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1.
The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen 总被引:1,自引:1,他引:0
The life of aerobes is dependent on iron and oxygen for efficient bioenergetics. Due to potential risks associated with iron/oxygen
chemistry, iron acquisition, concentration, storage, utilization, and efflux are tightly regulated in the cell. A central
role in regulating iron/oxygen chemistry in animals is played by mRNA translation or turnover via the iron responsive element
(IRE)/iron regulatory protein (IRP) system. The IRE family is composed of three-dimensional RNA structures located in 3′ or
5′ untranslated regions of mRNA. To date, there are 11 different IRE mRNAs in the family, regulated through translation initiation
or mRNA stability. Iron or oxidant stimuli induce a set of graded responses related to mRNA-specific IRE substructures, indicated
by differential responses to iron in vivo and binding IRPs in vitro. Molecular effects of phosphorylation, iron and oxygen remain to be added to the structural information of the IRE-RNA and
IRP repressor in the regulatory complex.
Received 21 April 2007; received after revision 13 July 2007; accepted 2 August 2007 相似文献
2.
Heike Betat Christiane Rammelt Mario Mörl 《Cellular and molecular life sciences : CMLS》2010,67(9):1447-1463
RNA polymerases are important enzymes involved in the realization of the genetic information encoded in the genome. Thereby,
DNA sequences are used as templates to synthesize all types of RNA. Besides these classical polymerases, there exists another
group of RNA polymerizing enzymes that do not depend on nucleic acid templates. Among those, tRNA nucleotidyltransferases
show remarkable and unique features. These enzymes add the nucleotide triplet C–C–A to the 3′-end of tRNAs at an astonishing
fidelity and are described as “CCA-adding enzymes”. During this incorporation of exactly three nucleotides, the enzymes have
to switch from CTP to ATP specificity. How these tasks are fulfilled by rather simple and small enzymes without the help of
a nucleic acid template is a fascinating research area. Surprising results of biochemical and structural studies allow scientists
to understand at least some of the mechanistic principles of the unique polymerization mode of these highly unusual enzymes. 相似文献
3.
4.
Hepatitis C virus (HCV) translation is mediated by an internal ribosome entry site (IRES) located at the 5′ end of the genomic
RNA. The 3′ untranslatable region (3′UTR) stimulates translation by the recruitment of protein factors that simultaneously
bind to the 5′ end of the viral genome. This leads to the formation of a macromolecular complex with a closed loop conformation,
similar to that described for the cap-translated mRNAs. We previously demonstrated the existence of a long-range RNA–RNA interaction
involving subdomain IIId of the IRES region and the stem–loop 5BSL3.2 of the CRE element at the 3′ end of the viral genome.
The present study provides evidence that the enhancement of HCV IRES-dependent translation mediated by the 3′UTR is negatively
controlled by the CRE region in the human hepatoma cell lines Huh-7 and Hep-G2 in a time-dependent manner. Domain 5BSL3.2
is the major partner in this process. Mutations in this motif lead to an increase in IRES activity by up to eightfold. These
data support the existence of a functional high order structure in the HCV genome that involves two evolutionarily conserved
RNA elements, domain IIId in the IRES and stem–loop 5BSL3.2 in the CRE region. This interaction could have a role in the circularisation
of the viral genome. 相似文献
5.
Laurence Meyer Christine Patte-Mensah Omar Taleb Ayikoe Guy Mensah-Nyagan 《Cellular and molecular life sciences : CMLS》2010,67(17):3017-3034
Painful neuropathy is a major side-effect limiting cancer chemotherapy. Therefore, novel strategies are required to suppress
the neuropathic effects of anticancer drugs without altering their chemotherapeutic effectiveness. By combining biochemical,
neuroanatomical/neurochemical, electrophysiological and behavioral methods, we demonstrated that progesterone-derived neurosteroids
including 5α-dihydroprogesterone and 3α,5α-tetrahydroprogesterone suppressed neuropathic symptoms evoked in naive rats by
vincristine. Neurosteroids counteracted vincristine-induced alterations in peripheral nerves including 2′,3′-cyclic nucleotide
3′-phosphodiesterase, neurofilament-200 kDa and intraepidermal nerve fiber repression, nerve conduction velocity, and pain
transmission abnormalities (allodynia/hyperalgesia). In skin-tumor rats generated with carcinosarcoma-cells, vincristine,
which suppressed the skin tumor and restored normal blood concentration of vascular endothelial growth factor (VEGF), reproduced
neuropathic side-effects. Administered alone, neurosteroids did not affect the tumor and VEGF level. Combined with vincristine,
neurosteroids preserved vincristine anti-tumor action but counteracted vincristine-induced neural side-effects. Together,
these results provide valuable insight into the cellular and functional mechanisms underlying anticancer drug-induced neuropathy
and suggest a neurosteroid-based strategy to eradicate painful neuropathy. 相似文献
6.
