RESUMO
Upstream open reading frames (uORFs) are major gene expression regulatory elements. In many eukaryotic mRNAs, one or more uORFs precede the initiation codon of the main coding region. Indeed, several studies have revealed that almost half of human transcripts present uORFs. Very interesting examples have shown that these uORFs can impact gene expression of the downstream main ORF by triggering mRNA decay or by regulating translation. Also, evidence from recent genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of many human diseases, including malignancies, metabolic or neurologic disorders, and inherited syndromes. In this review, we will briefly present the mechanisms through which uORFs regulate gene expression and how they can impact on the organism's response to different cell stress conditions. Then, we will emphasize the importance of these structures by illustrating, with specific examples, how disturbed uORF-mediated translational control can be involved in the etiology of human diseases, giving special importance to genotype-phenotype correlations. Identifying and studying more cases of uORF-altering mutations will help us to understand and establish genotype-phenotype associations, leading to advancements in diagnosis, prognosis, and treatment of many human disorders.
Assuntos
Doença/genética , Regulação da Expressão Gênica , Fases de Leitura Aberta/genética , Estabilidade de RNA , Regiões 5' não Traduzidas/genética , Estudos de Associação Genética , Humanos , Mutação , Biossíntese de Proteínas/genética , Sequências Reguladoras de Ácido Nucleico/genéticaRESUMO
Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and rapidly degrades mRNAs containing premature termination codons (PTC). The strength of the NMD response appears to reflect multiple determinants on a target mRNA. We have previously reported that mRNAs containing PTCs in close proximity to the translation initiation codon (AUG-proximal PTCs) can substantially evade NMD. Here, we explore the mechanistic basis for this NMD resistance. We demonstrate that translation termination at an AUG-proximal PTC lacks the ribosome stalling that is evident in an NMD-sensitive PTC. This difference is associated with demonstrated interactions of the cytoplasmic poly(A)-binding protein 1, PABPC1, with the cap-binding complex subunit, eIF4G and the 40S recruitment factor eIF3 as well as the ribosome release factor, eRF3. These interactions, in combination, underlie critical 3'-5' linkage of translation initiation with efficient termination at the AUG-proximal PTC and contribute to an NMD-resistant PTC definition at an early phase of translation elongation.
Assuntos
Códon sem Sentido , Fatores de Iniciação em Eucariotos/metabolismo , Degradação do RNAm Mediada por Códon sem Sentido , Proteína I de Ligação a Poli(A)/metabolismo , Códon de Iniciação , Códon de Terminação , Fator de Iniciação 3 em Eucariotos/metabolismo , Fator de Iniciação Eucariótico 4G/metabolismo , Células HeLa , Humanos , Iniciação Traducional da Cadeia Peptídica , Terminação Traducional da Cadeia Peptídica , Fatores de Terminação de Peptídeos/metabolismo , Proteína I de Ligação a Poli(A)/antagonistas & inibidores , RNA Mensageiro/química , Proteínas de Ligação a RNA/metabolismo , Ribossomos/metabolismoRESUMO
Messenger RNA (mRNA) stability is a critical determinant that affects gene expression. Many pathways have evolved to modulate mRNA stability in response to developmental, physiological and/or environmental stimuli. Eukaryotic mRNAs have a considerable range of half-lives, from as short as a few minutes to as long as several days. Human globin mRNAs constitute an example of highly stable mRNAs. However, a wide variety of naturally occurring mutations that result in the clinical syndrome of thalassemia can trigger accelerated mRNA decay thus controlling mRNA quality prior to translation. Distinct surveillance mechanisms have been described as being targeted for specific defective globin mRNAs. Here, we review mRNA stability mechanisms implicated in the control of ß-globin gene expression and the surveillance pathways that prevent translation of aberrant ß-globin mRNAs. In addition, we emphasize the importance of these pathways in modulating the severity of the ß-thalassemia phenotype.
Assuntos
Fenótipo , Estabilidade de RNA/genética , RNA Mensageiro/metabolismo , Globinas beta/genética , Globinas beta/metabolismo , Talassemia beta/genética , Talassemia beta/fisiopatologia , Regulação da Expressão Gênica , Humanos , Mutação/genética , Processamento Pós-Transcricional do RNA , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Transcrição GênicaRESUMO
MPTP-induced dopaminergic neurotoxicity involves major biochemical processes such as oxidative stress and impaired energy metabolism, leading to a significant reduction in the number of nigrostriatal dopaminergic neurons. Glutathione S-transferase pi (GSTpi) is a phase II detoxifying enzyme that provides protection of cells from injury by toxic chemicals and products of oxidative stress. In humans, polymorphisms of GSTP1 affect substrate selectivity and stability increasing the susceptibility to parkinsonism-inducing effects of environmental toxins. Given the ability of MPTP to increase the levels of reactive oxygen species and the link between altered redox potential and the expression and activity of GSTpi, we investigated the effect of MPTP on GSTpi cellular concentration in an in vivo model of Parkinson's disease. The present study demonstrates that GSTpi is actively expressed in both substantia nigra pars compacta and striatum of C57BL/6 mice brain, mostly in oligodendrocytes and astrocytes. After systemic administration of MPTP, GSTpi expression is significantly increased in glial cells in the vicinity of dopaminergic neurons cell bodies and fibers. The results suggest that GSTpi expression may be part of the mechanism underlying the ability of glial cells to elicit protection against the mechanisms involved in MPTP-induced neuronal death.