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Results for “RNA Stability”

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PubMed1990

Glutamine synthetase modulation in astrocyte cultures of different mouse brain areas.

Astroglial cells from mouse cerebral hemispheres, cerebellum, olfactory bulbs, and medulla oblongata were grown in the presence of either hormones (hydrocortisone, insulin) or cell second messengers (dBcAMP, dBcGMP). Glutamine synthetase (GS) specific activity, GS protein level, and GS translation were investigated under the effect of these factors. Hydrocortisone produced a simultaneous increase in GS translation, GS level, and activity. This increase was observed in the astrocytes cultured from the four brain areas but at a variable magnitude depending on the area. The hydrocortisone effect appeared at the transcriptional level. Inversely, insulin decreased both the GS activity and the in vitro translated GS. This effect was seen only in the olfactory bulbs and the medulla. DBcAMP increased the GS biological activity only in the cerebral hemisphere cultures. It raised, however, the level of translated GS and GS protein in astrocytes from all the areas, suggesting a post-translational effect for intracellular cAMP. DBcGMP only affected GS in the astrocytes from cerebral hemispheres and the medulla modulating either the GS transcription or the messenger RNA stability. These results suggest specific regulation for GS expression, depending on the brain area from which the cells were dissociated or on the astroglial cell population present in these cultures affecting either the transcription, the mRNA stability, or the biological activity of the protein.

Animals↗

PubMed2006

Transforming growth factor-beta receptor inhibition enhances adenoviral infectability of carcinoma cells via up-regulation of Coxsackie and Adenovirus Receptor in conjunction with reversal of epithelial-mesenchymal transition.

Expression of the Coxsackie and Adenovirus Receptor (CAR) is frequently reduced in carcinomas, resulting in decreased susceptibility of such tumors to infection with therapeutic adenoviruses. Because CAR participates physiologically in the formation of tight-junction protein complexes, we examined whether molecular mechanisms known to down-regulate cell-cell adhesions cause loss of CAR expression. Transforming growth factor-beta (TGF-beta)-mediated epithelial-mesenchymal transition (EMT) is a phenomenon associated with tumor progression that is characterized by loss of epithelial-type cell-cell adhesion molecules (including E-cadherin and the tight junction protein ZO-1), gain of mesenchymal biochemical markers, such as fibronectin, and acquisition of a spindle cell phenotype. CAR expression is reduced in tumor cells that have undergone EMT in response to TGF-beta. This down-regulation results from repression of CAR gene transcription, whereas altered RNA stability and increased proteasomal protein degradation play no role. Loss of CAR expression in response to TGF-beta is accompanied by reduced susceptibility to adenovirus infection. Indeed, treatment of carcinoma cells with LY2109761, a specific pharmacologic inhibitor of TGF-beta receptor types I and II kinases, resulted in increased CAR RNA and protein levels as well as improved infectability with adenovirus. This was observed in cells induced to undergo EMT by addition of exogenous TGF-beta and in those that were transformed by endogenous autocrine/paracrine TGF-beta. These findings show down-regulation of CAR in the context of EMT and suggest that combination of therapeutic adenoviruses and TGF-beta receptor inhibitors could be an efficient anticancer strategy.

Adenoviridae↗

PubMed1994

Human chorionic gonadotropin decreases insulin-like growth factor-I gene transcription in rat Leydig cells.

