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.

ABSTRACT

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.