- Open Access
AUF1 and HuR: possible implications of mRNA stability in thyroid function and disorders
Thyroid Research volume 4, Article number: S5 (2011)
RNA-binding proteins may regulate every aspect of RNA metabolism, including pre-mRNA splicing, mRNA trafficking, stability and translation of many genes. The dynamic association of these proteins with RNA defines the lifetime, cellular localization, processing and the rate at which a specific mRNA is translated. One of the pathways involved in regulating of mRNA stability is mediated by adenylate uridylate-rich element (ARE) binding proteins. These proteins are involved in processes of apoptosis, tumorigenesis and development. Out of many ARE-binding proteins, two of them AUF1 and HuR were studied most extensively and reported to regulate the mRNA stability in vivo. Our previously published data demonstrate that both proteins are involved in thyroid carcinogenesis. Several other reports postulate that mRNA binding proteins may participate in thyroid hormone actions. However, until now, exacts mechanisms and the possible role of post-transcriptional regulation and especially the role of AUF1 and HuR in those processes remain not fully understood. In this study we shortly review the possible function of both proteins in relation to development and various physiological and pathophysiological processes, including thyroid function and disorders.
Cytoplasmic stability of eukaryotic mRNA is a substantially important check point in the control for gene expression. During differentiation of the cell some mRNAs are expressed stronger and some others are degraded or down regulated. Such a post-transcriptional gene-inactivation (gene silencing) occurs through alterations in translational efficiency and in mRNA stability. Stability of mRNA is mainly controlled by RNA interference processes (e.g. siRNA, microRNA) and RNA binding proteins, which act to selectively degrade or stabilize mRNAs. In mammals, a common feature of many unstable mRNAs is the presence of an Adenylate-Uridylate-rich element (ARE) within the 3'-untranslated region (3'-UTR) [1–3]. This ARE in the 3'-untranslated region is a part of the regulation system, which is responsible for the mRNA degradation or stabilisation and is linked to an interaction with ARE binding proteins. Out of many ARE-binding proteins studied, two of them AUF1 and HuR were investigated most extensively and demonstrated to affect the mRNA stability in vivo. AUF1 (A+U rich RNA-binding factor 1, heterogeneous nuclear ribonucleoprotein D) is expressed as a family of four proteins designated by their molecular masses as p37, p40, p42 and p45 arising from a single transcript. HuR (human antigen R) is a ubiquitously expressed member of the embryonic lethal abnormal vision (ELAV) family . Although there are some examples demonstrating stabilizing function of AUF1, it is generally related to degradation of target mRNAs while HuR is known to promote stabilization of several transcripts by enhancing their stability, altering their translation, or performing both functions [5–7]. Both proteins are mainly expressed in nucleus but their function is related with cytoplasmic localisation. Predominantly nuclear AUF1 and HuR shuttle between the nucleus and cytoplasm via nucleocytoplasmic shuttling sequences called DNS and HNS, respectively. In case of AUF1, its nuclear import is mediated by transportin-1 [8, 9]. The mechanisms of AUF1 and HuR are believed to be mediated by binding-competition to target mRNAs. It is postulated that AUF1 and HuR could functionally act with target mRNAs both within the nucleus and in the cytoplasm . It suggests that precise mechanism of antagonising and/or cooperative actions of AUF1 and HuR is not entirely understood. Both proteins do not posses any enzymatic activity, but were identified with ARE-mRNA-protein-ligand complexes. Previous reports identified the ubiquitin-conjugating enzyme E2I and three RNA binding proteins: NESP-1, NSAP-1 and IMP-2, as AUF1 interacting proteins. Importantly, NSEP-1 revealed an endoribonuclease activity, providing possible explanation for AUF1-mediated poly(A) shortening . With regard to HuR, affinity chromatography and co-immunoprecipitation experiments identified four protein ligands SETa, SETb, pp32 and acidic protein rich in leucine (APRIL) . First three had been previously characterised as inhibitors of protein phosphatase 2A (PP2A) regulating its ability to convert between holoenzyme forms upon stimulation [13, 14]. PP2A is known serine/threonine phosphatase participating in diverse cellular processes such as proliferation, cell cycle, DNA replication, development and morphogenesis . Recently, HuR and AUF1 were identified as components of the RNA-induced silencing complex (RISC). In this study HuR employed AUF1 as cofactor to promote p16 mRNA decay .