Insulin-like growth factor-I (IGF-I) and hCG have synergistic effects on Leydig cell steroidogenesis in primary culture. In the present study, we investigated the effects of hCG on IGF-I gene transcription in Leydig cells. Purified Leydig cells (8-10 x 10(6) cells/100-mm dish) obtained from 50- to 65-day-old male Sprague-Dawley rats were cultured for 24 h. After medium change, hCG (0.1-10 ng/ml) or 8-bromo-cAMP (0.1 mM) was added, and cultures were continued for varying periods of time. In response to stimulation with hCG, there was a marked increase in the expression of cholesterol side-chain cleavage cytochrome P450 mRNA. In contrast, hCG caused time- and dose-dependent decrements in IGF-I mRNA levels. Both large [7.5-kilobase (kb)] and small (0.8- to 1.2-kb) species of IGF-I mRNAs were markedly decreased 6 h after treatment with hCG. hCG in a concentration of 0.1 ng/ml did not alter IGF-I mRNA levels. Higher concentrations of hCG (1 and 10 ng/ml) markedly decreased both 7.5- and 0.8- to 1.2-kb IGF-I mRNAs (80% and 56% reductions, respectively). 8-Bromo-cAMP (0.1 mM) also markedly reduced IGF-I mRNA levels. Finally, we evaluated the effects of hCG on the stability and transcription rates of IGF-I mRNA. We found that t1/2 of IGF-I mRNA for control Leydig cells was 3.86 h, which was not significantly different from that of hCG-treated cells (t1/2 = 3.41 h). This indicates that treatment with hCG did not change the stability of IGF-I mRNA. The average transcription rate per h for IGF-I mRNA decreased from 1 (for control cells) to 0.74 (for hCG-treated cells). The t1/2 values and rates of transcription for beta-actin were 7.39 and 7.16 h, and 1 and 0.94 for control and hCG-treated cells, respectively, showing that RNA stability and rates of transcription did not change significantly for the beta-actin transcript. In conclusion, we have unequivocally demonstrated that hCG decreases the expression and transcription of IGF-I mRNA in Leydig cells.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2004

Inhibition of human La protein by RNA interference downregulates hepatitis B virus mRNA in 2.2.15 cells.

AIM: To investigate the role of human La protein in HBV mRNA expression. METHODS: Three human La protein (hLa) specific siRNA expression cassettes (SECs) containing U6+1 promoter were prepared via one-step overlapping extension PCR. After transfection with SECs into HepG2 cells, inhibition effects on hLa expression were analyzed by semi-quantitative RT-PCR and Western blotting. Then, effective SECs were screened out and transfected into 2.2.15 cells, a stable HBV-producing cell line. HBV surface antigen (HBsAg) and e antigen (HBeAg) secretions into culture media were detected by microparticle enzyme immunoassay (MEIA) and HBs and HBe mRNA levels were analyzed by semi-quantitative RT-PCR. RESULTS: SEC products containing U6+1 snRNA promoter, and 3 sites of hLa mRNA specific siRNA were obtained successfully by one-step overlapping extension PCR and could be directly transfected into HepG2 cells, resulting in inhibition of La protein expression in both mRNA and protein levels, among which U6+1-hLa833 was the most efficient, which reduced 18.6-fold mRNA and 89% protein level respectively. In 2.2.15 cells, U6+1-hLa833 was also efficient on inhibition of hLa expression. Furthermore, semi-quantitative RT-PCR showed that HBs and HBe mRNA levels were significantly decreased by 8- and 66-fold in U6+1-hLa833 transfected cells compared to control. Accordingly, HBsAg and HBeAg secretions were decreased partly posttransfection with SECs. CONCLUSION: PCR-based SECs can be used to mediate RNAi in mammalian cells and provide a novel approach to study the function of La protein. The inhibition of La protein expression can result in a significant decrease of HBV mRNA, which implies that the hLa protein is also involved HBV RNA metabolism as one of the HBV RNA-stabilizing factors in human cells.

Autoantigens↗

PubMed1986

Regulation of rat luteinizing hormone subunit messenger ribonucleic acids by gonadal steroid hormones.

