Protein biosynthesis is fundamentally critical to the full expression of any gene. A rate-limiting enzyme for the initiation of protein biosynthesis is the Eukaryotic Initiation Factor Two (eIF2). This protein consists of three subunits (eIF2-alpha, eIF2-beta and eIF2- gamma). The transcription factor, alpha-Pal, apparently coordinates the basal transcription of these housekeeping genes to ensure adequate levels of the mRNAs. One expects its regulation to be linked to those of major physiological pathways which rely on efficient synthesis of needed proteins. Alpha-Pal appears to link the transcription of key metabolic genes to cellular growth and development; processes which rely on timely and efficient synthesis of needed proteins. In support of this, we observe that: 1) Potential targets for alpha-Pal, are genes involved in cellular proliferation, or the growth-responsive metabolic pathways, energy transduction, translation and DNA replication/repair; suggesting that alpha-Pal functions to modulate the transcription of metabolic genes required for cellular growth. 2) Both the protein sequence and the DNA-recognition site of alpha-Pal, are strongly homologous to those of two evolutionarily-distant developmental transcription factors; sea Urchins P3A2 and Drosophilas ewg. This suggests that alpha-Pal transcriptionally regulates developmental functions during human embryogenesis, possibly growth. A regulatory link between a cells translation and cycle pathways may point to mechanisms for efficient expression of genes in response to the cells metabolic and growth status. Understanding such mechanisms may facilitate the development of technologies for efficient expression of transgenes in vivo. To determine if alpha-Pal can mediate a coordinated regulation of protein synthesis, growth and the cell cycle, we studied the effects of its overexpression on cellular translation, growth and division cycle activities. Overexpression of alpha-Pal increased both protein synthesis and growth, but retarded cell cycle progression. The molecular bases for these effects are as follows. 1) Overexpression of alpha-Pal led to an increase in a modified species of alpha-Pal that preferentially bound to sites on eIF2-alpha gene promoter and upregulated transcription, leading to the upregulation of cellular protein content and growth. 2) Overexpression of alpha-Pal also led to an increase in a putative unmodified alpha-Pal species that bound to a unique site on E2F-1 gene promoter and downregulated transcription, leading to a retarded cell proliferation (E2F-1 is a transcription factor that regulates cell cycle S-phase transition). These are evidence that alpha-Pal is a molecular link for coordinated regulation of cellular global protein synthesis, growth and division cycle.
