The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index; 10 of the 43 sources its claims cite were checked for support.
Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA
Open accessAbstract
An increased understanding of low-density lipoprotein receptor (LDLR) and its regulation may facilitate drug development for the treatment of hypercholesterolemia. Triciribine (TCN), which is a highly selective AKT inhibitor, increases the stability of LDLR mRNA downstream of extracellular signal-regulated kinase (ERK) in human hepatoma cells (HepG2). Here, a candidate approach was used in order to determine whether the RNA-binding proteins (RBPs) ZFP36 ring finger protein like 1 (ZFP36L1) and Hu antigen R (HuR) play a role in TCN-mediated stabilization of LDLR mRNA. The depletion of HuR led to a reduction of LDLR mRNA stability, an event that was more pronounced in TCN-treated cells. TCN was found to induce the translocation of nuclear HuR to cytoplasm in an ERK-dependent manner. ZFP36L1 depletion increased the stability of LDLR mRNA consistent with its destabilizing role. However, in contrast to HuR, TCN had no effect on LDLR mRNA turnover in ZFP36L1-depleted cells. TCN induced the phosphorylation of ZFP36L1 in an ERK/RSK-dependent manner and promoted its dissociation from the CCR4-NOT complex. In sum, these data suggest that TCN utilizes ERK signaling to increase the activity of HuR and inhibit ZFP36L1 to stabilize LDLR mRNA in HepG2 cells.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Triciribine (TCN) stabilizes LDLR mRNA in HepG2 cells by ERK-dependent activation of HuR and inhibition of ZFP36L1. HuR depletion reduces LDLR mRNA stability, while ZFP36L1 depletion increases it; TCN promotes cytoplasmic HuR translocation and ERK/RSK1-dependent ZFP36L1 phosphorylation with dissociation from CNOT7.
Key findings
- HuR depletion reduced LDLR protein and mRNA by approximately 30% and only slightly decreased LDLR mRNA stability; in TCN-treated cells, HuR depletion more prominently reduced LDLR expression and increased LDLR mRNA turnover.
- ZFP36L1 depletion enhanced LDLR protein and mRNA expression twofold and increased LDLR mRNA stability; in ZFP36L1-depleted cells, TCN had no effect on LDLR protein, mRNA, or mRNA turnover.
- TCN induced ZFP36L1 phosphorylation in an ERK/RSK1-dependent manner, as shown by gel mobility shift that was lost with U0126 or BI-D1870 and eliminated by CIAP; TCN also reduced ZFP36L1 interaction with CNOT7, partially reversed by U0126.
- TCN increased cytoplasmic HuR about twofold and promoted nuclear-to-cytoplasmic HuR translocation in an ERK-dependent manner; approximately 30% of the TCN induction on LDLR mRNA stability could be explained by HuR and ZFP36L1.
Methods
- HepG2 human hepatoma cells were treated with 1 µM triciribine (TCN), 100 ng/mL PMA, 10 µM U0126, 10 µM BI-D1870, and 5 µg/mL actinomycin D; siRNA was used against HuR, ZFP36L1, or RSK1.
- Main analyses included Western blotting, quantitative real-time PCR, mRNA stability assays after actinomycin D, immunoprecipitation of FLAG- or HA-tagged proteins, subcellular fractionation, and confocal immunofluorescence microscopy.
- Statistical comparisons used unpaired or paired two-tailed Student’s t-tests with p < 0.05 considered significant; experiments with target knockdown below 70% or failed TCN induction of LDLR mRNA (2–4 fold) were excluded.
Limitations
- The paper states that HuR knockdown efficiency was only approximately 70%, that the HuR-depletion effect on LDLR mRNA stability was less prominent than in another study, and that a stronger effect would be expected with more efficient knockdown.
- The paper states that only approximately 30% of the TCN induction on LDLR mRNA stability could be explained by HuR and ZFP36L1, and that other transacting proteins are likely involved; a more comprehensive screen of proteins binding the LDLR 3′UTR after TCN treatment is needed.
- Evident from the text: the study is limited to HepG2 cells and a candidate-protein approach, with no in vivo or broader cell-type validation reported.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Verification
Claims the paper makes
10 of 43 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured
- Premisecitation
HuR confers stability to LDLR mRNA.
“Among these, Hu antigen R (HuR) is one of the few RBPs identified that confers stability to LDLR mRNA [9,13,14]”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [9] Singh, 2018, Farnesoid X Receptor Activation by Obeticholic Acid Elevates Liver Low-Density Lipoprotein Receptor Expression by mRNA Stabilization and Reduces Plasma Low-Density Lipoprotein Cholesterol in Mice, Arterioscler. Thromb. Vas. Biol. source
- cites [13] Li, 2009, Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements, J. Lipid Res. source
The paper’s abstract identifies hnRNP D, hnRNP I, and KSRP as regulators of LDLR mRNA stability, but does not identify HuR as a stabilizer. A search for HuR found it in titles of cited works, not in a passage linking HuR to LDLR mRNA stability; the claim cannot be verified from our copy. (LLM, conf=0.73)
Experimental — accuracy not yet measured - cites [14] Yashiro, 2013, 5-Aminoimidazole-4-carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via ERK-dependent HuR binding to an AU-rich element, Atherosclerosis source
- Premisecitation
ZFP36L1 recruits the CCR4-NOT deadenylase complex to LDLR 3′ UTR through interaction with CNOT7, resulting in LDLR mRNA degradation.