Little is known about the hormonal regulation of luteinizing hormone (LH) biosynthesis. We have studied the regulation of LH messenger RNA (mRNA) levels by gonadal-steroid hormones in the rat. In one set of experiments, male and female rats were surgically gonadectomized (GDX) and killed 1, 3, 7, 14, 22, and 31 d postoperatively. In another set of experiments, male and female rats were surgically GDX and were injected subcutaneously with testosterone propionate (500 micrograms/100 g body wt per d) or 17 beta-estradiol 3-benzoate (10 micrograms/100 g body wt per d), respectively, beginning 3 wk postoperatively. Levels of serum LH were determined by radioimmunoassay and levels of LH subunit mRNAs in single pituitary glands were determined by blot hybridization analysis using labeled synthetic oligodeoxyribonucleotide probes that correspond to portions of the coding regions of the rat alpha- and LH beta-subunit mRNAs. 4 wk after gonadectomy, serum LH levels rose nine- and 20-fold, while alpha-subunit mRNA levels rose six- and 10-fold, and LH beta-subunit levels rose seven- and 14-fold, compared with controls in males and females, respectively. In gonadal-steroid hormone-treated male and female GDX rats, serum LH levels fell to 8 and 36% of control values, while alpha-subunit mRNA levels declined to 22 and 19%, and LH beta-subunit mRNA levels declined to 6 and 10% of control values, 48 h after injections were initiated, in males and females, respectively. We conclude that gonadal-steroid hormones negatively regulate the levels of both subunit mRNAs in GDX rats in a pattern that parallels the changes in serum LH values. These data suggest that gonadal-steroid hormone regulation of LH biosynthesis occurs, at least in part, at the level of LH subunit mRNAs due to effects at the transcriptional and/or RNA stability levels.

Animals↗

PubMed1993

Differential promoter activation in two human insulin-like growth factor-II-producing tumor cell lines.

Several lines of evidence suggest that the growth factor insulin-like growth factor-II (IGF-II) is involved in the genesis of several types of tumors and may have autocrine effects on tumor progression when overexpressed. The human IGF-II gene is a complex transcription unit. Multiple transcripts are synthesized as a result of alternate promoter usage and the splicing of unique 5'-untranslated regions to common coding exons. We have examined two human tumor cell lines that both produce IGF-II protein which can function as an autocrine growth factor. Interestingly, each cell line uses a different IGF-II promoter; Hep3B cells predominantly activate P3, whereas in SW613 cells P4 is the preferred promoter. Here, we examine the differential transcriptional activation of the human IGF-II gene in Hep3B and SW613 cells by means of transient transfection assays and electrophoretic mobility shift analysis. The results indicate that production of IGF-II protein is mainly regulated at the level of transcription. Additional regulation takes place at the levels of messenger RNA stability and efficiency of translation.

Carcinoma, Hepatocellular↗

PubMed2002

Trypanosoma brucei expression-site-associated-gene-8 protein interacts with a Pumilio family protein.

The expression site (ES) loci of Trypanosoma brucei are a valuable model for allelic exclusion and post-transcriptional regulation in a highly divergent eukaryote. ES exist to facilitate the expression and switching of the variant surface glycoproteins (VSG) that are central to trypanosome virulence and persistence. A collection of other potential virulence determinants, known as expression-site-associated-genes (ESAGs), are co-transcribed from the single upstream promoter. ESAGs may be involved in regulating the transcriptional state of the ES, as well as contributing additional surface proteins and receptors. We have previously shown that a putative regulatory protein, ESAG8, accumulates within the nucleolus, although 20% of the protein is cytoplasmic. Here we identify TbPUF1, a cytoplasmic ESAG8-interacting protein that falls into the Puf family of regulators of mRNA stability. Our experiments show that, as in other Puf family proteins, the most C-terminal repeats of TbPUF1 mediate its interaction with ESAG8. TbPUF1 is essential for cell viability, and preliminary results suggest that its overexpression seriously affects parasite virulence. T. brucei is the most evolutionary divergent organism in which a Puf family protein has been identified, and our initial experiments suggest that this protein may also regulate RNA stability in trypanosomes.

Amino Acid Sequence↗

PubMed2003

Regulated recruitment and cooperativity in the design of biological regulatory systems.

What distinguishes a man from a mouse is not so much different proteins, but rather the appearance of common proteins (etc.) at different times and positions in the developing organisms. Thus specific genes are transcribed or repressed, proteins degraded or stabilized, RNA transcripts spliced one way or another, and so on. These are examples of 'regulatory' decisions. A rather simple mechanism - called regulated recruitment - lies at the heart of many of these regulatory decisions.

