Sequence homology shared by neurofibromatosis type-1 gene and IRA-1 and IRA-2 negative regulators of the RAS cyclic AMP pathway.
Neurofibromatosis type-1 (NF-1) is one of the most frequently inherited genetic disorders affecting humans. NF-1 primarily affects cells of neural crest origin and is characterized by patches of skin pigmentation (café-au-lait spots) and neurofibromas. Cloning of the human NF-1 gene shows that it encodes an 11-13 kilobase transcript that is frequently disrupted in NF-1 patients. The frequent disruption of the NF-1 gene in NF-1 patients combined with the autosomal dominant mode of inheritance of NF-1 strongly suggest that the NF-1 gene is a tumour-suppressor gene. We have now sequenced a portion of the murine NF-1 gene and show that the predicted amino-acid sequence is nearly the same as the corresponding region of the human NF-1 gene product. Northern blotting identified mouse NF-1 transcripts that are equivalent in size and complexity to those in human tissues, and Southern blotting shows that this region of the NF-1 gene is evolutionarily well conserved. Finally, computer searches identified homology between the mouse NF-1 gene and IRA-1 and IRA-2, two genes identified in Saccharomyces cerevisiae that negatively regulate the RAS-cyclic AMP pathway. These findings provide important new insights into the possible function of the NF-1 gene.
Buchberg
A M
AM
ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702.
Cleveland
L S
LS
Jenkins
N A
NA
Copeland
N G
NG
D000262:Adenylyl Cyclases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D000242:Cyclic AMP / Q000096:biosynthesis*; D005656:Fungal Proteins / Q000235:genetics*; D020690:GTPase-Activating Proteins; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009456:Neurofibromatosis 1 / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012097:Repressor Proteins; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D012689:Sequence Homology, Nucleic Acid; D013489:Suppression, Genetic; D020703:ras GTPase-Activating Proteins
D005656:Fungal Proteins; D020690:GTPase-Activating Proteins; C065725:IRA1 protein, S cerevisiae; C064960:IRA2 protein, S cerevisiae; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D020703:ras GTPase-Activating Proteins; D000242:Cyclic AMP; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000262:Adenylyl Cyclases