RNA turnover and translational regulation of specific crystallin synthesis.
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Amino Acids↗
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Antidepressant and other centrally acting drugs regulate glucocorticoid receptor messenger RNA levels in rat brain.
The effect of imipramine, desipramine, ketanserin and lithium on Type II glucocorticoid receptor (GR) mRNA levels was studied in rat brain regions involved in the control of the hypothalamo-pituitary-adrenal (HPA) axis, the dysregulation of which has been implicated in the pathophysiology of major depression. Northern blot analysis of Type II GR mRNA showed that treatment of male rats with either desipramine or imipramine increased hypothalamic and hippocampal GR mRNA levels. Upregulation of GR mRNA following administration of imipramine was found in brain regions of female rats, while desipramine had no effect. Ketanserin increased levels of GR mRNA in hippocampus of male, but not female, rats. Lithium also was able to induce important increases rat brain GR mRNA; this effect was particularly marked in females. We conclude that desipramine, imipramine, ketanserin and lithium can modulate GR mRNA in regions of rat brain involved in the control of the HPA axis and may have a common mechanism of action at the level of the GR gene. Sexual dimorphism for drug regulation of brain GR mRNA content was shown and may be related to sex differences in the prevalence of certain affective disorders.
Amygdala↗
Coordinate hormonal and synaptic regulation of vasopressin messenger RNA.
Previous studies have shown that adrenalectomy augments arginine vasopressin (AVP) messenger RNA levels in the adult paraventricular nucleus. It is now demonstrated that unilateral lesions in the lateral septal nucleus enhance the adrenalectomy-induced expression of AVP mRNA. This effect was entirely ipsilateral to the lesion and most prominent in the rostral paraventricular nucleus and related nuclei. Moreover, AVP and AVP mRNA were found to be colocalized with oxytocin in a few neurons. These results indicate that mRNA expression is modulated by synaptic influences and raise the possibility that synaptically mediated selection of neuronal phenotypes is a dynamic feature of the mature central nervous system.
Adrenalectomy↗
In vivo regulation of Zif268 messenger RNA expression by 17 beta-estradiol in the rat uterus.
Administration of 17 beta-estradiol (E2) induces a mitogenic response in the rat uterus. Previous studies have shown that this effect involves the transient activation of c-fos and c-myc expression, followed by significant increases in both DNA synthesis and cell proliferation. Zif268 is a zinc finger-containing, DNA-binding transcription factor that has been implicated in the regulation of cell growth and development and has been shown to be coregulated with c-fos in a number of systems. To determine whether Zif268 is also a target for estrogen regulation, we measured the effects of E2 on Zif268 mRNA expression in the uterus of the ovariectomized rat. In this report we demonstrate that although low levels of Zif268 mRNA expression are detectable in the uteri from ovariectomized control rats, treatment with E2 (4, 40, or 400 micrograms/kg BW) induces a rapid and transient 45- to 50-fold increase in the level of Zif268 mRNA 2 h after E2 treatment. The elevated levels of Zif268 mRNA returned to basal 6 h after hormone treatment. Lower doses of E2 (0.004, 0.04, and 0.4 micrograms/kg) had little or no effect on Zif268 mRNA expression, while higher doses of E2 (4-400 micrograms/kg) resulted in maximal increases in Zif268 expression. Dexamethasone, 5 alpha-dihydrotestosterone, and progesterone had no effect on uterine Zif268 mRNA expression, and the induction of Zif268 by E2 was abolished by pretreating the animals with the RNA synthesis inhibitor actinomycin-D. In addition, stimulation of Zif268 mRNA expression was observed with the short-acting estrogen estriol, suggesting that the response may be specific for estrogenic steroids.(ABSTRACT TRUNCATED AT 250 WORDS)
Actins↗
Genomic analysis using conditional phenotypes generated by antisense RNA.
Antisense technology has been widely used to regulate gene expression. A tetracycline (tet)-regulated antisense-RNA-expressing system has been developed and used to downregulate chromosomally derived genes expressed in Staphylococcus aureus. This downregulation subsequently provides an evaluation of the virulence factor and drug targets. The regulated antisense RNA library allows for genome-wide analyses of the functions of staphylococcal gene products for growth in culture and survival during infection. Moreover, this antisense RNA technology may provide a key tool to identify mechanisms of novel antibacterial compound action.