Enzyme Activators↗

PubMed1989

Dietary protein restriction in artificially reared neonatal rats causes a reduction of insulin-like growth factor-I gene expression.

To determine in neonates the effects of protein restriction on growth, serum IGF-I, and IGF-I gene expression, we adapted a technique for rearing neonatal rats (days 6-18 of life) artificially by continuous infusion of milk through a gastrostomy. The artificially reared (AR) animals were given isocaloric diets containing 8%, 13.5%, or 18% lactalbumin protein. The AR rats were compared to rats reared by their mothers (MR) for 18 days. The growth of AR rats was related to the amount of dietary protein, with the pups given 18% protein having the best growth (25.55 g gained during the 12 days of the study) and those given 8% protein having the worst (13.42 g). The 13.5% protein-fed animals were intermediate in weight gain (18.39 g). The weight gains of the 18% and 8% protein-fed pups were significantly different from that of the MR animals (18.37 g). An identical pattern of tail length growth was noted among the groups. Mean serum IGF-I concentrations followed the same pattern (MR, 1.66 U/ml on day 18 of life; 18% AR, 2.53; 13.5% AR, 1.52; 8% AR, 1.31). Liver IGF-I mRNA was rank-ordered identically with weight gain and serum IGF-I [MR, 23.10 pg/micrograms poly(A+) RNA; 18% AR, 27.66; 13.5% AR, 21.02; 8% AR, 18.76]. Unexpectedly, the 7.5-kilobase IGF-I mRNA size class showed a 2- to 3-fold higher abundance in all groups of AR rats compared to that in MR controls (P less than 0.01), suggesting that this IGF-I size class is regulated independently of the other species. The reductions in serum IGF-I and IGF-I mRNA during protein restriction of neonatal rats suggest that these responses are mediated by decreased IGF-I gene expression at the level of transcription or RNA stabilization.

Animals↗

PubMed1989

Modulation of basal and corticotropin-releasing factor-stimulated proopiomelanocortin gene expression by vasopressin in rat anterior pituitary.

In several anterior pituitary hormone systems, factors that stimulate hormone release also stimulate hormone biosynthesis. In the corticotropes of the anterior pituitary, CRF stimulates ACTH release as well as cAMP accumulation and transcription of the POMC gene. Arginine vasopressin (AVP) is a well documented coregulator of ACTH release and potentiates CRF-stimulated cAMP accumulation. The present studies were undertaken to determine if AVP also potentiates the early effects of CRF on POMC gene expression in rat anterior pituitary primary cultures. We have measured the levels of the POMC primary transcript, processing intermediate, and mature mRNA in nuclear RNA samples and POMC mRNA in cytoplasmic RNA samples as well as ACTH release after treatment with CRF and/or AVP. After a 30-min treatment with 0.5 nM CRF, POMC primary transcript levels were increased by 200-400%. Thirty-minute or 1-h treatments with AVP alone (10 or 100 nM) did not affect primary transcript levels, but increased the amount of the processing intermediate, while a 2-h incubation with 100 nM AVP significantly decreased POMC primary transcript levels. The effects of CRF on the POMC primary transcript and nuclear processing intermediate were not potentiated by cotreatment with AVP, although a potentiation of CRF-stimulated ACTH release was observed. POMC nuclear and cytoplasmic mRNA levels were not affected by these 2-h or less treatments, while an 18-h incubation with 0.5 nM CRF alone or in combination with 100 nM AVP increased POMC cytoplasmic mRNA levels to about 140% of vehicle-treated control values. When a 1-h AVP treatment (100 nM) preceded presentation of CRF, we observed an attenuation of the stimulation of POMC primary transcript and processing intermediate levels by the 1-h CRF treatment. The effects of CRF on POMC primary transcript and processing intermediate levels in these experiments are consistent with a CRF-induced increase in POMC gene transcription. Our findings that AVP decreased primary transcript levels and attenuated the effects of CRF on this end point suggest that: 1) AVP clearly does not act in a synergistic manner with CRF to stimulate POMC gene expression; and 2) AVP possibly affects RNA stability and/or processing.