“ZFP36L1 has been shown to recruit the CCR4-NOT deadenylase complex to LDLR 3′ UTR through interaction with CNOT7, which results in its mRNA degradation [15].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
- Findingown data
HuR depletion only slightly decreased LDLR mRNA stability.
“though its mRNA stability was only slightly decreased (Figure 1c).”
Quote in the paperSubstantial claim - Findingown data
TCN has no effect on LDLR mRNA turnover in ZFP36L1-depleted cells.
“However, in contrast to HuR, TCN had no effect on LDLR mRNA turnover in ZFP36L1-depleted cells.”
- Also stated in: § 2.2. HuR and ZFP36L1 Contribute to TCN-Mediated Stabilization of LDLR mRNA · plain
“In ZFP36L1-depleted cells, TCN had no effect on LDLR protein or mRNA (Figure 2a,b), or its mRNA turnover (Figure 2c), contrary to HuR.”
Quote in the paperSubstantial claim - Also stated in: § 2.2. HuR and ZFP36L1 Contribute to TCN-Mediated Stabilization of LDLR mRNA · plain
- Findingown data
TCN-induced phosphorylation of ZFP36L1 is dependent on RSK1 activity.
“TCN-induced phosphorylation of ZFP36L1 is dependent on RSK1 activity (Figure 4 and Figures S2 and S3)”
Quote in the paperSubstantial claim
- Findingown data
Upon subcellular fractionation, TCN treatment caused a two-fold increase in HuR protein levels in the cytoplasm.
“but, upon subcellular fractionation, a two-fold increase in HuR protein levels was detected in the cytoplasm (Figure 6b), similar to that for PMA (Figure S4).”
Quote in the paperSubstantial claim - Findingown data
Nuclear HuR was reduced upon TCN and PMA exposure.
“Nuclear HuR was accordingly reduced upon TCN and PMA exposure (Figure 6f).”
Quote in the paperSubstantial claim - Findingown data
Depletion of ZFP36L1 increased LDLR mRNA stability in HepG2 cells.
“which was echoed by an increase in mRNA stability (Figure 1b,c)”
Quote in the paperSubstantial claim - Findingown data
The LDLR mRNA level consistently echoed that of its protein.
“The LDLR mRNA level consistently echoed that of its protein (Figure 4c).”
Quote in the paperSubstantial claim - Findingown data
Inhibition of ERK with U0126 partially reversed the inhibitory effect of TCN on CNOT7 and ZFP36L1 interaction.
“the inhibition of ERK with U0126 partially reversed the inhibitory effect of TCN on CNOT7 and ZFP36L1 interaction (Figure 5a–c)”
Quote in the paperSubstantial claim - Findingown data
ZFP36L1 depletion increases the stability of LDLR mRNA.
“ZFP36L1 depletion increased the stability of LDLR mRNA consistent with its destabilizing role.”
- Also stated in: § 2.1. HuR and ZFP36L1 Modulate Endogenous LDLR Expression and mRNA Stability in HepG2 Cells · plain
“The depletion of ZFP36L1 enhanced LDLR protein (Figure 1a and Figure S1) and mRNA expression twofold (Figure 1b) and were echoed by increased mRNA stability (Figure 1c).”
Quote in the paperSubstantial claim - Also stated in: § 2.1. HuR and ZFP36L1 Modulate Endogenous LDLR Expression and mRNA Stability in HepG2 Cells · plain
- Findingown data
The TCN-induced gel mobility shift of ZFP36L1 disappeared upon inhibiting ERK.
“which disappeared upon inhibiting ERK (Figure 3)”
Quote in the paperSubstantial claim - Findingown data
A siRNA-mediated decrease in HuR levels reduced LDLR protein and its mRNA approximately 30%.
“Figure 1a and Figure S1 show that a siRNA-mediated decrease in HuR levels reduced LDLR protein and its mRNA approximately 30% (Figure 1b)”
Quote in the paperSubstantial claim - Findingown data
Co-treatment of TCN-exposed cells with U0126 prominently reduced HuR abundance in the cytoplasm.
“Co-treatment of TCN-exposed cells with U0126 prominently reduced HuR abundance in the cytoplasm, as judged from the western blot presented in Figure 6c and Figure S5.”
Quote in the paperSubstantial claim - Findingown data
The proportion of cells with cytoplasmic HuR-staining prominently increased upon TCN and PMA-treatment compared to untreated cells.
“The proportion of cells with cytoplasmic HuR-staining prominently increased upon TCN and PMA-treatment, when compared to untreated cells (Figure 6f).”
Quote in the paperSubstantial claim - Findingown data
Upon co-treatment with U0126, TCN was unable to induce ZFP36L1 phosphorylation.
“Indeed, upon the co-treatment of cells with U0126, TCN was unable to induce ZFP36L1 phosphorylation (Figure 3b,c).”
Quote in the paperSubstantial claim - Findingown data
HuR-depleted cells exhibited reduced LDLR protein and mRNA expression in response to TCN.
“HuR depleted cells exhibited reduced LDLR protein and mRNA expression in response to TCN, as shown in Figure 2a,b and Figure S1.”
