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Developmental regulation of a proinsulin messenger RNA generated by intron retention.

Proinsulin gene expression regulation and function during early embryonic development differ remarkably from those found in postnatal organisms. The embryonic proinsulin protein content decreased from gastrulation to neurulation in contrast with the overall proinsulin messenger RNA increase. This is due to increasing levels of a proinsulin mRNA variant generated by intron 1 retention in the 5' untranslated region. Inclusion of intron 1 inhibited proinsulin translation almost completely without affecting nuclear export or cytoplasmic decay. The novel proinsulin mRNA isoform expression was developmentally regulated and tissue specific. The proportion of intron retention increased from gastrulation to organogenesis, was highest in the heart tube and presomitic region, and could not be detected in the pancreas. Notably, proinsulin addition induced cardiac marker gene expression in the early embryonic stages when the translationally active transcript was expressed. We propose that regulated unproductive splicing and translation is a mechanism that regulates proinsulin expression in accordance with specific requirements in developing vertebrates.

5' Untranslated Regions↗

The role of transcription and messenger RNA stability in the regulation of epidermal growth factor receptor gene expression in regenerating mouse liver.

The influence of partial hepatectomy on epidermal growth factor receptor gene expression was studied in mouse liver. Epidermal growth factor receptor binding and epidermal growth factor receptor messenger RNA levels in the liver showed a rapid peak 8 hr after partial hepatectomy, whereas the sham operation had no effects on these levels. The peak epidermal growth factor receptor messenger RNA level was approximately threefold higher than preoperative values. The increase in epidermal growth factor receptor messenger RNA levels occurred primarily as a consequence of an increase in the rate of transcription. Partial hepatectomy slightly increased the half-life of epidermal growth factor receptor messenger RNA in the liver from 2.8 to 3.6 hr. Treatment of partially hepatectomized mice with cycloheximide increased hepatic epidermal growth factor receptor messenger RNA levels about fivefold by prolonging the half-life of the messenger RNA to 11.2 hr, although this treatment inhibited the increase in transcription induced by partial hepatectomy. Cycloheximide also increased epidermal growth factor receptor messenger RNA levels in the liver or kidney of sham-operated mice about threefold, primarily through stabilizing epidermal growth factor receptor messenger RNA. In contrast, cycloheximide had no effects on beta-actin messenger RNA levels in the liver and kidney. These results suggest that transcription induced by partial hepatectomy requires protein synthesis and that labile proteins are involved in the regulation of the stability of epidermal growth factor receptor messenger RNA.

Actins↗

Initiation and regulation mechanisms of ribosomal RNA transcription in the eukaryote Acanthamoeba castellanii.

Acanthamoeba rRNA transcription involves the binding of a transcription initiation factor (TIF) to the core promoter of rDNA to form the preinitiation complex. This complex is formed in the absence of RNA polymerase I, and persists for multiple rounds of initiation. Polymerase I next binds to form the initiation complex. This binding is DNA sequence-independent, and is directed by protein-protein contacts with TIF. DNA melting occurs in a separate step. In contrast to most prokaryotic transcription, melting occurs only following nucleotide addition and beta-gamma hydrolysis of ATP is not required as for polymerase II. Growth-dependent regulation of rRNA transcription is accomplished by modification of RNA polymerase I. The inactive form of polymerase (PolE) is unable to bind to the promoter and has altered heat stability. PolE is still active in elongation; thus, the modification affects the polymerase site involved in TIF contact. Modification of a polymerases I and III common subunit has been detected leading to the suggestion that transcription of stable RNAs of the ribosome might be co-regulated by this mechanism.

Acanthamoeba↗

Role of chromatin structure in the regulation of transcription by RNA polymerase II.

Recent studies on chromatin have concentrated on the relationship between its structure and gene activity. This topic, which addresses the fundamental mechanisms by which genes are expressed, has become a controversial issue, and the present data support the hypothesis that the structure of chromatin is an important component of transcriptional regulation. Notwithstanding, the complexity of this problem suggests that the current models are probably only a rough approximation of the truth.

Animals↗

Rapid isolation of tissue-specific and developmentally regulated brain cDNAs using RNA arbitrarily primed PCR (RAP-PCR).