Drug Resistance, Bacterial↗
Developmentally-regulated changes of Xist RNA levels in single preimplantation mouse embryos, as revealed by quantitative real-time PCR.
Xist RNA localizes to the inactive X chromosome in cells of late cleavage stage female mouse embryos (Sheardown et al., 1997: Cell 91:99-107). Fluorescence in situ hybridization (FISH), however, does not quantify the number of Xist transcripts per nucleus. We have used real-time reverse transcription-polymerase chain reaction (RT-PCR) to measure Xist RNA levels in single preimplantation embryos and to establish developmental profiles in both female and male samples. The gender of each embryo was readily established based on Xist RNA levels, by counting Xist gene copies per cell, and by independent detection of the presence/absence of Sry, a Y chromosome-specific gene. Xist expression in males was found to be very low at all stages, as suggested by FISH. In contrast, female embryos contained measurable levels of Xist mRNA starting at the late 2-cell stage and rapidly accumulated Xist transcripts until morula stage. Xist RNA accumulation per embryo then reached a plateau, while cell division continued. We propose that during early cleavage high enough levels of Xist mRNA are transcribed to generate a pool of unbound molecules. This pool would serve to temporarily maintain X chromosome inactivation without additional transcription while the trophectoderm and inner cell mass (ICM) differentiate. The ICM would then loose the paternally imprinted pattern of X inactivation originally present in all embryonic cells.
Animals↗
TFIIH functions in regulating transcriptional elongation by RNA polymerase II in Xenopus oocytes.
We investigated the role of TFIIH in transcription by RNA polymerase II (pol II) in vivo by microinjection of antibodies against this factor into Xenopus oocytes. Five different antibodies directed against four subunits of TFIIH were tested for effects on transcription of coinjected human immunodeficiency virus type 2 and c-myc templates. Each of these antibodies severely reduced the efficiency of elongation through human immunodeficiency virus type 2 and c-myc terminator elements. In contrast, an anti-TFIIB antibody did not inhibit elongation. Anti-TFIIH antibodies also had a much smaller inhibitory effect on total transcription than did anti-TFIIB or anti-pol II large subunit. Three inhibitors of TFIIH kinase activity, H-7, H-8, and dichlororibofuranosylbenzimidazole (DRB), inhibited elongation similarly to anti-TFIIH antibodies. These results strongly suggest a role for TFIIH in the stimulation of transcriptional elongation in vivo.
Animals↗
RNA silencing of checkpoint regulators sensitizes p53-defective prostate cancer cells to chemotherapy while sparing normal cells.
p53 is frequently mutated in patients with prostate cancer, especially in those with advanced disease. Therefore, the selective elimination of p53 mutant cells will likely have an impact in the treatment of prostate cancer. Because p53 has important roles in cell cycle checkpoints, it has been anticipated that modulation of checkpoint pathways should sensitize p53-defective cells to chemotherapy while sparing normal cells. To test this idea, we knocked down ataxia telangiectasia mutated (ATM) gene by RNA interference in prostate cancer cell lines and in normal human diploid fibroblasts IMR90. ATM knockdown in p53-defective PC3 prostate cancer cells accelerated their cell cycle transition, increased both E2F activity and proliferating cell nuclear antigen expression, and compromised cell cycle checkpoints, which are normally induced by DNA damage. Consequently, PC3 cells were sensitized to the killing effects of the DNA-damaging drug doxorubicin. Combining ATM knockdown with the Chk1 inhibitor UCN-01 further increased doxorubicin sensitivity in these cells. In contrast, the same strategy did not sensitize either IMR90 or LNCaP prostate cancer cells, both of which have normal p53. However, IMR90 and LNCaP cells became more sensitive to doxorubicin or doxorubicin plus UCN-01 when both p53 and ATM functions were suppressed. In addition, knockdown of the G(2) checkpoint regulators ATR and Chk1 also sensitized PC3 cells to doxorubicin and increased the expression of the E2F target gene PCNA. Together, our data support the concept of selective elimination of p53 mutant cells by combining DNA damage with checkpoint inhibitors and suggest a novel mechanistic insight into how such treatment may selectively kill tumor cells.