Quote in the paperSubstantial claim - Findingown data
TCN and PMA-treated cells co-treated with U0126 had an equal proportion of HuR in nuclei and cytoplasm for all treatments.
“In addition, TCN and PMA-treated cells co-treated with U0126 had an equal proportion of HuR in nuclei and cytoplasm for all treatments (Figure 6f).”
Quote in the paperSubstantial claim - Findingown data
ZFP36L1-depleted cells had a similar increase in LDLR mRNA stability as control cells upon TCN treatment.
“ZFP36L1-depleted cells had however a similar increase in LDLR mRNA stability as compared to control cells upon TCN-treatment (Figure 2).”
Quote in the paperSubstantial claim- Rests on an assumption: TCN inactivation of ZFP36L1 precedes its knockdown by siRNA.
- Findingown data
In ZFP36L1-depleted cells, TCN had no effect on LDLR protein or mRNA.
“In ZFP36L1-depleted cells, TCN had no effect on LDLR protein or mRNA (Figure 2a,b)”
Quote in the paperSubstantial claim - Findingown data
Depletion of ZFP36L1 enhanced LDLR protein and mRNA expression twofold.
“The depletion of ZFP36L1 enhanced LDLR protein (Figure 1a and Figure S1) and mRNA expression twofold (Figure 1b)”
Quote in the paperSubstantial claim - Findingown data
CNOT7 and ZFP36L1 interact.
“As can be seen in Figure 5, CNOT7 immunocomplexes contained ZFP36L1 indicating that these two proteins interact.”
- Also stated in: § 2.5. TCN Inhibits Association of ZFP36L1 with CNOT7 · hedged
“HA-ZFP36L1 immunocomplexes contained CNOT7 indicating interaction between these two proteins.”
Quote in the paperSubstantial claim - Also stated in: § 2.5. TCN Inhibits Association of ZFP36L1 with CNOT7 · hedged
- Findingown data
TCN prominently reduced the expression and stability of LDLR mRNA upon HuR-depletion.
“However, TCN prominently reduced the expression and stability of LDLR mRNA upon HuR-depletion.”
Quote in the paperSubstantial claim - Findingown data
TCN induced a gel mobility shift of ZFP36L1 due to phosphorylated forms of the protein.
“TCN induced a gel mobility shift of ZFP36L1 due to phosphorylated forms of the protein”
Quote in the paperSubstantial claim - Findingown data
Depletion of ZFP36L1 enhanced LDLR protein and mRNA expression twofold in HepG2 cells.
“depletion of ZFP36L1 enhanced LDLR protein (Figure 1a and Figure S1) and mRNA expression twofold”
Quote in the paperSubstantial claim - Findingown data
TCN treatment does not cause an obvious change in total HuR expression.
“Western blot analysis using whole-cell lysates revealed no obvious change in the total HuR expression upon TCN treatment (Figure 6a)”
Quote in the paperSubstantial claim - Findingown data
Exposure of cells to TCN or PMA reduced the level of CNOT7 in ZFP36L1 immunoprecipitates.
“The exposure of cells to TCN or PMA reduced the level of CNOT7 in ZFP36L1 immunoprecipitates.”
Quote in the paperSubstantial claim - Findingown data
TCN and PMA phosphorylate ZFP36L1, an event abolished upon co-treatment with U0126.
“TCN and PMA phosphorylates ZFP36L1, an event that is abolished upon co-treatment with U0126 (total lysate in Figure 5).”
Quote in the paperSubstantial claim - Findingown data
Inhibiting ERK1/2 with U0126 increases the binding affinity of ZFP36L1 and CNOT7 compared to TCN- and PMA-treatment alone.
“Inhibiting ERK1/2 with the co-treatment of U0126 increases the binding affinity of ZFP36L1 and CNOT7, compared to TCN- and PMA-treatment alone (Figure 5a–c).”
Quote in the paperSubstantial claim - Findingown data
Co-treatment with U0126 increased the interaction between CNOT7 and ZFP36L1 compared to TCN- and PMA-treated cells.
“Additionally, co-treatment with U0126 increased the interaction between CNOT7 and ZFP36L1 when compared to TCN- and PMA-treated cells.”
Quote in the paperSubstantial claim - Findingown data
TCN increased the turnover rate of LDLR mRNA in HuR-depleted cells.
“Consistently, TCN increased the turnover rate of LDLR mRNA in HuR-depleted cells (Figure 2c).”
Quote in the paperSubstantial claim - Findingown data
TCN-mediated stabilization of LDLR mRNA requires ERK and its downstream target RSK1.
“present data showing that TCN-mediated stabilization of LDLR mRNA, require ERK and its downstream target RSK1”
Quote in the paperSubstantial claim - Findingown data
Co-treatment with U0126 partially reversed the inhibitory effect of TCN on CNOT7 and ZFP36L1 interaction.
“Furthermore, co-treatment with U0126 partially reversed the inhibitory effect of TCN on CNOT7 and ZFP36L1 interaction (Figure 5a).”
Quote in the paperSubstantial claim - Findingreasoning
Approximately 30% of the TCN induction on LDLR mRNA stability could be explained by HuR and ZFP36L1.