7.
In the hepatitis delta virus, ribozymes are encoded in both the genomic strand RNA and its complement, the antigenomic strand.
The two ribozymes are similar in sequence and structure, are most active in the presence of divalent cation and catalyze RNA
cleavage reactions which generate a 5′-hydroxyl group and a 2′,3′-cyclic phosphate group. Recent progress has been made in
understanding the catalytic mechanism. One key was a crystal structure of the genomic ribozyme that revealed a specific cytosine
positioned to act as a general acid-base catalyst. The folding of the ribozyme in the context of the longer viral RNA is another
area of interest. The biology requires that each ribozyme act only once, and mechanisms proposed for regulation of ribozyme
activity sometimes invoke alternative RNA structures. Likewise, interference of ribozyme function by polyadenylation of the
antigenomic RNA strand could be controlled through alternative structures, and a model for such control is proposed.
Received 21 June 2001; received after revision 18 July 2001; accepted 20 July 2001 相似文献
8.
Differential use of an in-frame translation initiation codon regulates human mu opioid receptor (OPRM1) 总被引:1,自引:1,他引:0
Kyu Young Song Hack Sun Choi Cheol Kyu Hwang Chun Sung Kim Ping-Yee Law Li-Na Wei Horace H. Loh 《Cellular and molecular life sciences : CMLS》2009,66(17):2933-2942
The pharmacological effects of morphine and morphine-like drugs are mediated primarily through the μ opioid receptor. Here
we show that differential use of an in-frame translational start codon in the 5′-untranslated region of the OPRM1 generates
different translational products in vivo and in vitro. The 5′-end of the OPRM1 gene is necessary for initiating the alternate
form and for subsequent degradation of the protein. Initiation of OPRM1 at the upstream site decreases the initiation at the
main AUG site. However, alternative initiation of the long form of OPRM1 produces a protein with a short half-life, resulting
from degradation mediated by the ubiquitin–proteasome pathway. Reporter and degradation assays showed that mutations of this
long form at the second and third lysines reduce ubiquitin-dependent proteasome degradation, stabilizing the protein. The
data suggest that MOP expression is controlled in part by initiation of the long form of MOP at the alternate site. 相似文献
9.
Translation initiation is a critical step in protein synthesis. Previously, two major mechanisms of initiation were considered
as essential: prokaryotic, based on SD interaction; and eukaryotic, requiring cap structure and ribosomal scanning. Although
discovered decades ago, cap-independent translation has recently been acknowledged as a widely spread mechanism in viruses,
which may take place in some cellular mRNA translations. Moreover, it has become evident that translation can be initiated
on the leaderless mRNA in all three domains of life. New findings demonstrate that other distinguishable types of initiation
exist, including SD-independent in Bacteria and Archaea, and various modifications of 5′ end-dependent and internal initiation
mechanisms in Eukarya. Since translation initiation has developed through the loss, acquisition, and modification of functional
elements, all of which have been elevated by competition with viral translation in a large number of organisms of different
complexity, more variation in initiation mechanisms can be anticipated. 相似文献
10.
The polypyrimidine tract binding protein (PTB) is a 58-kDa RNA binding protein involved in multiple aspects of mRNA metabolism
including splicing regulation, polyadenylation, 3′end formation, internal ribosomal entry site-mediated translation, RNA localization
and stability. PTB contains four RNA recognition motifs (RRMs) separated by three linkers. In this review we summarize structural
information on PTB in solution that has been gathered during the past 7 years using NMR spectroscopy and small-angle X-ray
scattering. The structures of all RRMs of PTB in their free state and in complex with short pyrimidine tracts, as well as
a structural model of PTB RRM2 in complex with a peptide, revealed unusual structural features that provided new insights
into the mechanisms of action of PTB in the different processes of RNA metabolism and in particular splicing regulation.