Antibiotics, Antineoplastic↗
The polymorphic expression of lactase in adults is regulated at the messenger RNA level.
BACKGROUND/AIMS: Lactase phlorizin hydrolase (LPH) activity is high in infants but declines 80%-90% before adulthood in most mammals, including humans. However, 95% of whites show autosomal dominant inheritance of a lifelong high lactose digesting capacity (LDC). This study attempted to clarify the molecular mechanism(s) of this phenomenon (posttranslational vs. pretranslational). METHODS: A race- and sex-balanced cohort (n = 20) was studied, and lactose tolerance and levels of jejunal lactase protein, activity, and messenger RNA (mRNA) were measured. RESULTS: These data confirm that black heritage predicts low LDC, and white heritage predicts high LDC. Lactase breath hydrogen and determination of lactase/sucrase ratio (L/S) from jejunal biopsy specimens divide the group by high and low LDC phenotypes concordantly. All subjects with an L/S ratio > 0.5 had immunodetectable LPH protein and measurably higher LPH mRNA levels than the remaining subjects. LPH mRNA levels are highly correlated with lactase specific activity (r = 0.80) and L/S ratio (r = 0.88). CONCLUSIONS: The direct correlation between LPH mRNA levels and lactase expression argues that the gene responsible for the human lactase polymorphism regulates the level of LPH mRNA.
Adult↗
Ligand-induced down-regulation of Trk messenger RNA, protein and tyrosine phosphorylation in rat cortical neurons.
Chronic exposure of brain neurons to nerve growth factor in vitro and in vivo results in increased levels of the nerve growth factor receptor TrkA. In contrast, in the present study, we have found that chronic exposure of rat embryonic cortical neurons to brain-derived neurotrophic factor (BDNF) leads to a pronounced reduction of the levels of protein and messenger RNA for the full-length but not the truncated BDNF receptor TrkB. Similar effects were observed with the other TrkB ligands neurotrophin-3 and neurotrophin-4/5. After pretreatment with BDNF, neurotrophin-3 or neurotrophin-4/5, subsequent tyrosine phosphorylation responses of the remaining Trks to the same factors were greatly reduced. Three days exposure of rat embryonic cortical neurons to BDNF induced an absolute refractory period of several hours, with no subsequent response to the same factor. Similar but less pronounced refractory effects were observed with neurotrophin-3 and neurotrophin-4/5. Our results suggest a negative regulatory effect of BDNF and other TrkB ligands on TrkB receptors. Down-regulation of the TrkB response by its ligands might play a role in the control of BDNF action during early development, when BDNF levels significantly increase. Our findings are also of potential clinical relevance, since the possibility of ligand-induced down-regulation of the receptor response needs to be addressed when considering BDNF or other neurotrophins for the therapy of neurodegeneration.
Animals↗
ADAR2-mediated editing of RNA substrates in the nucleolus is inhibited by C/D small nucleolar RNAs.
Posttranscriptional, site-specific adenosine to inosine (A-to-I) base conversions, designated as RNA editing, play significant roles in generating diversity of gene expression. However, little is known about how and in which cellular compartments RNA editing is controlled. Interestingly, the two enzymes that catalyze RNA editing, adenosine deaminases that act on RNA (ADAR) 1 and 2, have recently been demonstrated to dynamically associate with the nucleolus. Moreover, we have identified a brain-specific small RNA, termed MBII-52, which was predicted to function as a nucleolar C/D RNA, thereby targeting an A-to-I editing site (C-site) within the 5-HT2C serotonin receptor pre-mRNA for 2'-O-methylation. Through the subcellular targeting of minigenes that contain natural editing sites, we show that ADAR2- but not ADAR1-mediated RNA editing occurs in the nucleolus. We also demonstrate that MBII-52 forms a bona fide small nucleolar ribonucleoprotein particle that specifically decreases the efficiency of RNA editing by ADAR2 at the targeted C-site. Our data are consistent with a model in which C/D small nucleolar RNA might play a role in the regulation of RNA editing.
Adenosine Deaminase↗
A noncoding RNA is a potential marker of cell fate during mammary gland development.