“Approximately 30% of the TCN induction on LDLR mRNA stability could be explained by these two proteins.”
Quote in the paperSubstantial claim - Findingown data
TCN reduced the interaction of ZFP36L1 and CNOT7.
“cells exposed to TCN had reduced interaction of ZFP36L1 and CNOT7, as shown by co-immunoprecipitation experiments presented in Figure 5a–c.”
Quote in the paperSubstantial claim - Findingown data
siRNA targeting RSK1 abrogated the effects of TCN and PMA on LDLR protein levels.
“In order to confirm the results using RSK1-inhibitor BI-D1870 presented in Figure 4b), siRNA targeting RSK1 was performed and the abrogated effects of TCN and PMA on LDLR protein levels were also seen in RSK1-depleted cells (Figure 4d and Figure S3).”
Quote in the paperSubstantial claim - Findingown data
Exposure of cells to TCN or PMA reduced the level of ZFP36L1 in CNOT7 immunoprecipitates.
“Importantly, the exposure of cells to TCN or PMA reduced the level of ZFP36L1 in CNOT7 immunoprecipitates.”
Quote in the paperSubstantial claim - Premisecitation
Triciribine (TCN) increases the stability of LDLR mRNA downstream of ERK in human hepatoma cells (HepG2).
“Triciribine (TCN), which is a highly selective AKT inhibitor, increases the stability of LDLR mRNA downstream of extracellular signal-regulated kinase (ERK) in human hepatoma cells (HepG2).”
- Also stated in: § 1. Introduction · plain
“Recently, it was reported that TCN increases LDLR levels by preventing the degradation of LDLR mRNA in an ERK activity-dependent manner [12].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Bjune, 2018, Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA, Sci. Rep. source
- Also stated in: § 1. Introduction · plain
- Interpretationreasoning
ERK is the common denominator linking TCN to regulation of ZFP36L1 phosphorylation.
“place ERK as the common denominator linking TCN to regulation of ZFP36L1 phosphorylation”
Quote in the paperSubstantial claim - Interpretationown data
TCN exerts an inhibitory effect on the association of ZFP36L1 with CNOT7 in an ERK-dependent manner.
“these results indicate that TCN exerts an inhibitory effect on the association of ZFP36L1 with CNOT7 in an ERK-dependent manner.”
Quote in the paperSubstantial claim - Interpretationown data
TCN promotes the nuclear export of HuR to the cytoplasm in an ERK-dependent manner.
“In sum, these results show that TCN promotes the nuclear export of HuR to cytoplasm in an ERK-dependent manner.”
- Also stated in: § Abstract · plain
“TCN was found to induce the translocation of nuclear HuR to cytoplasm in an ERK-dependent manner.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Interpretationown data
TCN promotes dissociation of ZFP36L1 from the CCR4-NOT complex.
“TCN induced the phosphorylation of ZFP36L1 in an ERK/RSK-dependent manner and promoted its dissociation from the CCR4-NOT complex.”
- Also stated in: § 2.5. TCN Inhibits Association of ZFP36L1 with CNOT7 · plain
“Together, these complementary data presented in Figure 5a-c show that the interaction between ZFP36L1 and CNOT7 is reduced upon TCN and PMA-treatment.”
Quote in the paperSubstantial claim - Also stated in: § 2.5. TCN Inhibits Association of ZFP36L1 with CNOT7 · plain
- Interpretationown data
TCN induces translocation of nuclear HuR to the cytoplasm in an ERK-dependent manner.
“TCN was found to induce the translocation of nuclear HuR to cytoplasm in an ERK-dependent manner.”
- Also stated in: § 2.6. TCN Induces Translocation of Nuclear HuR to the Cytoplasm in an ERK-Dependent Manner · plain
“In sum, these results show that TCN promotes the nuclear export of HuR to cytoplasm in an ERK-dependent manner.”
- Also stated in: § 3. Discussion · hedged
“Confocal immunofluorescence data confirmed the biochemical fractionation data and strongly suggest that HuR translocate from the nucleus to the cytoplasm upon TCN treatment in an ERK-dependent manner and protects LDLR mRNA from the mRNA decay machinery (Figure 6d–f).”
Quote in the paperSubstantial claim - Also stated in: § 2.6. TCN Induces Translocation of Nuclear HuR to the Cytoplasm in an ERK-Dependent Manner · plain
- Interpretationown data
HuR acts as a mediator of the stabilizing effect of TCN on LDLR mRNA.
“These data indicate a role for HuR as a mediator of the stabilizing effect of TCN on LDLR mRNA.”
- Also stated in: § 3. Discussion · hedged
“These data indicate a role for HuR as a mediator of the stabilizing effect of TCN on LDLR mRNA.”
Quote in the paperSubstantial claim - Also stated in: § 3. Discussion · hedged
- Study design and conductown data
HuR siRNA reduced HuR protein levels by only approximately 70%.
“HuR siRNA reduced HuR protein levels by only approximately 70% (Figure 1a).”
- Also stated in: § 3. Discussion · plain
“In this report the knockdown efficiency of HuR was 70% and the effect on LDLR mRNA stability upon HuR-depletion was less prominent than that reported by Yashiro et al. [14].”
Quote in the paperSubstantial claim - Also stated in: § 3. Discussion · plain
- Interpretationown data
ZFP36L1 is a LDLR mRNA-destabilizing protein in HepG2 cells.