Received 16 August 2007; received after revision 18 September 2007; accepted 2 October 2007 相似文献
11.
M. V. Nogués M. Moussaoui E. Boix M. Vilanova M. Ribó C. M. Cuchillo 《Cellular and molecular life sciences : CMLS》1998,54(8):766-774
The enzymatic catalysis of polymeric substrates such as proteins, polysaccharides or nucleic acids requires precise alignment
between the enzyme and the substrate regions flanking the region occupying the active site. In the case of ribonucleases,
enzyme-substrate binding may be directed by electrostatic interactions between the phosphate groups of the RNA molecule and
basic amino acid residues on the enzyme. Specific interactions between the nitrogenated bases and particular amino acids in
the active site or adjacent positions may also take place. The substrate-binding subsites of ribonuclease A have been characterized
by structural and kinetic studies. In addition to the active site (p1 ), the role of other noncatalytic phosphate-binding subsites in the correct alignment of the polymeric substrate has been
proposed. p2 and p0 have been described as phosphate-binding subsites that bind the phosphate group adjacent to the 3′ side and 5′ side, respectively,
of the phosphate in the active site. In both cases, basic amino acids (Lys-7 and Arg-10 in p2 , and Lys-66 in p0 ) are involved in binding. However, these binding sites play different roles in the catalytic process of ribonuclease A.
The electrostatic interactions in p2 are important both in catalysis and in the endonuclease activity of the enzyme, whilst the p0 electrostatic interaction contributes only to binding of the RNA. 相似文献
12.
Hurtaud C Gelly C Bouillaud F Lévi-Meyrueis C 《Cellular and molecular life sciences : CMLS》2006,63(15):1780-1789
Uncoupling protein 2 (UCP2) belongs to a family of transporters of the mitochondrial inner membrane. In vivo low expression of UCP2 contrasts with a high UCP2 mRNA level, and induction of UCP2 expression occurs without change in mRNA
level, demonstrating a translational control. The UCP2 mRNA is characterized by a long 5′ untranslated region (5′UTR), in
which an upstream open reading frame (uORF) codes for a 36-amino-acid sequence. The 5′UTR and uORF have an inhibitory role
in the translation of UCP2. The present study demonstrates that the 3′ region of the uORF is a major determinant for this
inhibitory role. In this 3′ region, a single-base substitution that kept the codon sense unchanged significantly modified
UCP2 translation, whereas some important amino acid changes had no effect. We discuss our results within the framework of
the existing models explaining initiation of translation downstream of a uORF.
Received 22 March 2006; received after revision 19 May 2006; accepted 8 June 2006
C. Hurtaud and C. Gelly contributed equally to this work. 相似文献
13.
Mammalian oocytes grow and undergo meiosis within ovarian follicles. Fully grown oocytes are arrested at the first meiotic
prophase by a mural granulosa origin “arrester” until a surge of luteinizing hormone (LH) from the pituitary at the mid-cycle
stimulates the immature oocyte to resume meiosis. Recent evidence indicates that natriuretic peptide precursor type C (NPPC)
produced by mural granulosa cells stimulates the generation of cyclic guanosine 3′,5′-monophosphate (cGMP) by cumulus cell
natriuretic peptide receptor 2 (NPR2), which diffuses into oocyte via gap junctions and inhibits oocyte phosphodiesterase
3A (PDE3A) activity and cyclic adenosine 3′,5′-monophosphate (cAMP) hydrolysis and maintains meiotic arrest with a high intraoocyte
cAMP level. This cAMP is generated through the activity of the Gs G-protein by the G-protein-coupled receptor, GPR3 and GPR12,
and adenylyl cyclases (ADCY) endogenous to the oocyte. Further studies suggest that endocrine hormones, such as follicle-stimulating
hormone (FSH), LH, 17β-estradiol (E2) and oocyte-derived paracrine factors (ODPFs), participate in oocyte meiosis possibly
by the regulation of NPPC and/or NPR2. A detailed investigation of NPPC and NPR2 expression in follicle cells will elucidate
the precise molecular mechanisms of gonadotropins, and control the arrest as well as resumption of meiosis. 相似文献
14.
15.