PINC is a large, alternatively spliced, developmentally regulated, noncoding RNA expressed in the regressed terminal ductal lobular unit-like structures of the parous mammary gland. Previous studies have shown that this population of cells possesses not only progenitor-like qualities (the ability to proliferate and repopulate a mammary gland) and the ability to survive developmentally programmed cell death but also the inhibition of carcinogen-induced proliferation. Here we report that PINC expression is temporally and spatially regulated in response to developmental stimuli in vivo and that PINC RNA is localized to distinct foci in either the nucleus or the cytoplasm in a cell-cycle-specific manner. Loss-of-function experiments suggest that PINC performs dual roles in cell survival and regulation of cell-cycle progression, suggesting that PINC may contribute to the developmentally mediated changes previously observed in the terminal ductal lobular unit-like structures of the parous gland. This is one of the first reports describing the functional properties of a large, developmentally regulated, mammalian, noncoding RNA.
Alternative Splicing↗
The role of viral and cellular nuclear proteins in herpes simplex virus replication.
Following infection of cells by herpes simplex virus, the cell nucleus is subverted for transcription and replication of the viral genome and assembly of progeny nucleocapsids. The transition from host to viral transcription involves viral proteins that influence the ability of the cellular RNA polymerase II to transcribe a series of viral genes. The regulation of RNA polymerase II activity by viral gene products seems to occur by several different mechanisms: (1) viral proteins complex with cellular proteins and alter their transcription-promoting activity (e.g., alpha TIF), (2) viral proteins bind to specific DNA sequences and alter transcription (e.g., ICP4), and (3) viral proteins affect the posttranslational modification of viral or cellular transcriptional regulatory proteins (e.g., possibly ICP27). Thus, HSV may utilize several different approaches to influence the ability of host-cell RNA polymerase II to transcribe viral genes. Although it is known that viral transcription uses the host-cell polymerase II, it is not known whether viral infection causes a change in the structural elements of the nucleus that promote transcription. In contrast, HSV encodes a new DNA polymerase and accessory proteins that complex with and reorganize cellular proteins to form new structures where viral DNA replication takes place. HSV may encode a large number of DNA replication proteins, including a new polymerase, because it replicates in resting cells where these cellular gene products would never be expressed. However, it imitates the host cell in that it localizes viral DNA replication proteins to discrete compartments of the nucleus where viral DNA synthesis takes place. Furthermore, there is evidence that at least one specific viral gene protein can play a role in organizing the assembly of the DNA replication structures. Further work in this system may determine whether assembly of these structures is essential for efficient viral DNA replication and if so, why assembly of these structures is necessary. Thus, the study of the localization and assembly of HSV DNA replication proteins provides a system to examine the mechanisms involved in morphogenesis of the cell nucleus. Therefore, several critical principles are apparent from these discussions of the metabolism of HSV transcription and DNA replication. First, there are many ways in which the activity of RNA polymerase II can be regulated, and HSV proteins exploit several of these in controlling the transcription of a single DNA molecule. Second, the interplay of these multiple regulatory pathways is likely to control the progress of the lytic cycle and may play a role in determining the lytic versus latent infection decision.(ABSTRACT TRUNCATED AT 400 WORDS)
DNA Replication↗
Regulation of proopiomelanocortin messenger RNA concentrations by opioid peptides in primary cell cultures of rat hypothalamus.
The effects of opioid peptides on a 1.1-kb long proopiomelanocortin messenger RNA (POMC mRNA) have been investigated in rat hypothalamic cells maintained in culture. Most opioid peptides exerted an inhibitory control on POMC mRNA steady-state concentrations. beta-Endorphin caused a 65% maximal inhibitory effect (IC50 = 6.1 x 10(-9) M) while slightly less inhibition was caused by Met- and Leu-enkephalin, dynorphin A and DADLE ([D-Ala2,D-Leu5] enkephalin). The effects of beta-endorphin and of Met-enkephalin were completely reversed by the delta opioid antagonist ICI 174,864 while the kappa-receptor specific antagonist binaltorphimine or the sigma-receptor specific antagonist DTG (1,3-di(2-tolyl) guanidine) respectively blocked the inhibitory actions of dynorphin A and of DADLE. The mu-receptor specific agonist DAGO ([D-Ala2,N-Me-Phe4,Gly5-OL]enkephalin) did not affect POMC mRNA levels. The failure of the dopaminergic D2 antagonist haloperidol to modify the inhibitory effects of opioid peptides argues for a direct inhibitory opioid peptide modulation of hypothalamic POMC mRNA levels mediated by the delta-, kappa- and sigma- (but not mu-) receptors in vivo.