“confirms ZFP36L1 as a LDLR mRNA-destabilizing protein in HepG2 cells [9,13,14,15]”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [9] Singh, 2018, Farnesoid X Receptor Activation by Obeticholic Acid Elevates Liver Low-Density Lipoprotein Receptor Expression by mRNA Stabilization and Reduces Plasma Low-Density Lipoprotein Cholesterol in Mice, Arterioscler. Thromb. Vas. Biol. source
- cites [13] Li, 2009, Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements, J. Lipid Res. source
- cites [14] Yashiro, 2013, 5-Aminoimidazole-4-carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via ERK-dependent HuR binding to an AU-rich element, Atherosclerosis source
- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
- Interpretationreasoning
Other transacting proteins are likely involved in the TCN-induced stabilization of LDLR mRNA.
“Other transacting proteins are likely involved in the TCN-induced stabilization of LDLR mRNA”
Quote in the paperNot a substantial claim - Premisecitation
ZFP36L1, ZFP36L2, and KSRP accelerate the turnover of LDLR mRNA.
“whereas ZFP36 ring finger protein like-1 and -2 proteins (ZFP36L1 and ZFP36L2) and KH-type splicing regulatory protein (KSRP) accelerate the turnover of LDLR mRNA [13,15].”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
ZFP36L1 and ZFP36L2, upon binding AREs in target mRNA 3′UTRs, recruit the CCR4-NOT complex to the adjoining polyA tail, promoting deadenylation and degradation.
“ZFP36L1 and ZFP36L2 belong to the TPA-inducible sequence 11 (TIS11) protein families that, upon binding to AREs in the 3′ UTRs of their target mRNAs, recruit the CCR4-NOT complex to the adjoining polyA tail, thus promoting the deadenylation of mRNA and ultimately its degradation [15].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
- Premisecitation
LDLR mRNA becomes stabilized two- to three-fold in response to extracellular stimuli including PMA, bile acids, berberine, and TCN.
“LDLR mRNA has a half-life of approximately 1–2 h in HepG2 cells and it becomes stabilized two- to three-fold in response to extracellular stimuli, including phorbol 12-myristate 13-acetate (PMA) [7], bile acids [8,9], berberine (BBR) [5,10,11], and triciribine (TCN) [12].”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [7] Wilson, 1997, Modulation of LDL receptor mRNA stability by phorbol esters in human liver cell culture models, J. Lipid Res. source
- cites [8] Nakahara, 2002, Bile acids enhance low density lipoprotein receptor gene expression via a MAPK cascade-mediated stabilization of mRNA, J. Biol. Chem. source
- cites [9] Singh, 2018, Farnesoid X Receptor Activation by Obeticholic Acid Elevates Liver Low-Density Lipoprotein Receptor Expression by mRNA Stabilization and Reduces Plasma Low-Density Lipoprotein Cholesterol in Mice, Arterioscler. Thromb. Vas. Biol. source
- cites [5] Kong, 2004, Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins, Nat. Med. source
- cites [10] Abidi, 2005, Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine, Arterioscler. Thromb. Vas. Biol. source
- cites [11] Abidi, 2006, The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms, J. Lipid Res. source
- Study design and conductown data
siRNA directed against ZFP36L1 efficiently reduced ZFP36L1 protein level.
“In contrast, siRNA directed against ZFP36L1 efficiently reduced ZFP36L1 protein level (Figure 1a).”
Quote in the paperSubstantial claim - Interpretationown data
TCN induces phosphorylation of ZFP36L1 in an ERK/RSK-dependent manner.
“TCN induced the phosphorylation of ZFP36L1 in an ERK/RSK-dependent manner and promoted its dissociation from the CCR4-NOT complex.”
- Also stated in: § 2.3. TCN Induces Phosphorylation of ZFP36L1 Downstream of ERK · plain
“Thus, TCN induces phosphorylation and a gel mobility shift of ZFP36L1.”
- Also stated in: § 2.4. TCN-Induced ZFP36L1 Phosphorylation is Mediated by the ERK Downstream Target RSK1 · boosted
“These results show that TCN requires the activity of RSK1 to induce ZFP36L1 phosphorylation, an event that is associated with TCN-induced LDLR mRNA.”
Quote in the paperSubstantial claim - Also stated in: § 2.3. TCN Induces Phosphorylation of ZFP36L1 Downstream of ERK · plain
- Interpretationown data
The interaction between ZFP36L1 and CNOT7 is reduced upon TCN and PMA treatment.
“Together, these complementary data presented in Figure 5a-c show that the interaction between ZFP36L1 and CNOT7 is reduced upon TCN and PMA-treatment.”
Quote in the paperSubstantial claim - Premisecitation
The destabilizing effect of ZFP36L1 on LDLR mRNA requires the binding of the CCR4-NOT-deadenylase complex to its 3′UTR.
“Adachi et al. [15] demonstrated that the destabilizing effect of ZFP36L1 on LDLR mRNA requires the binding of the CCR4-NOT-deadenylase complex to its 3‘UTR.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
- Probably not a substantial claim. 16
- It may state two separate claims as one. 18
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOnly the ERK-dependent phosphorylation of endogenous ZFP36L1 has been rigorously examined.