Manfred Hüttig 《Archive for History of Exact Sciences》2000,55(2):163-176
Summary The conical sundial from the museum Thyrrheion is found to be designed with cardinal parameters
geographical latitude ϕ = arc tan(3/5) = 30°57′50″
half cone angle α = arc tan(4/9) = 23°57′45″
radius at equinox r0 = 4 unciae = 98.7mm (pes monetalis)
position of the cone tip h = 18 unciae = 444.3 mm
The half cone angle is equal to the angle of the ecliptic which leads to the special case of a conical sundial with the associated
sphere being tangent at the day line of the winter solstice. The ratio of sides in the generating triangle 4:9 may thus be
interpreted as an approximation for the angle of ecliptic.
The place of finding (operation) is 10° North of the intended latitude (design). The error of the sundial's indications due
to the displacement are analyzed.
(Received July 15, 2000) 相似文献
16.
MicroRNAs (miRNAs) are short ~21-nt non-coding RNA molecules that have been shown to regulate a number of biological processes.
Previous reports have shown that overexpression of miR-128 in glioma cells inhibited cell proliferation. Literature also suggests
that miR-128 negatively regulates prostate cancer cell invasion. Here, we show that overexpression of hsa-miR-128, a brain-enriched
microRNA, induces apoptosis in HEK293T cells as elucidated by apoptosis assay, cell cycle changes, loss of mitochondrial membrane
potential and multicaspase assay. By in silico analysis, we identified a putative target site within the 3′ untranslated region
(UTR) of Bax, a proapoptotic member of the apoptosis pathway. We found that ectopic expression of hsa-miR-128 suppressed a
luciferase reporter containing the Bax-3′ UTR and reduced the levels of Bax in HEK293T cells. Taken together, our study demonstrates
that overexpression of hsa-miR-128 not only induces apoptosis in HEK293T cells but also is an endogenous regulator of Bax
protein. 相似文献
17.
T. Yamada K. Kageyama Y. Joh J. Konishi K. Ienaga 《Cellular and molecular life sciences : CMLS》1998,54(2):125-128
2′-O-Methylinosine (1) has been isolated for the first time and shown to be an intrinsic hypotensive principle. Its probable in vivo precursor,
2′-O-methyladenosine (3), showed stronger and even orally potent hypotensive activity. Resistance of the methyladenosine (3) against adenosine deaminase is thought to contribute to its long-lasting activity. The effect of both nucleosides (1 and 3) was not accompanied with any significant change in heart rate, which is often observed with adenosine.
Received 2 October 1997; accepted 28 October 1997 相似文献
18.
Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development 总被引:12,自引:0,他引:12
Kageyama T 《Cellular and molecular life sciences : CMLS》2002,59(2):288-306
Five types of zymogens of pepsins, gastric digestive proteinases, are known: pepsinogens A, B, and F, progastricsin, and
prochymosin. The amino acid and/or nucleotide sequences of more than 50 pepsinogens other than pepsinogen B have been determined
to date. Phylogenetic analyses based on these sequences indicate that progastricsin diverged first followed by prochymosin,
and that pepsinogens A and F are most closely related. Tertiary structures, clarified by X-ray crystallography, are commonly
bilobal with a large active-site cleft between the lobes. Two aspartates in the center of the cleft, Asp32 and Asp215, function
as catalytic residues, and thus pepsinogens are classified as aspartic proteinases. Conversion of pepsinogens to pepsins proceeds
autocatalytically at acidic pH by two different pathways, a one-step pathway to release the intact activation segment directly,
and a stepwise pathway through a pseudopepsin(s). The active-site cleft is large enough to accommodate at least seven residues
of a substrate, thus forming S4 through S3′ subsites. Hydrophobic and aromatic amino acids are preferred at the P1 and P1′ positions. Interactions at additional subsites are important in some cases, for example with cleavage of κ-casein by chymosin. Two potent naturally occurring inhibitors are known: pepstatin, a pentapeptide from Streptomyces, and a unique proteinous inhibitor from Ascaris. Pepsinogen genes comprise nine exons and may be multiple, especially for pepsinogen A. The latter and progastricsin predominate
in adult animals, while pepsinogen F and prochymosin are the main forms in the fetus/infant. The switching of gene expression
from fetal/infant to adult-type pepsinogens during postnatal development is noteworthy, being regulated by several factors,
including steroid hormones.
Received 25 May 2001; received after revision 27 August 2001; accepted 30 August 2001 相似文献
19.