RNA arbitrarily primed PCR (RAP-PCR) was used to isolate cDNAs that represent developmentally regulated brain-specific genes. Five clones with a restricted pattern of expression were identified and sequenced. Four cDNAs had no obvious homology to the sequences in GenBank. One clone had over 95% homology to a Ca2+/calmodulin-insensitive adenylyl cyclase, a recently cloned gene that was isolated from rat brain and was shown to be expressed only in adult brain and lung. Two novel cDNAs were investigated further by Northern blot analysis and were found to be expressed differentially during development; their expression was confined to the forebrain in the adult mouse. Further characterization by in situ hybridization showed that the mRNA corresponding to one clone was localized to a limited number of differentiating functional structures in the developing nervous system. In the adult brain, this message is confined to the forebrain with the highest level of expression in the cortex. These data suggest that the product of this gene is involved in the establishment of neuronal networks during brain development and in synaptic plasticity in the mature cortex. This work demonstrates that RAP-PCR is a powerful method for the simultaneous detection of differences between multiple RNA populations and, as such, can be used to study differential gene expression in the brain.

Animals↗

Mapping of elements involved in regulating normal temporal period and timeless RNA expression patterns in Drosophila melanogaster.

Although transcriptional regulation is a major force in generating circadian oscillations of clock molecules, posttranscriptional mechanisms also contribute to molecular rhythms. Applying novel transgenic period-luciferase constructs in transgenic Drosophila, the authors show that sequences within per's 5'-untranslated region mediate posttranscriptional regulation at the RNA level. Further mapping suggests that the relevant sequences for the correct phasing of period mRNA expression are located within the first intron. The results are consistent with a clock-regulated temporal stabilization of period mRNA during its daily upswing in the morning. This process is inferred to depend on a function of the PERIOD and TIMELESS proteins, and could further contribute to the observed delay between RNA and protein accumulation. Similarly, applying timeless-luciferase constructs led to the demonstration that regulatory elements for proper temporal timeless expression are present in a 4 kb promoter fragment and in sequences within the first intron. The results establish that, for normal rhythmicity, expression of clock genes requires regulation at the transcriptional, posttranscriptional, and posttranslational levels.

5' Untranslated Regions↗

Regulation of adenovirus alternative RNA splicing by dephosphorylation of SR proteins.

SR proteins are a family of essential splicing factors required for early recognition of splice sites during spliceosome assembly. They also function as alternative RNA splicing factors when overexpressed in vivo or added in excess to extracts in vitro. SR proteins are highly phosphorylated in vivo, a modification that is required for their function in spliceosome assembly and splicing catalysis. Here we show that SR proteins purified from late adenovirus-infected cells are inactivated as splicing enhancer or splicing repressor proteins by virus-induced dephosphorylation. We further show that the virus-encoded protein E4-ORF4 activates dephosphorylation by protein phosphatase 2A of HeLa SR proteins and converts their splicing properties into that of SR proteins purified from late adenovirus-infected cells. Taken together, our results suggest that E4-ORF4 is an important factor controlling the temporal shift in adenovirus alternative RNA splicing. We conclude that alternative pre-mRNA splicing, like many other biological processes, is regulated by reversible protein phosphorylation.

Adenoviridae↗

Concomitant transcriptional and post-transcriptional control of mRNA abundance during human myeloid cell differentiation.

The mechanisms controlling the expression of two genes during the differentiation of HL60 cells have been studied. The relative abundance of one mRNA, designated 2B5, increases during retinoic acid-induced differentiation; this increase can be accounted for, in part at least, by a marked increase in the rate of transcription of the gene. The relative abundance of the second, pCG56, decreases during retinoic acid-induced differentiation although the rate of transcription of this gene also increases during the course of differentiation. The bulk of pCG56 transcripts, though polyadenylated and apparently fully processed, are located in the nuclei of the uninduced cells, but on the polysomes of the induced cells. The data indicate that the change in the expression of the gene encoding pCG56 RNA is regulated differently from that encoding 2B5 RNA, and are interpreted as evidence that the pCG56 gene is regulated by an interaction between transcriptional and post-transcriptional controls. Furthermore, the latter includes both mRNA stability and a post-transcriptional mechanism that has not previously been demonstrated in differentiating cells, viz. nucleo-cytoplasmic transport of mRNA.