“only the ERK-dependent phosphorylation of endogenous ZFP36L1 has been rigorously examined [15]”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
In Results, ‘ZFP36L1 is regulated by phosphorylation downstream of ERK’ (page unavailable), the authors report phosphorylation of endogenous ZFP36L1 at serine-334 after PMA treatment. They establish ERK-pathway dependence using tagged ZFP36L1, but the cited passage does not establish ERK dependence specifically for endogenous protein or the broader claim that only this phosphorylation has been rigorously examined. (LLM, conf=0.84)
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationHuR and ZFP36L1 were considered likely candidates because they have been reported to modulate LDLR mRNA stability in response to agents that activate ERK and their mechanisms have been partially resolved.
“These two proteins were considered to be likely candidates, because (1) they have been reported to modulate LDLR mRNA stability in response to agents that activate ERK and (2) the mechanisms underlying their regulatory effect on LDLR mRNA stability have been partially resolved [9,13,14,15].”
Quote in the paperSubstantial claim3 of 4 sources checked- cites [9] Singh, 2018, Farnesoid X Receptor Activation by Obeticholic Acid Elevates Liver Low-Density Lipoprotein Receptor Expression by mRNA Stabilization and Reduces Plasma Low-Density Lipoprotein Cholesterol in Mice, Arterioscler. Thromb. Vas. Biol. source
- cites [13] Li, 2009, Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements, J. Lipid Res. source
The Results (page not supplied) report that ELAVL1 (HuR) depletion diminished berberine’s effect on LDLR mRNA expression, supporting a role for HuR in the response. Our copy does not report a comparable finding for ZFP36L1 or partially resolve the mechanisms of these two proteins. It identifies berberine-related regulation but does not establish the claimed ERK link for both proteins. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [14] Yashiro, 2013, 5-Aminoimidazole-4-carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via ERK-dependent HuR binding to an AU-rich element, Atherosclerosis source
- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
The Introduction and Discussion report that ZFP36L1 destabilizes LDLR mRNA and that ERK–RSK signaling inhibits this activity; the Introduction also describes phosphorylation of ZFP36L1 as part of the mechanism. These passages support the claim for ZFP36L1, but our copy does not establish the corresponding claim for HuR. Page numbers were not provided. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim.
PremisecitationERK induces phosphorylation of ZFP36L1 through its downstream target RSK1.
“ERK induces phosphorylation of ZFP36L1 through its downstream target, p90 ribosomal S6 kinase 1 (RSK1) [15]”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
Probably not a substantial claim.
PremisecitationPMA increased LDLR mRNA stability through phosphorylation of ZFP36L1 and its subsequent release from CNOT7.
“Adachi et al. demonstrated that PMA increased LDLR mRNA stability through the phosphorylation of ZFP36L1 and its subsequent release from CNOT7 [15].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
It may state two separate claims as one.
PremisecitationUpon phosphorylation of ZFP36L1, it dissociates from the CCR4-NOT complex and consequently stabilizes LDLR mRNA.
“Upon phosphorylation of ZFP36L1, it dissociates from the CCR4-NOT complex and consequently stabilizes LDLR mRNA [15].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
It may state two separate claims as one.
Findingown dataDepletion of HuR reduces LDLR mRNA stability, and this reduction is more pronounced in TCN-treated cells.
“The depletion of HuR led to a reduction of LDLR mRNA stability, an event that was more pronounced in TCN-treated cells.”
- Also stated in: § 2.2. HuR and ZFP36L1 Contribute to TCN-Mediated Stabilization of LDLR mRNA · plain
“Consistently, TCN increased the turnover rate of LDLR mRNA in HuR-depleted cells (Figure 2c).”
Quote in the paperSubstantial claim- Also stated in: § 2.2. HuR and ZFP36L1 Contribute to TCN-Mediated Stabilization of LDLR mRNA · plain
It may state two separate claims as one.
Findingown dataCells treated with TCN or PMA had increased LKB1 phosphorylation and LDLR protein expression, and this was abrogated in BI-D1870-treated cells.
“Consistently, cells that were treated with TCN or PMA, had increased LKB1 phosphorylation, as well as LDLR protein expression, an event that was abrogated in BI-D1870 treated cells (Figure 4b and Figure S2).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTCN treatment led to a prominent ZFP36L1 gel mobility shift that was associated with increased LDLR protein expression.
“TCN treatment led to a prominent ZFP36L1 gel mobility shift, an event that was associated with an increased LDLR protein expression, as shown in Figure 3a.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn untreated cells, HuR localized mainly to nuclei, whereas upon TCN or PMA exposure HuR localization was more prominent in the cytoplasm.
“In untreated cells, HuR localized mainly to nuclei, whereas upon TCN or PMA-exposure HuR localization was more prominent in the cytoplasm (Figure 6d–f).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCo-treatment with either U0126 or BI-D1870 reduced ZFP36L1 phosphorylation and abolished RSK1 activity.
“Indeed, co-treatment of cells with either U0126 or BI-D1870 reduced ZFP36L1 phosphorylation and abolished RSK1-activity.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTCN induced ZFP36L1 phosphorylation and increased RSK1 activity, as judged by phosphorylation of its substrate LKB1.