Animals↗
Regulation of nitrogenase messenger RNA synthesis and stability in Klebsiella pneumoniae.
Nitrogenase messenger RNA synthesis in Klebsiella pneumoniae was determined by labelling cells with (3H)uracil and isolating total RNA, which was then hybridized to filter-bound recombinant plasmid pSA30 DNA carrying the nitrogenase structural genes nifH, D, and K, Derepression of nitrogenase mRNA starts 1.5 h before the onset of nitrogenase activity (as measured by acetylene reduction). Exposure of nif-derepressed cultures to either NH4+, air, or high temperatures (39 degree C) results in a rapid decrease of the synthesis rates both of nitrogenase mRNA and nitrogenase polypeptides. Nitrogenase mRNA is remarkably stable. After blocking transcription with rifampicin, hybridizable and actively translatable nitrogenase mRNA survives with an average half-life of 18 min. Half-lives are considerably shorter when rifampicin-inhibited cultures are simultaneously shifted to conditions which are non-permissive for nitrogenase synthesis, pointing to some posttranscriptional influence on nitrogenase mRNA stability. In all experiments performed there was no evidence for uncoupling of nitrogenase mRNA synthesis from nitrogenase mRNA translation, indicating that nitrogenase synthesis is regulated solely by transcriptional control.
Genes, Bacterial↗
Regulation of eukaryotic ribosomal RNA transcription by RNA polymerase modification.
Forms of RNA polymerase I prepared from growing or encysted Acanthamoeba are equal in the ability to transcribe poly(dl:dC). Polymerase from cysts, whose rRNA genes are transcriptionally inactive, is unable to utilize the rDNA promoter in vitro, whereas the transcription initiation factor from cysts is fully able to bind the promoter and direct transcription. Footprinting shows that polymerase from cysts is functionally inactive because of its inability to bind to the promoter. The polymerase footprint moves downstream the appropriate number of base pairs upon various nucleotide additions, without affecting the factor footprint. These results support our hypothesis that rRNA synthesis in eukaryotes is regulated by polymerase I modification and not by alterations to additional DNA-binding proteins.
Amoeba↗
The effect of down-regulation of mitochondrial RNA-binding proteins MRP1 and MRP2 on respiratory complexes in procyclic Trypanosoma brucei.
MRP1 and MRP2 are multifunctional mitochondrial RNA-binding proteins with a regulatory role in RNA editing and putative role(s) in RNA processing in Trypanosoma brucei. Silencing of MRP1 and/or MRP2 by RNA interference affected the assembly and functionality of respiratory complexes. The absence of several subunits of complexes I, III and IV resulted in their disintegration and subsequent decrease of specific activities and also caused a significant decrease of membrane potential. The overall respiration in the interfered cells decreased by only about 20%, since the trypanosome alternative oxidase effectively replaced the missing cytochromes and became the principal terminal oxidase.
Animals↗
Glucocorticoids and cyclic AMP synergistically regulate the abundance of preproenkephalin messenger RNA in neuroblastoma-glioma hybrid cells.
Regulation of preproenkephalin gene expression was studied in NG108-15 neuroblastoma-glioma hybrid cells. Untreated cells contain 20-120 fg preproenkephalin mRNA per microgram cellular RNA. Treatment of cells with a glucocorticoid (e.g. dexamethasone) for 24 hr or 8 days elevated the abundance of this mRNA to 3 or 9 times the control, respectively. Treatment with 8-bromo-cyclic AMP or an adenylate cyclase activator such as prostaglandin E1 or forskolin elevated preproenkephalin mRNA to twice the control or less. Treatment with both glucocorticoid and forskolin for 24 hr or 8 days markedly increased preproenkephalin mRNA to 5-8 and 30 times the control, respectively. Intracellular Met-enkephalin immunoreactivity was increased in parallel with the mRNA abundance. The results demonstrate that preproenkephalin gene expression is synergistically regulated by glucocorticoids and cAMP.
Base Sequence↗