Adrenocorticotropic Hormone↗

PubMed1990

Thyroid hormone and dexamethasone increase the levels of a messenger ribonucleic acid for a mitochondrially encoded subunit but not for a nuclear-encoded subunit of cytochrome c oxidase.

The nuclear genome is the primary locus of activity for thyroid hormone and dexamethasone; however, one well described secondary effect of treatment with these hormones is increased mitochondrial respiratory activity. To examine the mechanism of the increase in respiration, we have treated a rat hepatoma cell line, HTC cells, with thyroid hormone and dexamethasone and measured their effects on the activity of a respiratory chain enzyme and on mitochondrial (mt) RNA and mtDNA levels. Thyroid hormone, but not dexamethasone, increased cytochrome c oxidase activity in HTC cells; the increase in activity was nearly 2-fold over control values. To determine whether this increased activity was the result of coordinate increases in expression of nuclear and cytoplasmic genes for this enzyme, we measured changes in the levels of messenger RNAs for both nuclear and mitochondrially encoded cytochrome oxidase subunits. Treatment of HTC cells with thyroid hormone and/or dexamethasone resulted in 3- to 4-fold increases in the levels of several RNAs encoded in the mt genome, including subunit II of cytochrome c oxidase. In contrast, this treatment had no effect on the messenger RNA encoding a nuclear subunit of this same enzyme. Neither of these hormones had any effect on cell number or on the level of mtDNA. Dose response and time course of thyroid hormone and dexamethasone administration on mtRNA levels were consistent with these hormones acting through their nuclear hormone receptors. Increased expression of the mt genome by alteration of transcription or RNA stability is a likely candidate for a mechanism by which these hormones can regulate mitochondrial activity.

Animals↗

PubMed1996

Polyadenylation accelerates degradation of chloroplast mRNA.

The expression of chloroplast genes is regulated by several mechanisms, one of which is the modulation of RNA stability. To understand how this regulatory step is controlled during chloroplast development, we have begun to define the mechanism of plastid mRNA degradation. We show here that the degradation petD mRNA involves endonucleolytic cleavage at specific sites upstream of the 3' stem-loop structure. The endonucleolytic petD cleavage products can be polyadenylated in vitro, and similar polyadenylated RNA products are detectable in vivo. PCR analysis of the psbA and psaA-psaB-rps14 operons revealed other polyadenylated endonucleolytic cleavage products, indicating that poly(A) addition appears to be an integral modification during chloroplast mRNA degradation. Polyadenylation promotes efficient degradation of the cleaved petD RNAs by a 3'-5' exoribonuclease. Furthermore, polyadenylation also plays an important role in the degradation of the petD mRNA 3' end. Although the 3' end stem-loop is usually resistant to nucleases, adenylation renders the secondary structure susceptible to the 3'-5' exoribonuclease. Analysis of 3' ends confirms that polyadenylation occurs in vivo, and reveals that the extent of adenylation increases during the degradation of plastid mRNA in the dark. Based on these results, we propose a novel mechanism for polyadenylation in the regulation of plastid mRNA degradation.

Chloroplasts↗

PubMed1986

Immunochemical analysis of mammalian RNA polymerase II subspecies. Stability and relative in vivo concentration.

