Disease relevance of CPA1

• The protein sequence data provide strong evidence that the carbamyl phosphate synthetase I gene of rat, the carAB gene of E. coli, and the CPA1 and CPA2 genes of yeast were derived from common ancestral genes [1].

High impact information on CPA1

• Conversely, a uORF-containing mRNA that lacks an STE, such as CPA1, is degraded by the NMD pathway [2].
• The expression of gene CPA1, encoding the glutaminase subunit of the arginine pathway carbamoyl-phosphate synthetase, is repressed by arginine at a posttranscriptional level [3].
• The 5' region of CPA1 mRNA contains a 25 codon upstream open reading frame [3].
• Negative translational regulation of CPA1 occurs when the nascent AAP responds to arginine (Arg) by stalling ribosomes at the uORF termination codon [4].
• The Saccharomyces cerevisiae GCN4 mRNA 5'-leader contains four upstream open reading frames (uORFs) and the CPA1 leader contains a single uORF [5].

Biological context of CPA1

• In strains overproducing GCN4 protein, the translational control completely overrode transcriptional activation of CPA1 by general amino acid control [6].
• The observed increase was GCN4 dependent and was genetically separable from arginine-specific repression of CPA1 mRNA translation [6].
• The nucleotide sequence of a 2.2-kilobase region of the DNA insert carrying the CPA1 gene has been determined [7].
• The yeast gene CPA1 coding for the small subunit of arginine-specific carbamyl phosphate synthetase has been cloned by complementation of a cpa 1 mutant with a plasmid library of total yeast chromosomal DNA [7].
• An important new finding illustrated by ARG1 and CPA1, is that contrary to what all the previous data suggested, repression can be mediated by ARC elements located far upstream of the TATA-box [8].

Anatomical context of CPA1

• In contrast, for mRNA containing the CPA1 uORF, ribosomes reached the downstream start codon by scanning past the uORF [5].

Associations of CPA1 with chemical compounds

• Arginine deprivation imposed by PALO also caused increased expression of CPA1 and CPA2, coding respectively for the small and large subunits of arginine-specific carbamyl-phosphate synthetase [6].
• Although differences exist in AAP sequence, there were three absolutely conserved amino acid residues in the predicted peptide, including an aspartic acid crucial for arginine-dependent regulation of arg-2 and CPA1 [9].
• Finally, we have found that the CPS-A antiserum also cross-reacts with carbamoyl-phosphate synthetases from bacteria, yeast, and mammals [10].

Physical interactions of CPA1

• Our results indicate that the NMD destabilizes the 5' end of the CPA1 message and this decay is strongly enhanced when arginine is present in the growth medium [11].

Other interactions of CPA1

• For 53 genes, including GCN4, CPA1, and ICY2, three genes for which translational control is known to play a key role in regulation, most mRNA molecules were associated with a single ribosome [12].
• Similarly, the behavior of fusions of the leader sequence of CPA1 with those of ARG4 or GAL10 confirmed that the regions of this leader located upstream and downstream from the uORF are dispensable for the regulation by arginine [13].
• Two of these correspond to previously known genes (CPA1, SLY41), whereas 15 correspond to new genes [14].
• A similar analysis of expression of the gene CPA1, for which a translational regulation by arginine has been clearly demonstrated (M. Werner, A. Feller, F. Messenguy, and A. Piérard, Cell 49:805-813, 1987), indicates that this gene is also partly regulated at the transcriptional level by the ARGR repressor system [15].
• The MIP1 gene was cloned by genetic complementation of the mip1-1 allele after cell transformation with a yeast genomic library and was mapped to the right arm of chromosome XV about 20 centimorgans distal to the cpa1 gene by Southern blot hybridization and tetrad analysis [16].

Analytical, diagnostic and therapeutic context of CPA1

• Oligonucleotide site-directed mutagenesis of this uORF as well as sequencing of constitutive cis-dominant mutations has suggested that the leader peptide product of the CPA1 uORF is an essential negative element for repression of the CPA1 gene by arginine [13].

References