Transcriptional Autoregulation and Inhibition of mRNA Translation of Amino Acid Regulator GenecpcAof Filamentous FungusAspergillus nidulans

Abstract

The CPCA protein of the filamentous fungus Aspergillus nidulans is a member of the c-Jun-like transcriptional activator family. It acts as central transcription factor of the cross-pathway regulatory network of amino acid biosynthesis and is functionally exchangeable for the general control transcriptional activator Gcn4p of Saccharomyces cerevisiae. In contrast to GCN4, expression of cpcA is strongly regulated by two equally important mechanisms with additive effects that lead to a fivefold increased CPCA protein amount under amino acid starvation conditions. One component of cpcA regulation involves a transcriptional autoregulatory mechanism via a CPCA recognition element (CPRE) in the cpcA promoter that causes a sevenfold increased cpcA mRNA level when cells are starved for amino acids. Point mutations in the CPRE cause a constitutively low mRNA level of cpcA and a halved protein level when amino acids are limited. Moreover, two upstream open reading frames (uORFs) in the 5Ј region of the cpcA mRNA are important for a translational regulatory mechanism. Destruction of both short uORFs results in a sixfold increased CPCA protein level under nonstarvation conditions and a 10-fold increase under starvation conditions. Mutations in both the CPRE and uORF regulatory elements lead to an intermediate effect, with a low cpcA mRNA level but a threefold increased CPCA protein level independent of amino acid availability. These data argue for a combined regulation of cpcA that includes a translational regulation like that of yeast GCN4 as well as a transcriptional regulation like that of the mammalian jun and fos genes.

Cross-Species Hybridization with Fusarium verticillioides Microarrays Reveals New Insights into Fusarium fujikuroi Nitrogen Regulation and the Role of AreA and NMR

“…Many of these genes are well-known target genes of a complex transcriptional system, referred to as the CPC network, which enables yeast cells and filamentous fungi to respond to amino acid starvation (28,43,50). In general, starvation for a single amino acid results in specific uncharged tRNAs activating the sensor kinase Cpc3 followed by activation of the central transcriptional activator Cpc1, which induces genes involved in the biosynthesis of amino acids, purines, or aminoacyl-tRNA synthetases among others (reviewed in reference 33).…”

Recognition of a Novel Stage of Betaherpesvirus Latency in Human Herpesvirus 6

“…1), were considered to be translated into the IE1 protein at this novel, intermediate stage. For some mRNAs that have small uORFs that restrict the translation of the downstream ORFs, it has been reported that modulation of both translational regulation and the mRNA level is important for release from the uORF control (14,28). An alteration in the regulation of translation as well as the increase of the H6LTs might have contributed to the increased IE1 protein expression (Table 2).…”

Evolution of 3-deoxy- d - arabino -heptulosonate-7-phosphate synthase-encoding genes in the yeast Saccharomyces cerevisiae

“…In addition to the feedback control of yeast Aro3p and Aro4p, the transcription of the corresponding genes is part of a complex regulatory network that couples transcriptional derepression of Ͼ500 genes to the availability of amino acids (22). This regulatory network is conserved between several fungi and is known as ''cross-pathway control'' in molds or as ''general control'' of amino acid biosynthesis in yeast (23)(24)(25). A key factor is the transcriptional activator Gcn4p of yeast and its interchangeable counterparts including, e.g., CPCA of A. nidulans (24).…”

“…This regulatory network is conserved between several fungi and is known as ''cross-pathway control'' in molds or as ''general control'' of amino acid biosynthesis in yeast (23)(24)(25). A key factor is the transcriptional activator Gcn4p of yeast and its interchangeable counterparts including, e.g., CPCA of A. nidulans (24). Gcn4p binds to the promoter region of target genes to a well characterized upstream activation site.…”