PubMed Health⌕ Search

Biomedical subjects

K Stuart

Publications and source records attributed to K Stuart.

At least 55 records · Page 3Linked to original sources

Guide RNA molecules not engaged in RNA editing form ribonucleoprotein complexes free of mRNA.

Mitochondrial pre-mRNAs in kinetoplastid organisms undergo uridine additions and deletions after transcription, a phenomenon termed kRNA editing. The reaction involves small, mitochondrial DNA transcripts, so called guide RNAs which provide the editing information via base pairing to the pre-mRNAs and furthermore may act as the U-nucleotide donors. Guide RNAs are not maintained as free molecules within the mitochondrial organelle, instead form several high molecular weight ribonucleoprotein complexes. Here we report the identification of two new gRNA containing RNP complexes, 8S and 15S in size, that only assemble with upstream gRNA molecules which require editing of their cognate pre-mRNA before they can base pair. The two complexes do not contain pre-mRNA molecules and the 8S RNP can be assembled in vitro. It contains two polypeptides under these conditions with apparent molecular weights of 90 and 21 kDa that can be cross-linked to the gRNA molecule. Our observation suggests the existence of structurally simple gRNA/protein complexes that might function as building blocks for the assembly of a high molecular weight editing machinery.

Animals↗

Quantitation of RNA editing substrates, products and potential intermediates: implications for developmental regulation.

Kinetoplast mitochondrial RNA editing is the developmentally regulated post-transcriptional process of uridine insertion and deletion in mRNAs directed by short guide RNAs (gRNAs), which creates functional mRNAs. Two mechanisms are proposed: transesterification which predicts gRNA/mRNA chimeric intermediates, and enzymatic steps which allow but do not require chimeric intermediates. We quantitated the copy number of apocytochrome b (CYb) gRNAs, edited/unedited mRNAs and gRNA/mRNA chimeras in bloodstream and procyclic form cells of Trypanosoma brucei. Both forms have 35 copies/cell of two gRNAs. Bloodstream forms contain 15 unedited and edited CYb mRNA molecules/cell while procyclic forms have four times as much unedited and over 10 times as much edited mRNA. Chimera levels are very low, 350-5000-fold lower than unedited mRNA or gRNAs, but are over 10 times more abundant in procyclic than bloodstream forms. These results are consistent with chimeras being editing intermediates if their resolution is rapid in respect to their formation, although they could be non-productive byproducts of the editing reaction. Bloodstream chimera sequences differ from procyclic chimeras. These results indicate that developmental regulation is not by gRNA abundance and suggest that it occurs at the level of gRNA utilization possibly by changing abundance of unedited CYb mRNA.

Animals↗

Cisplatin and chronic oral etoposide as salvage therapy for advanced colorectal carcinoma.

Patients with metastatic colorectal carcinoma who have failed 5-fluorouracil-based chemotherapy have no effective second-line treatment available. Recent studies demonstrating clinical synergy between cisplatin and etoposide, and others exploring the efficacy of etoposide regimens utilizing chronic oral administration, suggested the utility of a new regimen incorporating these elements to treat refractory colorectal carcinoma. Fourteen patients were treated with weekly cisplatin and daily oral etoposide for 21 days in cycles of 28-35 days. Toxicity was significant, both hematologic and gastrointestinal in these pretreated patients. There were no objective responses, and median survival was 9.5 months. Weekly cisplatin and daily oral etoposide are poorly tolerated and ineffective in the treatment of refractory colorectal carcinoma. Further studies are needed to discover effective therapy for this disease.

Adenocarcinoma↗

Increased expression of LD1 genes transcribed by RNA polymerase I in Leishmania donovani as a result of duplication into the rRNA gene locus.

