Human molecular genetics, 2004-03, Vol.13 (5), p.509-524
2004
Details
- Autor(en) / Beteiligte
- Titel
- Human tra2-beta1 autoregulates its protein concentration by influencing alternative splicing of its pre-mRNA
- Ist Teil von
- Human molecular genetics, 2004-03, Vol.13 (5), p.509-524
- Ort / Verlag
- Oxford: Oxford University Press
- Erscheinungsjahr
- 2004
- Link zum Volltext
- Quelle
- Oxford Journals 2020 Medicine
- Beschreibungen/Notizen
- HTRA2-BETA1 is an SR-like protein that regulates alternative splice site selection in a concentration-dependent manner. Its proper concentration is important as several pathological states are associated with its change. We investigated the mechanism that controls the cellular HTRA2-BETA1 concentration and found it utilizes a negative feedback loop to regulate the splicing of its exon 2. TRA2-BETA1 binds to four enhancers present in exon 2, which activates its inclusion. Inclusion of exon 2 generates mRNAs that are not translated into proteins. Mutations of exon 2 enhancers demonstrate that TRA2-BETA1 binds a degenerate sequence GHVVGANR, which is found more frequently in exons than in introns. Hyperphosphorylation of TRA2-BETA1 strongly reduces its binding to RNA. Presence of the CLK2 kinase prevents the usage of exons 2 and 3, generating the htra2-beta3 mRNA. The resulting HTRA2-BETA3 protein lacks the first RS domain of HTRA2-BETA1, is expressed in several tissues and has no influence on tra2-beta splice site selection. HTRA2-BETA1 interacting proteins promote exon 2 skipping by sequestering it, which upregulates the HTRA2-BETA1 protein synthesis. We propose that the regulation of the tra2-beta pre-mRNA alternative splicing provides a robust and sensitive molecular sensor that measures the ratio between HTRA2-BETA1 and its interacting proteins.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0964-6906, 1460-2083eISSN: 1460-2083DOI: 10.1093/hmg/ddh051Titel-ID: cdi_proquest_miscellaneous_19253670
- Format
- –
- Schlagworte
- Alternative Splicing - genetics, Alternative Splicing - physiology, Amino Acid Motifs, Biological and medical sciences, Blotting, Western, Classical genetics, quantitative genetics, hybrids, DNA Primers, Enhancer Elements, Genetic - genetics, Exons - genetics, Fundamental and applied biological sciences. Psychology, Gene Expression Regulation, Genetics of eukaryotes. Biological and molecular evolution, HTRA2-BETA1 protein, Human, Humans, Immune Sera, Molecular and cellular biology, Mutagenesis, Site-Directed, Mutation - genetics, Nerve Tissue Proteins - genetics, Nerve Tissue Proteins - metabolism, Nerve Tissue Proteins - physiology, Phosphorylation, Protein-Serine-Threonine Kinases - metabolism, Protein-Tyrosine Kinases, Reverse Transcriptase Polymerase Chain Reaction, RNA Precursors - metabolism, RNA-Binding Proteins - genetics, RNA-Binding Proteins - metabolism, RNA-Binding Proteins - physiology, Serine-Arginine Splicing Factors, Transfection