Three subspecies of RNA polymerase II, designated IIO, IIA, and IIB, have been described in a variety of eukaryotic cells and shown to differ in the molecular weight of their largest subunit, designated IIo, IIa, and IIb, respectively. The objectives of this study were to establish the in vivo molecular structure of RNA polymerase II in mammalian cells and to examine conditions that influence the stability of RNA polymerase II subspecies. Subunit affinity-purified antibodies were used to determine the relative concentration of subunits IIo, IIa, and IIb in crude extracts of calf thymus tissue, cultured bovine kidney cells, and HeLa cells. HeLa cells contain exclusively RNA polymerase IIO whereas both cultured bovine kidney cells and calf thymus tissue contain RNA polymerases IIO and IIA. RNA polymerase IIB was not detected at significant levels in any of the cell extracts examined. Cell extracts were aged at either 4 degrees or 37 degrees C and the stability of RNA polymerases IIO and IIA determined by protein blotting. In the presence of buffer normally used for RNA polymerase purification, subunit IIo disappears from calf thymus extracts within 24 h at 4 degrees C or within 5 min at 37 degrees C. RNA polymerase IIO is partially stabilized by the inclusion of protease inhibitors and further stabilized by the presence of relatively high concentration of EDTA and EGTA. The prior fractionation of nuclei does not have an appreciable effect on RNA polymerase II stability. An increase in the amount of reducing agent causes a dramatic reduction in the stability of subunit IIo. The following manuscript (Bartholomew, B., Dahmus, M. E., and Meares, C. F. (1986) J. Biol. Chem. 14226-14231) examines the transcriptional activity of RNA polymerases IIO and IIA in reactions dependent on the major late promoter of adenovirus-2. Photoaffinity labeling of subunits IIo and IIa, relative to their concentration in the transcription extract, indicates that the transcriptional activity of RNA polymerase IIO is greater than 10 times that of IIA.

Animals↗

PubMed1994

Nonsense-mediated mRNA decay in Xenopus oocytes and embryos.

Mutant mRNAs carrying a premature stop codon have a reduced half-life in the cells of many species, probably due to the presence of "surveillance" pathways, which selectively target such mRNAs for degradation. It is reported here that this phenomenon may also occur in Xenopus. In vitro-synthesised transcripts encoding a Xenopus POU-domain protein, XLPOU-60, are stable after injection into the oocyte and embryo. However, introduction of a premature stop codon into these transcripts results in their rapid degradation following injection. In contrast, mutant transcripts with additional or deleted codons but retaining a correct reading frame are stable. These results suggest that RNA stability should be considered when designing control mRNAs for Xenopus injection experiments.

Animals↗

PubMed2004

Argonaute protein in the early divergent eukaryote Trypanosoma brucei: control of small interfering RNA accumulation and retroposon transcript abundance.

Members of the Argonaute protein family have been linked through a combination of genetic and biochemical studies to RNA interference (RNAi) and related phenomena. Here, we describe the characterization of the first Argonaute protein (AGO1) in Trypanosoma brucei, the earliest divergent eukaryote where RNAi has been described so far. AGO1 is predominantly cytoplasmic and is found in a ribonucleoprotein particle with small interfering RNAs (siRNAs), and this particle is present in a soluble form, as well as associated with polyribosomes. A genetic knockout of AGO1 leads to a loss of RNAi, and concomitantly, endogenous retroposon-derived siRNAs as well as siRNAs derived from transgenic double-stranded RNA are reduced to almost undetectable levels. Furthermore, AGO1 deficiency leads to an increase in retroposon transcript abundance via mechanisms operating at the transcriptional level and at the RNA stability level. Our results suggest that AGO1 function is required for production and/or stabilization of siRNAs and provide the first evidence for an Argonaute protein being involved in the regulation of retroposon transcript levels.

Amino Acid Sequence↗

PubMed2006

Expression of thyroid hormone receptor isoforms down-regulated by thyroid hormone in human medulloblastoma cells.