Eukaryotic protein-coding genes are generally transcribed by RNA polymerase II (Pol II), which has a lower transcription rate than that of Pol I. We report here the duplication of two LD1 genes into the rRNA locus and their resultant transcription by Pol I. The multigenic LD1 locus is present in a 2.2-Mb chromosome in all stocks of Leishmania spp. and is also present in multicopy 200- to 450-kb linear chromosomes or multicopy circular DNAs in over 15% of stocks examined. Genomic rearrangement in Leishmania donovani LSB-51.1 resulted in duplication of a 3.9-kb segment of LD1 containing two genes (orfF and orfG) and of a 1.3-kb segment from approximately 10 kb downstream into the rRNA gene repeat region of the 1.2-Mb chromosome. Short sequences (12 or 13 bp) common to the 2.2-Mb LD1 and 1.2-Mb rRNA loci suggest that this gene conversion occurred by homologous recombination. Transcription of the duplicated genes is alpha-amanitin resistant, indicating transcription by Pol I, in contrast to the alpha-amanitin-sensitive (Pol II) transcription of the genes in the 2.2-Mb LD1 locus. This results in higher transcript abundance than expected from the gene copy number in LSB-51.1 and in elevated expression of at least the orfF gene product.

Amanitins↗

RNA editing: transfer of genetic information from gRNA to precursor mRNA in vitro.

RNA editing in the mitochondrion of Trypanosoma brucei extensively alters the adenosine triphosphate synthase (ATPase) subunit 6 precursor messenger RNA (pre-mRNA) by addition of 447 uridines and removal of 28 uridines. In vivo, the guide RNA gA6[14] is thought to specify the deletion of two uridines from the editing site closest to the 3' end. In this study, an in vitro system was developed that accurately removed uridines from this editing site in synthetic ATPase 6 pre-mRNA when gA6[14] and ATP were added. Mutations in both the guide RNA and the pre-mRNA editing site suggest that base-pairing interactions control the number of uridines deleted in vitro. Thus, guide RNAs are required for RNA editing and for the transfer of genetic information to pre-mRNAs.

Adenosine Triphosphatases↗

Different Trypanosoma brucei guide RNA molecules associate with an identical complement of mitochondrial proteins in vitro.

RNA editing is a mitochondrial transcript maturation process which evolved in kinetoplastid protozoa. It entails the insertion and deletion of exclusively uridine nucleotides directed by gRNAs into pre-mRNAs. Other participating components are not currently known. The aim of this study was to identify mitochondrial proteins that are in direct physical contact with gRNAs thereby possibly involved in the editing reaction. At low monovalent cation concentration (30 mM KCl) 8 polypeptides with apparent molecular weights ranging from 124 to 9 kDa specifically cross-linked to gRNAs. Three of the proteins, 90, 21, and 9 kDa in size, were able to bind at higher salt concentrations (> or = 100 mM) indicating an enhanced affinity to the gRNA molecules. No cross-links were identified at > or = 250 mM KCl. Four gRNAs, specific for different editing domains of the ATPase 6 and ND7 pre-mRNAs, were in contact with the same set of mitochondrial polypeptides suggesting the assembly of an identical RNP complex that does not include pre-mRNA molecules. The binding of the 90 kDa protein was sensitive to the presence of U-nucleotides at the 3'-end of the gRNAs and could specifically be blocked by modifying free sulfhydryl groups. The interaction with the 124 kDa polypeptide was inhibited by vanadyl ribonucleosides, implicating a role for 2', 3' hydroxyl groups in the gRNA-protein interaction.

Animals↗

Mitochondrial transcripts are processed but are not edited normally in Trypanosoma equiperdum (ATCC 30019) which has kDNA sequence deletion and duplication.

Analyses of the Trypanosoma equiperdum (ATCC 30019) maxicircle reveals deletions, duplications and rearrangement compared to T. brucei. The genes for 9S rRNA and 12 proteins are absent. The 12S rRNA and cytochrome oxidase subunit I (COI) genes lack their 3' ends and are adjacent indicating deletion of intervening genes. The remaining two NADH dehydrogenase subunit genes (ND4 and ND5), the ribosomal protein RPS12 gene and the CR5 gene are duplicated and rearranged. ND4, RPS12 and the CR4 transcripts are abundant in steady state RNA while 12S rRNA and COI transcripts are not detected. Full length ND5 transcripts are rare, if present, but chimeric ND5/ND4 transcripts are abundant. The CR4 and RPS12 transcripts are the size of unedited RNAs suggesting that they are processed. However, they are not edited normally, presumably due to the absence of minicircle gRNA genes.