Cell Differentiation↗

Regulation of mitochondrial ribosomal RNA synthesis in yeast. I. In search of a relaxation of stringency.

Studies were undertaken to determine if mitochondrial rRNA synthesis in yeast is regulated by general cellular stringent control mechanism. Those variables affecting the relaxation of a cycloheximide-induced stringent response as a result of medium-shift-down or tyrosine limitation include: 1) the stage of cell growth, 2) carbon source, 3) strain differences and, 4) integrity of the cell wall. The extent of phenotypic relaxation decreased or was eliminated entirely in a strain dependent manner as cells entered stationary phase of growth or by growth of cells on galactose or in osmotically stabilized spheroplast cultures. Cytoplasmic and mitochondrial RNA species were extracted from regrowing spheroplast cultures subjected to different experimental regimens and analyzed by electrophoresis on 2.5% polyacrylamide gels. Relative rates of synthesis were determined in pulse experiments and normalized by double-label procedures to longterm label material. Tyrosine starvation was found to inhibit synthesis of the large and small rRNA species of both cytoplasmic and mitochondrial rRNAs to about 5-20% of the control values. Chloramphenicol inhibits mitochondrial and cytoplasmic rRNA synthesis to 60-80% of control; however, chloramphenicol addition does not relax the stringent inhibition of either class of rRNAs. Cycloheximide addition results in 70-80% inhibition of synthesis of both cellular speceis of rRNAs. As noted above, cycloheximide does not relax the stringent response of cytoplasmic rRNA synthesis in spheroplasts, and also does not relax the stringent inhibition of mitochondrial rRNA synthesis. From these studies, we conclude that both cytoplasmic and mitochondrial rRNA synthesis share common control mechanisms related to regulation of protein synthesis by shift-down or amino acid limitation.

Cycloheximide↗

Cell CAM 105 isoform RNA expression is differentially regulated during rat liver regeneration and carcinogenesis.

Cell CAM 105 (C-CAM) is a member of the carcinoembryonic antigen family and has been characterized as a rat hepatocyte cell-cell adhesion molecule via antibody activity. Two isoforms have been cloned and differ primarily in the length of the cytoplasmic domain. Despite extensive structural studies, little is known about their function and regulation in vivo. We have examined C-CAM expression during rat liver regeneration and hepatocarcinogenesis. Steady-state C-CAM RNA varied less than 3-fold during regeneration with subtle changes in the isoform ratio both before and after hepatocyte division. In liver tumors and transformed cells derived from tumors, however, large-scale decreases were observed in C-CAM RNA with wide variations in isoform ratios. In general, RNA decreases were reflected at the protein level. Our data suggest whereas down-regulation and alterations in C-CAM isoform ratio are transient during regulated liver growth, they are permanent in malignancy and may modulate hepatocyte adhesion.

Animals↗

Regulation of adenovirus alternative RNA splicing correlates with a reorganization of splicing factors in the nucleus.

Subcellular compartmentalization of splicing factors has been proposed to play a role in the regulation of alternative splicing. In the present work we have addressed this issue using adenovirus-infected cells to visualize an alternative splicing switch at the single cell level. The adenovirus gene expression program requires the activation of distal alternative 3' splice sites during the late phase of infection in major late transcripts. We have established in situ hybridization conditions that allow for the specific detection of 3' alternatively spliced adenoviral mRNAs from the L1 transcript family. Results show that the switch from proximal to distal 3' splice sites correlates with a massive reorganization of splicing factors in the cell nucleus, involving their recruitment from nuclear speckles to sites of viral transcription. This observation raises the possibility that the subnuclear organization of splicing factors may be regulated in response to events that lead to the activation of alternative splicing programs.

Adenoviridae↗

Possible role of variant RNA transcripts in the regulation of epidermal growth factor receptor expression in human placenta.