ARE-elements are found in many mRNAs encoding proteins related to normal and neoplastic cell growth and must be considered as a crucial target element in mammalian cells. The human genome project revealed that many mRNAs encoding proto-oncogenes (i.e. c-myc, c-jun, c-fos), growth factors such (i.e. EGF, VEGF), cytokines (i.e. TNFα) and cell cycle regulators (i.e. cyclin A, B1, D1, p21, p27) contain ARE-motifs [17, 18]. Analysis of thyroid related genes revealed that many of them contain these motifs and may be regulated at the post-transcriptional level. These include mRNAs related with thyroid function (pendrin, NIS, MCT8, peroxiredoxins, TPO, dual oxidase 1), regulation of thyroid function (TSHR), response to thyroid hormones (selenoprotein P, THR alpha and beta, THR associated protein 6, D1), thyroid development (Nkx2-1, PAX8, HHEX, EYA1, Hox-A3, Hox-A5, PAX9) and thyroid pathology (thyroid adenoma associated protein, papillary thyroid carcinoma encoded protein, thyroid cancer protein) (Table 1). However whether these mRNAs may serve as potential targets for AUF1 and HuR is still unclear. It is worth to note that both proteins may also interact with some mRNAs by employing non-canonical ARE-sites [19, 20].
Developmental expression of AUF1 and HuR
Both proteins are synchronous, but differential expressed during murine development. It had been demonstrated that there is no major translation control of AUF1 and HuR production, but their expression varies noticeably within tissues and at differential developmental stages. The tissue distribution of both proteins demonstrated that yolk-sack and fetal liver possessed very weak levels of AUF1 and HuR, contrary to strong expression in tail, limb bud, brain and heart between E13.5 and E16.5. Adult spleen, thymus, testis and intestine were very abundant in AUF1 and HuR, contrary to brain, liver, heart, kidneys, muscle, lungs and stomach, demonstrating low or no expression of both proteins. AUF1 and HuR revealed a coincident spatio-temporal tissue distribution from 10-somite stage to late embryogenesis [21, 22].
The data coming from human tissues revealed that AUF1 and HuR are also strictly involved in liver de-differentiation, development and progression of hepatocellular carcinoma. Those processes are tightly regulated by MAT1A (methionine adenosyltransferase 1A)- and MAT2A (methionine adenosyltransferase 2A. Both enzymes control the levels of S-adenosylmethionine (SAM), the key regulator of hepatocytes proliferation and differentiation. MAT1A is expressed in adult liver, whereas MAT2A is detected extrahepatic and is related with liver proliferation. The analysis of those expression patterns revealed that AUF1 and HuR are crucial post-transcriptional regulators of MAT1A and MAT2A mRNA stability. The authors demonstrated that AUF1 and HuR levels were upregulated in a time-dependent manner during liver de-dedifferentiation and the function of HuR is regulated by its methylation status. The interaction of HuR with MAT2A mRNA in the presence of SAM led unexpectedly to MAT2A mRNA decay, whereas its absence promoted HuR-mediated accumulation of MAT2A mRNA. It is worth to note that addition of SAM reduced the AUF1 interaction with this mRNA. The analysis of rat liver development revealed that there is a switch in the expression from MAT2A to MAT1A during embryogenesis. Proliferating liver express increased levels of SAM-methylated HuR which leads to decreased MAT2A mRNA expression and elevated levels of MAT1A mRNA. Furthermore, increased levels of AUF1 and HuR, and decreased levels of methylated-HuR were detected in hepatocellular carcinoma tissues. Normal liver tissues express very low levels of AUF1 and HuR, and high levels of methylated-HuR .
In vivo data on AUF1 and HuR knock-out mice models demonstrated that both proteins may play an important role in the development. Investigations of AUF1 -/- mice revealed symptoms which share similarity with human atopic dermatitis such as pruritus, chronic dermatitis, cutaneous atopy, xerosis, elevated serum IgE levels and staphylococcal skin infection . Cunningham et al. observed the presence of thyroid disorders in patients suffering from dermatitis herpetiformis. However the association between the clinical or serological thyroid abnormalities and skin disease could not be explained . Recently different skin findings and accompanying dermatoses could be detected in patients with thyroid diseases. The presence of each dermatosis, chronic urticaria, vitiligo and pruritus were found to be significantly higher in the patient group with thyroid disorders than in the control group. Autoimmune-hyperthyroidism patients demonstrated significantly higher incidence of vitiligo and diffuse alopecia, while vitiligo alone was found to be significantly higher in autoimmune hypothyroidism patients than in the control group . It had been demonstrated that AUF1-deficient mice revealed abnormal stabilisation of TNFα and IL-1β mRNAs. Such an excessive proinflammatory cytokines production resulted in endotoxic shock, loss of renal and liver function and in end effect caused increased mortality . In studies by Sadri et al. AUF1-deficiency led to disturbance in mature splenic B cell populations and impaired humoral immune responses. The authors observed decreased number of splenic lymphocytes, increased presentation of immature marginal zone lymphocytes and reduced number of mature follicular B lymphocytes .