Animals↗

Editing of Trypanosoma brucei maxicircle CR5 mRNA generates variable carboxy terminal predicted protein sequences.

RNA editing post-transcriptionally modifies several mRNAs from the maxicircle of kinetoplastid parasites by addition and removal of uridine residues. We report here that maxicircle CR5 transcripts of Trypanosoma brucei are edited in two domains separated by an eight nucleotide sequence that remains unedited. The large 5' domain is edited to a consensus sequence while the smaller 3' domain is edited to multiple final sequences. In all, 205-217 Us are inserted and 13-16 encoded uridines are deleted from the CR5 mRNA, producing a mature transcript 75-80% larger than the unedited transcript. The edited RNAs predict small, highly hydrophobic proteins. The carboxy terminal 15-30% of these predicted proteins have multiple different amino acid sequences as a result of the variable edited 3' mRNA sequence, but these fall into two families of sequence. Limited amino acid sequence and hydrophobicity profile similarities suggest that the protein encoded by edited CR5 mRNA may be a subunit of NADH dehydrogenase.

Amino Acid Sequence↗

The formation of mitochondrial ribonucleoprotein complexes involving guide RNA molecules in Trypanosoma brucei.

Transcripts from mitochondrial (maxicircle) genes of kinetoplastid organisms undergo RNA editing characterized by a series of reactions that insert and delete uridine nucleotides within the sequence of the pre-mRNAs. Guide RNAs, which complement fully edited mRNAs, provide the information for the edited sequence by an unknown mechanism. We report here that guide RNA molecules associate with other mitochondrial components to form four specific, stable ribonucleoprotein complexes. The complexes form very rapidly at a low monovalent cation concentration, and their formation is blocked by heparin or pretreatment of the mitochondrial lysate with SDS. ATP hydrolysis is not required but slightly stimulates complex association up to concentrations of 5 mM. The results are suggestive of a sequential assembly of the ribonucleoprotein complexes, and their possible involvement during the kinetoplastid RNA editing is discussed.

Amino Acid Sequence↗

Multiple guide RNAs for identical editing of Trypanosoma brucei apocytochrome b mRNA have an unusual minicircle location and are developmentally regulated.

We identified four different guide RNAs (gRNAs) that specify identical editing of Trypanosoma brucei apocytochrome b (CYb) mRNA, which indicates gRNA redundancy in T. brucei. All four gRNAs appear functional since they occur in chimeras, some of which contain an interesting gRNA 3' "extension." The gRNAs are encoded in different minicircles, rather than maxicircles as in other species. However, these gRNA genes are not between 18-base pair repeats as are the other minicircle gRNA genes in T. brucei. The three minicircles cloned contain the same gRNA genes, one of which is substantially diverged, all in the same order, indicating that they are related. CYb gRNA is less abundant in procyclic than bloodstream forms. Procyclic forms contain abundant edited CYb mRNA unlike bloodstream forms thus suggesting that CYb mRNA editing may be regulated at the level of gRNA utilization.

Animals↗

Trypanosoma brucei mitochondrial CR4 gene encodes an extensively edited mRNA with completely edited sequence only in bloodstream forms.

Several kinetoplastid mitochondrial genes cannot be expressed without RNA editing of their transcripts to create a functional open reading frame. We have examined one such mitochondrial gene, CR4, in Trypanosoma brucei EATRO164 and find extensive editing of transcripts in both bloodstream and procyclic life cycle stages. However, a consensus edited sequence for the entire mRNA occurs only in the bloodstream stage. The unedited CR4 transcript is 283 nucleotides in length, not including the poly(A) tail. A total of 325 uridines are inserted, and 40 uridines deleted, to create the mature mRNA which encodes a very hydrophobic protein.

