Transcriptional regulation of E2F-1 and eIF-2 genes by alpha-pal: a potential mechanism for coordinated regulation of protein synthesis, growth, and the cell cycle.
alpha-Pal regulates the basal transcription of the alpha and beta subunits of eukaryotic initiation factor two (eIF-2), a rate-limiting enzyme for the initiation of protein biosynthesis. We recently showed that its global function may be to modulate the expression of key metabolic genes in response to cellular proliferation. In this paper, we examined a potential molecular mechanism by which alpha-Pal may achieve this function. When overexpressed, alpha-Pal upregulated protein synthesis and growth, but downregulated the cell cycle. The mechanism for the increased protein synthesis and growth appeared to be a transcriptional upregulation of the eIF-2alpha and eIF-2beta genes. The mechanism for the cell cycle downregulation appeared to be a transcriptional downregulation of E2F-1, a transcription factor that regulates genes required for cell cycle progression beyond the G1/S interphase. Specifically, an apparently modified species of alpha-Pal bound to the eIF-2 promoters and induced transcriptional upregulation, whereas, an apparently unmodified species of the alpha-Pal bound to the E2F-1 promoter and induced transcriptional downregulation. By this mechanism, alpha-Pal may participate in coordinating the regulation of global protein synthesis, growth and the cell cycle; a regulation that is essential to cellular differentiation.
Efiok
B J
BJ
Laboratory of Molecular Hematology, Section on Protein and RNA Biosynthesis, NHLBI, National Institutes of Health, Bethesda, MD 20892, USA. efiokb@gwgate.nhlbi.nih.gov
Safer
B
B
D002352:Carrier Proteins; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051266:Nuclear Respiratory Factor 1; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D015852:Eukaryotic Initiation Factor-2; D051266:Nuclear Respiratory Factor 1; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; C088388:alpha-Pal transcription factor