Epidermal growth factor receptor (EGFR) plays an important role in growth and differentiation. The human placenta expresses high levels of the receptor. In the placenta, as in many other human tissues, EGFR is encoded by two RNA transcripts of 5.8 kb and 10.5 kb. The placenta also expresses a putative truncated EGFR transcript of 1.8 kb, which encodes only the ligand binding domain of the receptor. The etiology and role of these variant EGFR transcripts is unknown. Using the human placenta as a model to study this area, we report 1) the relationships among these transcripts suggest that the induction of alternate pathways of EGFR RNA processing is involved in their etiologies; 2) the 10.5 kb transcript may be the principal transcript involved in determining the level of the protein receptor; and 3) the isolation of a soluble protein with characteristics consistent with a translational product corresponding to the 1.8 kb transcript, which may act in regulating the activity of EGFR. Together these results suggest that alternate processing of EGFR RNA into variant transcripts may represent a novel mechanism involved in the regulation of the receptor protein.

Alternative Splicing↗

Analysis of U1 small nuclear RNA interaction with cyclin H.

TFIIH is a general transcription and repair factor implicated in RNA polymerase II transcription, nucleotide excision repair, and transcription-coupled repair. Genetic defects in TFIIH lead to three distinct inheritable diseases: xeroderma pigmentosa, Cockayne syndrome, and trichothiodystrophy, with xeroderma pigmentosa patients being highly susceptible to skin cancer. Earlier data revealed that the cyclin H subunit of TFIIH associates with U1 small nuclear RNA, a core-splicing component. In addition to its role in RNA processing U1 small nuclear RNA also regulates diverse stages of transcription by RNA polymerase II both in vivo and in vitro, including abortive initiation and re-initiation. Here we identify structural components of U1 and cyclin H implicated in the direct interaction and show how they affect function. Because of unique features of cyclin H we have developed a new methodology for mapping RNA interaction with the full-length cyclin H polypeptide based on electrospray ionization tandem mass spectrometry. We also demonstrate the importance of U1 stem-loops 1 and 2 for the interaction with cyclin H. Functional assays implicate the identified interaction with U1 in regulation of the activity of the cyclin H associated kinase CDK7.

Cross-Linking Reagents↗

Low temperature regulated DEAD-box RNA helicase from the Antarctic archaeon, Methanococcoides burtonii.

DEAD-box RNA helicases, by unwinding duplex RNA in bacteria and eukaryotes, are involved in essential cellular processes, including translation initiation and ribosome biogenesis, and have recently been implicated in enabling bacteria to survive cold-shock and grow at low temperature. Despite these critical physiological roles, they have not been characterized in archaea. Due to their presumed importance in removing cold-stabilised secondary structures in mRNA, we have characterised a putative DEAD-box RNA helicase gene (deaD) from the Antarctic methanogen, Methanococcoides burtonii. The encoded protein, DeaD is predicted to contain a core element involved in ATP hydrolysis and RNA-binding, and an unusual C-terminal domain that contains seven perfect, trideca-peptide, direct repeats that may be involved in RNA binding. Alignment and phylogenetic analyses were performed on the core regions of the M. burtonii and other DEAD-box RNA helicases. These revealed a loose but consistent clustering of archaeal and bacterial sequences and enabled the generation of a prokaryotic-specific consensus sequence. The consensus highlights the importance of residues other than the eight motifs that are often associated with DEAD-box RNA helicases, as well as de-emphasising the importance of the "A" residue within the "DEAD" motif. Cells growing at 4 degrees C contained abundant levels of deaD mRNA, however no mRNA was detected in cells growing at 23 degrees C (the optimal temperature for growth). The transcription initiation site was mapped downstream from an archaeal box-A element (TATA box), which preceded a long (113 nucleotides) 5'-untranslated region (5'-UTR). Within the 5'-UTR was an 11 bp sequence that closely matches (nine out of 11) cold-box elements that are present in the 5'-UTRs of cold-shock induced genes from bacteria. To determine if the archaeal 5'-UTR performs an analagous function to the bacterial 5'-UTRs, the archaeal deaD 5'-UTR was transcribed in E. coli under the control of the cspA promoter and transcriptional terminator. It has previously been reported that overexpression of the cspA 5'-UTR leads to an extended cold-shock response due to the 5'-UTR titrating cellular levels of a cold-shock repressor protein(s). In our hands, the cold-shock protein profiles resulting from overexpression of Escherichia coli cspA and M. burtonii deaD 5'-UTRs were similar, however they did not differ from those for the overexpression of a control plasmid lacking a 5'-UTR. In association with other recent data from E. coli, our results indicate that the role of the 5'-UTR in gene regulation is presently unclear. Irrespective of the mechanisms, it is striking that highly similar 5'-UTRs with cold-box elements are present in cold induced genes from E. coli, Anabaena and M. burtonii. This is the first study examining low temperature regulation in archaea and provides initial evidence that gene expression from a cold adapted archaeon involves a bacterial-like transcriptional regulatory mechanism. In addition, it provides the foundation for further studies into the function and regulation of DEAD-box RNA helicases in archaea, and in particular, their roles in low temperature adaptation.