Amino Acid Sequence↗

Developmental regulation of RNA editing and polyadenylation in four life cycle stages of Trypanosoma congolense.

The accumulation of many edited mRNAs is developmentally regulated in a transcript-specific fashion in Trypanosoma brucei. In addition, these transcripts are frequently present in two size classes which differ substantially in the lengths of their poly(A) tails, and poly(A) tail length is also developmentally regulated. Previously, these phenomena have only been studied in the mammalian bloodstream and insect procyclic forms (BF and PF, respectively) of T. brucei. In this paper, we examine developmental regulation of edited RNA abundance and poly(A) tail length of 3 mitochondrially encoded RNAs in mammalian BF and 3 insect stages (PF, epimastigotes, and metacyclics) of T. congolense. T. congolense BF and PF are similar, but not identical, to these stages of T. brucei with regard to edited RNA accumulation and poly(A) tail length. At the level of edited RNA, both epimastigotes and metacyclic stage parasites appear to be pre-adapted for the respiratory mechanisms of BF but not yet down-regulated from the cytochrome-based respiration of PF since edited RNAs encoding NADH dehydrogenase components are up-regulated and edited CYb RNA is abundant in these stages. Poly(A) tail lengths of mitochondrial mRNAs appear to be regulated independently of edited RNA abundance. These results indicate that multiple mechanisms for regulation of mitochondrial gene expression are active throughout the trypanosome life cycle.

Animals↗

Assembly of mitochondrial ribonucleoprotein complexes involves specific guide RNA (gRNA)-binding proteins and gRNA domains but does not require preedited mRNA.

RNA editing in kinetoplastids probably employs a macromolecular complex, the editosome, that is likely to include the guide RNAs (gRNAs) which specify the edited sequence. Specific ribonucleoprotein (RNP) complexes which form in vitro with gRNAs (H. U. Göringer, D. J. Koslowsky, T. H. Morales, and K. D. Stuart, Proc. Natl. Acad. Sci. USA, in press) are potential editosomes or their precursors. We find that several factors are important for in vitro formation of these RNP complexes and identify specific gRNA-binding proteins present in the complexes. Preedited mRNA promotes the in vitro formation of the four major gRNA-containing RNP complexes under some conditions but is required for the formation of only a subcomponent of one complex. The 5' gRNA sequence encompassing the RYAYA and anchor regions and the 3' gRNA oligo(U) tail are both important in complex formation, since their deletion results in a dramatic decrease of some complexes and the absence of others. UV cross-linking experiments identify several proteins which are in contact with gRNA and preedited mRNA in mitochondrial extracts. Proteins of 25 and 90 kDa are highly specific for gRNAs, and the 90-kDa protein binds specifically to gRNA oligo(U) tails. The gRNA-binding proteins exhibit a differential distribution between the four in vitro-formed complexes. These experiments reveal several proteins potentially involved in RNA editing and indicate that multiple recognition elements in gRNAs are used for complex formation.

Animals↗

Hepatic arterial chemoembolization for metastatic neuroendocrine tumors.

