5'-Noncoding sequences have been compiled from 699 vertebrate mRNAs. (GCC) GCCA/GCCATGG emerges as the consensus sequence for initiation of translation in vertebrates. The most highly conserved position in that motif is the purine in position -3 (three nucleotides upstream from the ATG codon); 97% of vertebrate mRNAs have a purine, most often A, in that position. The periodical occurrence of G (in positions -3, -6, -9) is discussed. Upstream ATG codons occur in fewer than 10% of vertebrate mRNAs-at-large; a notable exception are oncogene transcripts, two-thirds of which have ATG codons preceding the start of the major open reading frame. The leader sequences of most vertebrate mRNAs fall in the size range of 20 to 100 nucleotides. The significance of shorter and longer 5'-noncoding sequences is discussed.

An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.

https://pharmrev.aspetjournals.org/content/pharmrev/52/3/415.full.pdf

International Union of Pharmacology. XXIII. The Angiotensin II Receptors

Understanding the regulation of hepatic glucose metabolism had its foundation in the elucidation of several pathways, but recent advances have come from the application of molecular genetics. Five years ago little was known about the primary structure of the key regulatory enzymes. Since then, the primary sequence of liver GK, 6-PF-1-K, Fru-1,6-P2ase, PK, PEPCK, and 6-PF-2-K/Fru-2,6-P2ase have been derived from cDNA sequences and/or determined by direct protein sequencing. This has provided new insights into the molecular mechanisms of catalysis and the regulation of these enzymes by covalent modification. Isolation of the cDNAs for these enzymes also has allowed for the quantitation of specific mRNAs and permitted analysis of hormonal control of specific gene expression. The genes for these enzymes have been isolated and sequenced, and their promoter regions are being identified and characterized. Hormone response elements have been delineated in several of the promoters. The promoter regions for 6-PF-2-K/Fru-2,6-P2ase and Fru-1,6-P2ase have also been identified, and future research will focus on the elucidation of the mechanisms whereby hormones regulate the expression of these genes. A number of generalizations can be made about the regulation of gene expression of glycolytic/gluconeogenic enzymes. First, there is coordinate hormonal regulation of gene expression and these effects are consonant with their physiologic actions. Insulin induces the mRNAs that encode glycolytic enzymes and represses the mRNAs that encode gluconeogenic enzymes; cAMP has opposite effects. Both can increase or decrease transcription. Whereas insulin and cAMP affect all of these mRNAs, glucocorticoids appear to have a more restricted action. Second, transcriptional and posttranscriptional regulatory mechanisms are involved. The synthesis of all of the mRNAs discussed is regulated by hormones. Relatively little is known about how mRNA stability is regulated in general, but it is clear that PEPCK mRNA is stabilized by agents that increase the rate of transcription of the gene. Under appropriate metabolic signals this dual control of mRNA synthesis and stability provides for a long-term increase in PEPCK mRNA and protein. Studies with PK mRNA are less direct, but suggest a similar dual mechanism. It will be interesting to see whether multilevel regulation is restricted to these two mRNAs, both of which are involved in the same substrate cycle, or whether the stability of other mRNAs involved in hepatic glucose metabolism is also affected. Third, glucose appears to be important in the regulation of these hepatic genes.(ABSTRACT TRUNCATED AT 400 WORDS)

Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis.

The gene that is defective in patients with Duchenne and Becker muscular dystrophy consists of about 60 short exons scattered along a gigantic DNA region that spans some 2 megabase pairs1,2. The encoded protein, dystrophin, was recently characterized as a component of muscle intracellular membranes of low abundance3,4. The dystrophin messenger RNA is difficult to study in both normal and pathological tissue specimens because it is large (14 kilobases) and scarce (0.01–0.001% of total muscle mRNA)2. We report here that efficient in vitro co-amplifications of the mRNAs of the dystrophin gene and of a reporter gene, aldolase A, by the poly-merase chain reaction procedure5 enables us to obtain a quantitative estimate of the dystrophin gene transcript. A processed, transcribed segment was thus detected in 13 different human tissues. It ranged from 0.02–0.12% of total mRNA in skeletal muscle to 25,000 times less in lymphoblastoid cells.

Transcription of the dystrophin gene in human muscle and non-muscle tissues

The pituitary adenylate cyclase-activating polypeptide (PACAP)/ glucagon superfamily includes nine hormones in humans that are related by structure, distribution (especially the brain and gut), function (often by activation of cAMP), and receptors (a subset of seven-transmembrane receptors). The nine hormones include glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, glucose-dependent insulinotropic polypeptide (GIP), GH-releasing hormone (GRF), peptide histidine-methionine (PHM), PACAP, secretin, and vasoactive intestinal polypeptide (VIP). The origin of the ancestral superfamily members is at least as old as the invertebrates; the most ancient and tightly conserved members are PACAP and glucagon. Evidence to date suggests the superfamily began with a gene or exon duplication and then continued to diverge with some gene duplications in vertebrates. The function of PACAP is considered in detail because it is newly (1989) discovered; it is tightly conserved (96% over 700 million years); and it is probably the ancestral molecule. The diverse functions of PACAP include regulation of proliferation, differentiation, and apoptosis in some cell populations. In addition, PACAP regulates metabolism and the cardiovascular, endocrine, and immune systems, although the physiological event(s) that coordinates PACAP responses remains to be identified.

The origin and function of the pituitary adenylate cyclase-activating polypeptide (pacap)/glucagon superfamily

Bioactive enteroglucagon (oxyntomodulin): present knowledge on its chemical structure and its biological activities.

Pyruvate kinase subunits of red cells and liver differ in their molecular weights. Peptide mapping of the rat enzymes has shown that this difference is due to a single exon peptide present in the red cell enzyme1‐3. There is strong genetic evidence in man that both enzymes are encoded by the same structural gene (refs 4–8 and G. E. J. Staal et al., personal communication). Here we describe in vitro protein synthesis experiments using RNA extracted from rat red cells and liver which demonstrate that the difference is reflected in tissue-specific mRNAs. Thus the difference is not due to post-translational processing and presumably involves either gene rearrangement or differential processing of a common nuclear RNA precursor.

One gene, but two messenger RNAs encode liver L and red cell L' pyruvate kinase subunits

The genetic system of the L-type pyruvate kinase forms in man. Subunit structure, interrelation and kinetic characteristics of the pyruvate kinase enzymes from erythrocytes and liver.

Joelle Marie

Papers

Bioactive enteroglucagon (oxyntomodulin): present knowledge on its chemical structure and its biological activities.

One gene, but two messenger RNAs encode liver L and red cell L' pyruvate kinase subunits

The genetic system of the L-type pyruvate kinase forms in man. Subunit structure, interrelation and kinetic characteristics of the pyruvate kinase enzymes from erythrocytes and liver.

Structure of the rat L-type pyruvate kinase gene.

Human erythrocyte pyruvate kinase. Total purification and evidence for its antigenic identity with L-type enzyme.