molecule having at least 75% identity to SEQ ID NO: 14, and a molecule having at least 75% identity to SEQ ID NO: 16 after optimal alignment in an amount effective for the treatment of spinabifida or other physiological or genetic disorder. 
     
     
         13 . A method for detecting an embryo with a propensity to develop spinabifida said method comprising: contacting said embryo or a cell therefor with agents capable of detecting the level of expression of a transcription factor selected from the group consisting of: human SEQ ID NO: 2 (MGR p49), SEQ ID NO: 4 (human MGR p70), SEQ ID NO: 6 (human BOM), SEQ ID NO: 8 (human SOM), SEQ ID NO: 10 (murine MGR p61), SEQ ID NO: 12 (murine MGR p70), SEQ ID NO: 14 (murine BOM) and SEQ ID NO: 16 (murine SOM), a molecule having at least 75% identity to SEQ ID NO: 2, a molecule having at least 75% identity to SEQ ID NO: 4, a molecule having at least 75% identity to SEQ ID NO: 6, a molecule having at least 75% identity to SEQ ID NO: 8, a molecule having at least 75% identity to SEQ ID NO: 10, a molecule having at least 75% identity to SEQ ID NO: 12, a molecule having at least 75% identity to SEQ ID NO: 14, and a molecule having at least 75% identity to SEQ ID NO: 16 after optimal alignment. 
     
     
         14 . An animal model comprising a genetically modified animal comprising a nucleotide insertion, deletion, addition and/or substitution in a nucleic acid molecule comprising a nucleotide sequence having at least 75% identity after optimal alignment to one or more of the polynucleotides selected from the group consisting of: SEQ ID NO: 7 (human som), SEQ ID NO: 15 (murine som), a nucleotide sequence capable of hybridizing to SEQ ID NO: 7 a nucleotide sequence capable of hybridizing to SEQ ID NO:15, and a complementary form thereof under stringent conditions. 
     
     
         15 . A medical assessment system comprising the animal model of  claim 14 . 
     
     
         16 . The pharmaceutical composition of  claim 7 , wherein said genetic disorder is spinabifida. 
     
     
         17 . An isolated polypeptide comprising an amino acid sequence having at least 60% identity to SEQ ID NO:8 (human SOM) or SEQ ID NO:16 (murine SOM) after optimal alignment. 
     
     
         18 . The isolated polypeptide of  claim 17  comprising SEQ ID NO:8 or SEQ ID NO:16. 
     
     
         19 . The isolated polypeptide of  claim 17 , wherein said polypeptide has a nucleotide sequence selected from the group consisting of: SEQ ID NO:7 (human SOM), SEQ ID NO:15 (murine SOM), and a nucleotide sequence capable of hybridizing to SEQ ID NO:7, SEQ ID NO:15 or a complementary form of any of the foregoing under high stringency conditions (0.1×SSC, 0.1% w/v SDS at 65° C.). 
     
     
         20 . A pharmaceutical composition for the treatment of a patient with a genetic or physiological disorder, comprising the isolated polypeptide of  claim 17  and a pharmaceutically acceptable carrier and/or diluent. 
     
     
         21 . A method for treating spinabifida or other physiological or genetic disorders in a patient, comprising administering to said patient the isolated polypeptide of  claim 17  in an amount effective for the treatment of said disorder.