More severe abnormalities were observed in HuR -/- animals. It had been demonstrated that HuR was crucial for midgestational embryonic development. HuR expression increased in murine placenta between E12.5 and E13.5. Immunohistochemical analysis revealed its presence in both embryonic and extraembryonic layers; however HuR nucleo-cytoplasmic localisation varied between maternal and fetal sides. It was dominantly nuclear in maternal decidua cells and embryo-derived trophoblasts giant cells and spongiotrophoblasts. Contrary, labyrinth-trophoblasts showed nuclear and strong cytoplasmic staining. The presence of HuR in cytoplasm at this stage was probably related with its function. Furthermore, the HuR -/- led to midgestational death. In the absence of HuR the labyrinth branching morphogenesis and syncytiotrophoblast differentiation were impaired and caused not sufficient vascularization, labyrinthine apoptosis, and in end effect insufficient nutrient transport and embryos death. Most of the embryos died between E17.5 and E19.5. They revealed reduced size of skeleton and limbs and decreased spleen size. Furthermore, the lungs of HuR -/- mice revealed additional dysmorphologies, whereas the stomach and pancreas were properly located. However, whether the absence of HuR could lead to thyroid abnormalities was not investigated. It is worth to note that HuR was able to interact with several transcription factors crucial not only for proper morphogenesis, patterning and specification, but also for thyroid development such as Hox-A5 .The absence of Hox-A5 is related to disorganized follicle formation; decreased TPO; Nkx2.1, Titf2, altered Pax8 gene expression, but normal serum T4 level. As demonstrated in Table 1, these mRNAs bear ARE-sequences and are crucial for thyroid development (Table 2). However, whether their mRNA stability is regulated in ARE-dependent manner, especially in participation of AUF1 and HuR, is not clear.
Thyroid hormone and TSH-mRNA
There is still a growing body of evidence that actions of thyroid hormone (TH), thyroid function and disorders may also be regulated at post-transcriptional level by mRNA binding proteins. Krane at al. demonstrated that TH is able to regulate the stability of thyroid stimulating hormone (TSH) subunit mRNA. They showed that half-life of the TSH beta mRNA from rat pituitary cultures treated with triiodothyronine (T3) was shorter than that observed in corresponding controls. Furthermore, TSH mRNA was destabilized due to the loss of a portion of the poly(A) tail upon TH treatment . Staton at al. postulated that such a mechanism is highly conserved across the species. In addition to previous studies they observed that simple deadenylation of TSH messenger body is insufficient to induce its decay . This suggests the triggering of additional mechanism such as exonuclease digestion and actions of other still not identified mRNA binding proteins. Recently, Goulart-Silva et al. demonstrated a rapid effect of T3 on TSHβ mRNA stability. They showed that surgically hypothyroided rats revealed an increased TSHβ transcript poly(A) tail, its elevated content in ribosomes and enhanced attachment to cytoskeleton. Furthermore, hypothyroid rats subjected to acute T3 treatment demonstrated a reduction of TSHβ mRNA poly(A) tail and its weakened recruitment to ribosomes. Euthyroid rats did not present any changes in TSHβ mRNA stability, but revealed increased binding of TSHβ transcripts to ribosomes . Although exact mechanisms or proteins participating in mRNA degradation are not fully identified, Leedman et al. isolated a cytoplasmic trans-acting factor (80-85 kDa) capable to bind the 3’-UTR of TSHβ transcripts. Furthermore, its binding to TSHβ transcripts was positively regulated by T3 . With regard to AUF1 and HuR, their actions in regulating the TSHβ transcript stability may be elusive at present, but it is worth to note that AUF1 function is associated with polysomes .