“As shown in Figure 4a, TCN induced ZFP36L1 phosphorylation and increased the activity of RSK1, as judged by the phosphorylation of its substrate LKB1.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCIAP eliminated the TCN-induced gel mobility retardation of ZFP36L1, and this was inhibited when cell extracts were co-treated with phosphatase inhibitors.
“CIAP eliminated the TCN-induced gel mobility retardation of ZFP36L1, an event that was inhibited when cell extracts were co-treated with PI, as can be seen in Figure 3d.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenThe band intensity of the protein of interest was normalized to that of GAPDH or β-tubulin and plotted relative to the control value (vehicle-treated cells).
“the band intensity of the protein of interest was normalized to that of GAPDH or β-tubulin and plotted relative to the control value (vehicle-treated cells).”
Quote in the paperNot a substantial claimProbably not a substantial claim.
PremisecitationPhosphorylation of ZFP36L1 and ZFP36L2 by RSK1 induces their disengagement from the CCR4-NOT complex and loss of destabilizing function, resulting in stabilization of LDLR mRNA.
“Similarly, the phosphorylation of ZFP36L1 and ZFP36L2 by p90 ribosomal S6 kinase 1 (RSK1), a downstream effector of ERK signaling, has been shown to induce their disengagement from CCR4-NOT complex and the loss of its de-stabilizing function, resulting in the stabilization of LDLR mRNA [15].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenqPCRs were run in duplicate and GAPDH was used as the normalizing gene.
“qPCRs were run in duplicate and GAPDH was used as the normalizing gene.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationPhosphorylation of ZFP36 by MK2 diminishes its mRNA-destabilizing activity.
“For instance, phosphorylation of ZFP36 by MK2, a kinase downstream of p38 MAPK, has been found to diminish its mRNA-destabilizing activity [26].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Stoecklin, 2004, MK2-induced tristetraprolin:14–3-3 complexes prevent stress granule association and ARE-mRNA decay, EMBO J. source
It may state two separate claims as one.
Interpretationown dataConfocal immunofluorescence data suggest that HuR translocates from the nucleus to the cytoplasm upon TCN treatment in an ERK-dependent manner and protects LDLR mRNA from the mRNA decay machinery.
“Confocal immunofluorescence data confirmed the biochemical fractionation data and strongly suggest that HuR translocate from the nucleus to the cytoplasm upon TCN treatment in an ERK-dependent manner and protects LDLR mRNA from the mRNA decay machinery (Figure 6d–f).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationHuR is predominantly localized to the nucleus where it regulates pre-mRNA processing.
“HuR is predominantly localized to the nucleus where it carries out various functions, such as the regulation of pre-mRNA processing [21,22].”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenExperiments where LDLR mRNA deviate more than 5% from the expected mRNA (0.2) level after Act D treatment in NT control cells were dismissed from further statistical analysis.
“Experiments where LDLR mRNA deviate more than 5% from the expected mRNA (0.2) level after Act D treatment in NT control cells, were dismissed from further statistical analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
PremisecitationWhen translocated into the cytoplasm, HuR exerts a stabilizing effect on its mRNA targets.
“However, when translocated into the cytoplasm, HuR exerts a stabilizing effect on its mRNA targets [22,23,24].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [22] Lebedeva, 2011, Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR, Mol. Cell source
- cites [23] Atasoy, 1998, ELAV protein HuA (HuR) can redistribute between nucleus and cytoplasm and is upregulated during serum stimulation and T cell activation, J. Cell Sci. source
- cites [24] Lu, 2015, Saturated fatty acids induce post-transcriptional regulation of HAMP mRNA via AU-rich element-binding protein, human antigen R (HuR), J. Biol. Chem. source
It may state two separate claims as one.
PremisecitationTCN shares similarities to berberine, AICAR, and chenodeoxycholic acid by stabilizing LDLR mRNA through an ERK1/2-dependent pathway involving the LDLR 3′UTR.
“While the mechanism of LDLR mRNA stabilization by canadine and gemfibrozil is still unknown, triciribine (TCN) shares similarities to berberine, AICAR, and chenodeoxycholic acid by stabilizing LDLR mRNA through an ERK1/2-dependent pathway, and involve the LDLR 3′UTR [5,8,12,14].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [5] Kong, 2004, Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins, Nat. Med. source
- cites [8] Nakahara, 2002, Bile acids enhance low density lipoprotein receptor gene expression via a MAPK cascade-mediated stabilization of mRNA, J. Biol. Chem. source
- cites [12] Bjune, 2018, Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA, Sci. Rep. source
- cites [14] Yashiro, 2013, 5-Aminoimidazole-4-carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via ERK-dependent HuR binding to an AU-rich element, Atherosclerosis source
Probably not a substantial claim.
PremisecitationPMA partially increases LDLR mRNA stability through ERK-induced ZFP36L1 phosphorylation.
“PMA has been shown to partially increase LDLR-mRNA stability through ERK-induced ZFP36L1 phosphorylation [15].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
It may state two separate claims as one.
Interpretationown dataTCN utilizes ERK signaling to increase the activity of HuR and inhibit ZFP36L1 to stabilize LDLR mRNA in HepG2 cells.
“In sum, these data suggest that TCN utilizes ERK signaling to increase the activity of HuR and inhibit ZFP36L1 to stabilize LDLR mRNA in HepG2 cells.”