5' Untranslated Regions↗

Regulation of synthesis and activity of a mutant RNA polymerase in Escherichia coli.

The expression of the genes specifying the beta and beta' subunits of RNA polymerase (nucleosidetriphosphate: RNA nucleotidyltransferase, EC 2.7.7.6) was examined in an Escherichia coli strain bearing a temperature-sensitive mutation in the beta' subunit gene. A shift to 42 degrees results in a restriction of RNA chain initiation and a cessation of RNA synthesis. A shift to 39 degrees results in only partial restriction, allowing RNA and protein synthesis to continue. The partial restriction produces a 5- to 6-fold increase in the relative transcription rate of the beta and beta' genes and a concomitant increase in the relative synthesis rate of the beta and beta' proteins. The transcription rate of ribosomal protein genes was also increased somewhat. These results indicate that the genes specifying the beta and beta' subunits of RNA polymerase are regulated at the level of transcription and that this regulation is related to the transcription of ribosomal protein genes. Furthermore, the results indicate that this regulation of the beta and beta' RNA polymerase subunit genes is somehow triggered by a reduction in the ability of RNA polymerase to initiate transcription on the bacterial chromosome.

Bacterial Proteins↗

Epstein-Barr virus small RNA (EBER) genes: differential regulation during lytic viral replication.

In every latently Epstein-Barr virus-infected cell the viral genes EBER-1 and EBER-2 are transcribed by polymerase III. In lytically infected cells in vivo the EBER genes could not be detected. However, in cell culture downregulation could not be confirmed, and hence the relevance of this shutdown to the replication of the virus was not clear. We assayed the transcriptional activity of the EBER genes by nuclear run-on assays with enriched lytically infected cells and demonstrated that EBER-1 and EBER-2 are differentially downregulated on the transcriptional level during the switch to lytic viral replication. This downregulation was an early event during the lytic replication of the virus.

Base Sequence↗

Delta factor can displace sigma factor from Bacillus subtilis RNA polymerase holoenzyme and regulate its initiation activity.

A protein with a molecular weight of 21,000 daltons is found associated with a fraction of Bacillus subtilis RNA polymerase core. This protein (delta) does not react with antibody made against sigma factor and has a peptide map which is significantly different from sigma factor. At ratios of 2:1 to 4:1 (delta:holoenzyme) the delta displaces sigma factor completely from the core and associates in a 1:1 ratio with core to form delta-core. Under the same incubation conditions sigma factor at a ratio of 10:1 (sigma factor:delta-core) does not displace delta from the delta-core. The delta-core has much less activity as compared to holoenzyme on various DNA templates. However, sigma factor does stimulate the activity of delta-core enzyme under conditions of RNA synthesis. These observations and the results of others suggest that delta-core enzyme binds initially to specific DNA sites followed by delta release from the core-DNA complex and that the sigma factor binds to the core-DNA complex to initiate RNA synthesis. Thus both delta and sigma factors are required in a sequential fashion for specific transcription to occur in B subtilis.

Bacillus subtilis↗

RNA metabolism: strategies for regulation in the heat shock response.

It has long been appreciated that selective transcription and translation play important roles in the heat shock response. More recently, regulatory strategies acting at the levels of RNA processing and message degradation have been shown to exert a profound effect on gene expression both during heat shock and during recovery from heat shock. In turn, as heat shock proteins accumulate, they affect those very processes that govern their expression.

Base Sequence↗