Thyroid hormone and other mRNAs
Murphy et al. observed that growth hormone (GH) mRNA from TH-depleted rats is less abundant than euthyroid controls, but its stability is elevated due to the increased length of poly (A) tail. The authors observed that modulation of GH poly (A) is related to nucleus and its length may be regulated due to the interactions with free ribonucleoproteins. The existence of such a nuclear mechanism resulting in cytoplasmic stabilisation of mature GH mRNA raises the question which mRNA binding proteins may mediate these effects . Recent studies by Goulart da Silva et al., revealed that TH acutely increases GH mRNA translation rate and GH secretion in hypothyroid rats. It had been shown that soon after T3 administration, increased GH labelling was observed in the perinuclear region of somatotrophs and that these events coincided with cytoskeleton rearrangements. Indeed, the authors identified GH mRNA in complexes with F-actin, which provided additional protection for GH mRNA transcripts. Furthermore, as the authors postulated, insufficient GH synthesis in hypothyroid specimens resulted not only from reduced GH transcription rate but also decreased GH mRNA half-life . This novel finding directing GH mRNA soon after T3 administration to polysomes is related with TH nongenomic actions. However, whether additional molecular mechanisms are involved in those processes, remains an open question.
With regard to other mRNAs, the effects of TH on cardiovascular development may also be mediated by actions of mRNA-binding proteins. Minamisawa et al. demonstrated that stability of sarcolipin mRNA, an atrium-specific sarcoplasmic reticulum protein, is affected by thyroid hormone actions. Analysis of atria obtained from hyperthyroidism-induced and T3-treated neonatal rat atrial myocytes revealed accelerated decay of sarcolipin mRNA. The hyperthyroid mice revealed cardiac hypertrophy and sinus tachycardia. Contrary, hypothyroidism did not result in any changes of cardiac morphology and sarcolipin mRNA stability . It had been demonstrated that myocardial relaxation and associated cardiac hypertrophy and heart failure may be related with AUF1-mediated decrease of sarco(endo)plasmic reticulum calcium ATPase 2a (SERCA2a) mRNA stability. In those studies AUF1 was identified as a critical factor of these events. Interaction of AUF1 with SERCA2a 3' UTR was identified predominantly in nucleus, suggesting that AUF1-mediated decay of SERCA2a mRNA starts within the nucleus and further continues during shuttling to the cytoplasm .
The further role of AUF1 was shown in studies concerning the mRNA stability of Kv4 channels. Expression of cardiac myocyte Kv4 channels is down-regulated in hypertrophy and leads to decrease in the transient outward current. Studies in vitro demonstrated that employment of angiotensin II may recapitulate these effects and is accompanied by up-regulation of AUF1, which in turn binds and destabilises Kv4 mRNA .
Studies on cultured rat brown adipocytes revealed that at higher doses T3 inhibited deiodinase II (D2) activity. Similar effects were induced after administration of triiodothyroacetic acid (Triac) , a natural thermogenic compound in brown adipocytes. Low concentrations of Triac increased D2 activity, while its higher doses inhibited D2 activity. The authors postulate that D2-inhibiton by employing high T3 doses may exist as a regulatory pathway in which D2 triggers down-regulation of T3, against its excess. D2 activity is inhibited in hyperthyroidism, and decreases further after chronic cold exposition. This suggests that high T3 concentrations in brown adipocytes switch off the mechanisms of T3-production via D2. Furthermore, the inhibition of D2 activity was found on post-transcriptional level and was related with proteasome actions. It had been demonstrated that addition of ubiquitin led to D2 inactivation whereas protein deubiquitintating enzyme-1 reversed ubiquitin-mediated inactivation and prolonged D2 half-life. Furthermore, D2 was also stabilised by employing of proteasome inhibitor. Deubiquitintating enzyme-1 was found noticeably increased in brown adipocyte tissue upon cold exposure and was associated with increased D2 stability.
Although there is no direct evidence that T3 regulates proteasome activity or increase D2 decay, the authors could demonstrate that T3 at high doses and THR beta participate in regulation of D2 mRNA stability, T3 by shortening D2 half-life and induction of D2-degradation, and THR beta by stabilisation of D2 activity [39–43].