The role of thyroid hormone (T3) in the regulation of growth and development of the central nervous system including the cerebellum has been well established. However, the effects of thyroid hormone on malignant tumors derived from the cerebellum remain poorly understood. Our analysis mainly focused on expression levels of TR isoforms and the effects of thyroid hormone in human medulloblastoma HTB-185 cells. Northern blot analysis revealed TRalpha2 mRNA but not TRalpha1, beta1 or beta2 mRNA in the cell. The TRalpha1 and TRbeta1 mRNAs were detected only by RT-PCR method and TRbeta2 was not expressed. Incubation of T3 for 24 h decreased TRalpha1, TRalpha2 and TRbeta1 mRNA. Addition of actinomycin D caused an acute increase in the basal TR mRNA levels and the rate of decrease of all kinds of TR isoform mRNA was accelerated in the T3-treated groups compared to controls, indicating that the stability of TR mRNA was affected by T3. Incubation with cycloheximide also blocked a decrease in TR mRNA levels in the T3-treated HTB-185 cells suggesting that down-regulation of TR mRNA required the synthesis of new protein. Our data provide novel evidence for the expression of TRs down-regulated by T3 in HTB-185 cells, suggesting that TR expression is post-transcriptionally regulated by T3 at the level of RNA stability.

Brain Neoplasms↗

PubMed1999

La autoantigen specifically recognizes a predicted stem-loop in hepatitis B virus RNA.

We recently identified three nuclear proteins (p45, p39, and p26) that bind to a 91-nucleotide (nt) RNA element between nt 1243 and 1333 in hepatitis B virus (HBV) RNA, and we showed that these proteins and HBV RNA are regulated coordinately by gamma interferon and tumor necrosis factor alpha. Purification and sequence analysis of tryptic peptides obtained from p39 revealed sequence homology to the mouse La protein. Immunoprecipitation experiments showed that p45, p39, and p26 were recognized by anti-La-specific antiserum, indicating that p45 is the full-length La protein and that p39 and p26 are likely to be proteolytic La cleavage products. Furthermore, in competition experiments we found that all three La proteins bind, in a phosphorylation-dependent manner, to the same predicted stem-loop structure located between nt 1275 and 1291 of HBV, with Kds of approximately 1.0 nM. Collectively, these results support the notion that the La protein may contribute to HBV RNA stability, constitutively and in response to inflammatory cytokines.

Amino Acid Sequence↗

PubMed2026

Epitranscriptomic Regulation of ALDOA by SHMT2-Mediated m6A Modification Drives Gastric Cancer Malignancy.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic advancements despite progress in early detection. Serine hydroxymethyltransferase 2 (SHMT2), a key metabolic enzyme, and fructose-1,6-bisphosphate aldolase A (ALDOA), a glycolytic enzyme, are implicated in tumor progression. However, the molecular mechanisms linking SHMT2 and ALDOA in GC remain unclear. This study investigates how SHMT2 regulates ALDOA expression via m6A RNA modification to drive GC malignancy. Bioinformatic analyses (TCGA, LinkedOmics, and SRAMP) were used to assess SHMT2 expression in GC patients and identify its correlated genes. In vitro experiments (CCK-8, EdU, Transwell, and wound healing) evaluated the effects of SHMT2 overexpression or knockdown on GC cell proliferation, migration, invasion, and glycolysis. m6A modification of ALDOA was analyzed via MeRIP-PCR and dual-luciferase assays, while RNA stability was assessed using actinomycin D treatment. Xenograft models validated SHMT2's role in vivo. SHMT2 was upregulated in GC tissues and cell lines, correlating with advanced tumor stages and poor prognosis. SHMT2 knockdown suppressed GC cell viability, migration, invasion, and glycolysis, while overexpression enhanced these traits. Mechanistically, SHMT2 increased S-adenosylmethionine levels, promoting ALDOA m6A modification, likely mediated through the predicted site 1 (position 291). This modification stabilized ALDOA mRNA via IGF2BP1 recognition, an m6A reader. ALDOA overexpression reversed the tumor-suppressive effects of SHMT2 knockdown. In vivo, SHMT2 depletion reduced tumor growth and Ki67 expression in xenograft models. In conclusion, SHMT2 drives GC progression by enhancing ALDOA expression through m6A modification and IGF2BP1-mediated stabilization. Targeting the SHMT2-ALDOA axis represents a promising therapeutic strategy for gastric cancer.

Humans↗