An mRNA splice variant of the AFX gene with altered transcriptional activity.
Several studies indicate that FKHR and AFX, mammalian homologues of the Caenorhabditis elegans forkhead transcription factor DAF-16, function in the insulin signaling pathway. Here we describe the discovery of a novel AFX isoform, which we designated AFX zeta, in which the first 16 amino acids of the forkhead domain are not present. PCR analysis showed that this isoform is most abundant in the liver, kidney, and pancreas. In HepG2 cells, overexpressed AFX zeta induced reporter gene activity through the insulin-responsive sequences of the phosphoenolpyruvate carboxykinase (PEPCK), IGFBP-1, and G6Pase promoters. AFX zeta-mediated stimulation was repressed by insulin treatment, by bisperoxovanadate treatment, and by overexpression of constitutively active protein kinase B (PKB). Insulin treatment and PKB overexpression resulted in phosphorylation of AFX zeta. Furthermore, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR), an AMP-activated protein kinase activator, repressed AFX zeta-dependent reporter activation. Taken together, these findings suggest that AFX zeta is a downstream target of both the phosphatidylinositol 3-kinase/PKB insulin signaling pathway and an AMP-activated protein kinase-dependent pathway.
Yang
Zhenyu
Z
Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA.
Whelan
James
J
Babb
Robert
R
Bowen
Benjamin R
BR
D017398:Alternative Splicing; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors; D017930:Genes, Reporter; D006639:Histidine / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D014638:Vanadates / Q000494:pharmacology
D018797:Cell Cycle Proteins; D018076:DNA, Complementary; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D007328:Insulin; D009841:Oligonucleotides; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012265:Ribonucleotides; D014157:Transcription Factors; C069276:peroxovanadate; D000620:Aminoimidazole Carboxamide; D014638:Vanadates; D006639:Histidine; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C031143:AICA ribonucleotide