PURPOSE OF THE STUDY: To evaluate the effectiveness of chemoembolization of the liver with doxorubicin and iopamidol emulsified in ethiodized oil for the treatment of metastatic neuroendocrine tumors. PATIENTS AND METHODS: Twenty patients with hepatic islet cell or carcinoid metastases were treated with selected hepatic arterial embolization consisting of an emulsion of doxorubicin and iopamidol emulsified in ethiodol followed by Gelfoam powder embolization. Fifteen patients had failed intravenous chemotherapy. Two of the patients with carcinoid tumors had three embolizations over 4 and one 6 years earlier with gelatin sponge only. RESULTS: In 14 patients with hormonally active tumors, hormones secretion decreased 90% (range 69-98%) in 10 days with relief of symptoms in all patients. Average tumor size decrease was 84%. Average hospital stay was 8 days. Six patients are alive and asymptomatic at 14-33 months postembolization. Fourteen patients have died 2-16 months postembolization. Ten patients died 2-37 months postembolization from progressive liver disease. One of these patients was 103 months post-Gelfoam embolization and 13 months postchemoembolization. In 8 patients, the pancreas was the primary site: 5 were nonfunctioning islet cell carcinomas, 1 glucagonoma, 1 gastrinoma and 1 carcinoid. The primary site in 1 patient with carcinoid was the bronchus, and the primary site was unknown in 1 patient with gastrinoma. The remaining 4 patients died with liver disease under control from renal failure, peritonitis, carcinoid heart failure and generalized bone metastases. The response rate was 95% with median duration of response 8.5 months. The median survival was 24 months. CONCLUSION: Chemoembolization with doxorubicin and iopamidol emulsified in ethiodized oil is less morbid than embolization with particulate matter alone, is more convenient and less costly, and it is less morbid than the effects of systemic chemotherapy. The median survival, duration and response compare favorably with other reported therapies.

Adenoma, Islet Cell↗

Hepatic arterial chemoembolization for metastatic neuroendocrine tumors.

BACKGROUND: Patients with neuroendocrine neoplasma, even with metastases to the liver, often have indolent disease and are treated conservatively. However, when debilitating symptoms from hormonal syndromes or mass effect arise, more aggressive treatment may be warranted. METHODS: Thirty-nine chemoembolization procedures were performed in 30 patients with significant symptoms, with carcinoids and islet cell tumors. An emulsification of intraarterial doxorubicin, iodized oil, and water-soluble contrast was followed by embolization with absorbable gelatin powder or pledgets. RESULTS: Twenty-seven patients exhibited subjective improvement in clinical symptoms. Hormonal markers and/or tumor size decreased by at least 50% in 79% of patients. Inclusion of minor responses raises this to 92%. Seven complications were noted, and no procedure-related deaths occurred. Median survival was 24 months after chemoembolization or 53 months after diagnosis. Computed tomographic features of tumor vascularity, distribution of metastatic lesions, and distribution of ethiodized oil were not clearly correlated with outcome. Presence of a nonresected primary tumor had a negative effect on survival. CONCLUSIONS: Compared with previously described treatments for neuroendocrine liver metastases, this technique appears to be more effective and to be associated with less morbidity, and is recommended for patients with significant symptoms who have failed to respond to more conservative therapy and who are not surgical candidates.

Adult↗

Treatment of hepatocellular carcinoma using doxorubicin/ethiodized oil/gelatin powder chemoembolization.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy worldwide with limited effective therapeutic options available or appropriate for cirrhotic patients. METHODS: Chemoembolization, using sequential intra-arterial doxorubicin/ethiodized oil and gelatin sponge particle/ethanol embolization, was used to treat patients with unresectable HCC localized to the liver. Fifty-two patients were treated in this manner from 1988 to 1992. The objective response was determined by sequential computed tomography (CT) scans. RESULTS: Of the 47 patients evaluable for response, 20 (43%) achieved a partial response, and 12 (26%) achieved a minor response. Sixteen patients underwent repeated chemoembolization for locally recurrent disease as many as three times after the initial procedure. All 52 patients were evaluable for survival and toxicity, with a median follow-up of 14 months. Twelve-month survival was 60%, and median survival was 16 months. This compares favorably with values reported in the literature of approximately 20% and 6-14 weeks, respectively. There was a 17% 30-day mortality, with a slightly higher risk for patients with portal vein obstruction. Other toxicities generally were mild and transient, including fever, pain, encephalopathy, and malaise. CONCLUSIONS: Chemoembolization may enhance survival for patients with unresectable, localized HCC. It appears to be an effective alternative to standard treatment, even in cirrhotic patients.

Adult↗