TH is also implicated in regulation of neuroserpin mRNA stability. Neuroserpin is a serine protease inhibitor of the serpin family playing an important role in neural development and adult neural function. Neuroserpin dysfunction is related with different neurodegenerative diseases. It has been shown that its 3’UTR contains ARE motifs and interacts with HuD protein, belonging as HuR to the ELAV family. HuD is able to bind neuroserpin mRNA and its overexpression was associated with increased mRNA stability. Employment of T3 led to decreased half-life of neuroserpin, probably due to the HuD repression. The authors also suggest the involvement of other mRNA binding proteins .
In studies with retinoic acid receptors (RAR) it has been demonstrated that administration of TH led to enhanced mRNA levels of RARβ, decreased RXRγ and had no influence on RXRα. In addition to positive transcriptional regulation of RARβ by TH, investigations concerning the regulation of RXRγ, revealed that TH regulate its mRNA stability post-transcriptional . As RXRγ mRNA bears the ARE-motifs, it is a possible partner for ARE-binding proteins.
Recent studies revealed that also trace elements such as selenium, calcium or iron may regulate the mRNA stability of proteins related to their transport or metabolism [46–49]. Studies in vitro revealed potential roles of calcium and phosphate in AUF1-mediated mRNA stability of parathyroid hormone (PTH). PTH mRNA levels are post-transcriptional increased by hypocalcemia and decreased by hypophosphatemia. AUF1 was identified as a critical factor protecting and stabilizing PTH transcripts . With regard to thyroid function, it has been demonstrated that iodide and selenium may affect the stability of thyroid-related mRNAs. Bermano et al. showed that selenium depletion decreased the stability of cytosolic glutathione peroxidase mRNA. Furthermore, the incorporation of Se-cysteine at specific UGA codons in the selenoenzyme mRNAs was dependent on the presence of stem-loop structures in the 3'-UTRs of these mRNAs. It was demonstrated for selenoenzymes type I (D1) and type III deiodinases (D3) revealing that their translation efficiency was dependent on the structure or sequence of the 3'- UTR . The existence of Se-dependent post-transcriptional mechanisms regulating D1 mRNA stability was also reported in study by Riese et al., suggesting regulation in a sex and tissue specific manner . Although involvement of AUF1 and/or HuR in Se-regulated mRNA stability may be elusive at present, its worth to note that 3'- UTR of D1 bears ARE-motifs and may be regulated in ARE-dependent fashion.
Recent studies demonstrated that acute iodide administration decreased the mRNA stability of sodium-iodide symporter (NIS). The authors observed that NIS transcripts and the length of NIS poly (A) tail were significantly reduced during all periods of iodide treatment. The authors postulate that this mechanism involves the interaction of trace elements such as iodide with proteins bound to untranslated regions of mRNAs. This novel mechanism provide a new insight by which iodide may exert its autoregulatory function on thyroid gland . However whether iodide or other trace elements may bind and regulate the activity of exosome and/or proteasome components in ARE-dependent manner remains to be identified.
Current data from our group revealed that AUF1 and HuR may be involved in thyroid pathology by regulating the stability of several factors related to cell cycle and proliferation. We demonstrated that thyroid cancer tissues expressed AUF1 significantly stronger than benign tissues. Furthermore, AUF1-knock-down in follicular thyroid carcinoma cells FTC-133 led to decreased proliferation rates accompanied by increased expression of cell cycle inhibitors and down-regulation of cell cycle promoters. The analysis of AUF1-depleted clones revealed that in addition to AUF1-down-regulation, all clones demonstrated also decreased HuR levels . However exact mechanisms, thyroid-specific partners for AUF1 and HuR, the influence of AUF1 and HuR on thyroid specific functions and genes, the role of mRNA stability in thyroid carcinogenesis are still not fully understood. Recent studies by Braun et al. identified altered microRNA signatures as potent post-transcriptional markers for undifferentiated thyroid carcinoma that promote its de-/transdifferentiation and invasion .
Our previously published data revealed that expression of several tumor suppressor genes (TSG) and tumor promoting factors, may serve as novel biomarkers for thyroid carcinoma. We demonstrated that down-regulation of CD9, CD82 and RKIP may reflect an increased in vivo metastatic potential of thyroid cancer cells [56, 57]. Inversely, increased expression of S100A4 and ENO1 was correlated with increased proliferation and metastatic potential of thyroid carcinoma . Investigations performed on AUF1-depleted thyroid cancer cell lines revealed a cross-link between AUF1 and CD9, CD82, S100A4 and ENO1. We demonstrated that AUF1 knock-down led to increased expression of two tumor suppressor genes CD9 and CD82. Subsequently, decreased expression of tumor promoting S100A4, GAPDH and ENO1 was observed (Fig. 1).