- Also stated in: § 1. Introduction · plain
“In this report, it was shown that both HuR and ZFP36L1 contribute to the stabilizing effect of TCN on LDLR mRNA.”
Quote in the paperSubstantial claim- Also stated in: § 1. Introduction · plain
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe stabilizing effect of HuR on LDLR mRNA in response to AICAR requires ERK activity.
“Interestingly, the stabilizing effect of HuR on LDLR mRNA in response to AICAR appears to require the activity of ERK [14].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Yashiro, 2013, 5-Aminoimidazole-4-carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via ERK-dependent HuR binding to an AU-rich element, Atherosclerosis source
It may state two separate claims as one.
Interpretationown dataTCN requires the activity of RSK1 to induce ZFP36L1 phosphorylation, an event associated with TCN-induced LDLR mRNA.
“These results show that TCN requires the activity of RSK1 to induce ZFP36L1 phosphorylation, an event that is associated with TCN-induced LDLR mRNA.”
Quote in the paperSubstantial claimProbably not a substantial claim.
Study design and conductnone givenExperiments with inefficient knockdown efficiency of target gene (below 70%) or in which the expected induction of LDLR mRNA by TCN (2-4 fold) failed were dismissed from further statistical analysis.
“Experiments with inefficient knockdown efficiency of target gene (below 70%) or in which the expected induction of LDLR mRNA by TCN (2–4 fold) failed, were dismissed from further statistical analysis.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningTCN inhibits the LDLR mRNA-degrading activity of ZFP36L1, contributing to the stabilization of LDLR mRNA by TCN.
“These results imply that TCN inhibits the LDLR mRNA-degrading activity of ZFP36L1, an event that would contribute to the stabilization of LDLR mRNA by TCN.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataTCN induces phosphorylation and a gel mobility shift of ZFP36L1.
“Thus, TCN induces phosphorylation and a gel mobility shift of ZFP36L1.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningThe stabilizing effect of TCN is partially mediated by the activation of HuR and inactivation of ZFP36L1.
“this report shows that the stabilizing effect of TCN is partially mediated by the activation of HuR and inactivation of ZFP36L1.”
Quote in the paperSubstantial claimProbably not a substantial claim.
PremisecitationLDLR mRNA is stabilized in an HuR-dependent manner in response to farnesoid X receptor activation and the AMPK activator AICAR.
“One such target is LDLR mRNA [13], which is stabilized in an HuR-dependent manner in response to farnesoid X receptor activation and the AMPK activator, AICAR [9,14].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [9] Singh, 2018, Farnesoid X Receptor Activation by Obeticholic Acid Elevates Liver Low-Density Lipoprotein Receptor Expression by mRNA Stabilization and Reduces Plasma Low-Density Lipoprotein Cholesterol in Mice, Arterioscler. Thromb. Vas. Biol. source
- cites [14] Yashiro, 2013, 5-Aminoimidazole-4-carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via ERK-dependent HuR binding to an AU-rich element, Atherosclerosis source
Probably not a substantial claim.
Study design and conductnone givenAll experimental replicates refer to biological replicates.
“All of the experimental replicates refer to biological replicates.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBoth ZFP36L1 and ZFP36L2 isoforms have been shown to control the stability of LDLR mRNA via the ERK pathway.
“although both isoforms have been shown to control the stability of LDLR mRNA via the ERK pathway”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. source
The paper relies on this without support.
TCN inactivation of ZFP36L1 precedes its knockdown by siRNA.
“as inactivation of ZFP36L1 by TCN precedes its knockdown by siRNA”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting anti-HA dilution for confocal microscopy
MinorThe methods specify two different dilutions of the primary anti-HA antibody for confocal immunofluorescence microscopy.
“For confocal immunoflouroscence microscopy primary anti-HA (1:100) (#71–5500)”
“pcDNA4/TO-HA-HuR transfected cells were then incubated with anti-HA (1:200) (#71–5500)”
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Metadata
- Authors
- Sundvold, H.
- Affiliations
- Oslo University Hospital (NO)
- Corresponding author
- Sundvold, Hilde
- ORCID
- Sundvold, Hilde
- Venue
- Molecules
- Publisher
- MDPI AG
- Published
- 2020-10-01
- Volume
- 25
- Issue
- 19
- Pages
- 4505
- ISSN
- 1420-3049 (ISSN-L)
- PMC
- PMC7583736
- OpenAlex
- W3090321505
- Cited by
- 5
- References
- 30
- Citations by year
- 2025: 4 · 2023: 1
- FWCI
- 0.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecules (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- triciribine, ZFP36L1, HuR, RNA-binding proteins, AKT inhibitors, ERK signaling, RSK, CCR4-NOT complex, hypercholesterolemia, hepatoma cells, mRNA turnover
- MeSH terms
- ELAV-Like Protein 1, Cell Nucleus, Exoribonucleases, Humans, Phosphorylation, Receptors, LDL, Repressor Proteins, Ribonucleosides, RNA Stability, Protein Transport, Ribosomal Protein S6 Kinases, 90-kDa, Extracellular Signal-Regulated MAP Kinases, Butyrate Response Factor 1, Hep G2 Cells
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