It had been demonstrated that retinoic acid (RA) treatment induced beneficial effects in therapy of solid cancers [59, 60] including thyroid carcinomas [61–63]. Cell culture experiments performed on thyroid carcinoma cell lines revealed that RA treatment affects thyroid-specific functions, cell-cell or cell-matrix interaction, differentiation markers, growth, and tumorigenicity . Administration of RA demonstrated an anti-proliferative effect on the follicular thyroid carcinoma cell lines FTC-133 and FTC-238. Furthermore, pre-treatment of these cell lines with RA resulted in decreased in-vitro proliferation rates and reduced tumor cell growth of xenotransplants . Our published data revealed that RA led to significantly decreased levels of of glyceraldehyde-3-phpsphate dehydrogenase (GAPDH), pyruvate kinase isoenzymes M1/M2 (PKM1/M2), peptidyl-prolyl cis-trans isomerase A (PPIA), transketolase (TKT), annexin A2 (ANXA2), glutathione S-transferase P (GSTP1) and peroxiredoxin 2 (PRDX2) as compared to untreated control. Investigations on thyroid tissues demonstrated that the same proteins were significantly up-regulated in follicular, papillary and undifferentiated thyroid carcinomas . In addition to previously published data we found that RA pre-treatment led to down-regulation of AUF1 and HuR. Also depletion of ENO1 led to decreased levels of AUF1 and HuR (Fig. 2).
Other types of cancer
Both proteins were reported to be also related with other malignancies, and like in case of thyroid cancer, were expressed synchronous. Given that both proteins bind to common target mRNAs such an expression pattern is partly explainable. In studies on transgenic mice the overexpression of AUF1 led to development of sarcomas with strong expression of cyclin D1 . Other in vivo mice models demonstrated that malignant lung tissues expressed AUF1 significantly stronger as compared with normal and benign lung tissues. The same expression pattern was reported for HuR protein . With regard to HuR expression, its increased levels were demonstrated for malignant tissues of tongue, gingival, colon, breast, ovary and stomach as compared to corresponding controls [69, 70].
It had been shown that approximately 80% of anaplastic lymphoma kinase (ALK)-positive lymphomas express the fusion protein called nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which constitutively activates ALK tyrosine kinase and causes abnormal induction of down-stream signaling resulting in malignant transformation. Studies in vitro revealed that AUF1 was co-localised with NPM-ALK in the same cytoplasmic loci. Subsequent hyperphosphorylation of AUF1 in NPM-ALK expressing cells was also observed. It is worth to note that AUF1 hyperphosphorylation was associated with elevated stability of several target mRNAs encoding proteins crucial for cell proliferation and cell survival such as c-myc, and cyclin D1, cyclin A2, cyclin B1, and cyclin D3 .
Overexpression of AUF1 (especially isoforms p37 and p45) resulted in enhanced translation of internal ribosome entry site (IRES) of Hepatitis C virus (HCV), which is one of the major agents causing a virus-related hepatitis, liver cirrhosis and hepatocellular carcinoma. Depletion of AUF1 significantly hampered infection by HCV . Similar mechanisms were also reported by depletion of insulin-like growth factor 2 mRNA binding protein IGF2BP1 .
Increased expression of AUF1, heterogeneous nuclear ribonucleoprotein K (HNRNPK), MutS homolog 2 (MSH2) and grainyhead-like 2 (GRHL2), and subsequently elevated activity of human telomerase reverse transcriptase (hTERT) were detected in human oral squamous cell carcinoma cells (OSCC) when compared to normal cells, which do not exhibit hTERT activity. RNAi mediated knock-down of AUF1, MSH2 and GRHL2 resulted in decreased proliferation rates and hTERT promoter activity. Depletion of HNRNPK inhibited only proliferation of the cells without affecting the hTERT promoter activity .
Prostaglandin A2 (PGA2) is an experimental anti-cancer agent associated with decreased levels of cyclin D1 and decreased proliferation of cancer cells. It has been demonstrated that employment of PGA2 induced AUF1 expression and resulted in degradation of cyclin D1 mRNA in non small cell lung cancer (H1299) and breast carcinoma (MCF-7) cells. The other breast carcinoma cell line tested MDA-MB-453, bearing a large deletion in cyclin's D1 3'UTR, responded with unaltered cyclin D1 mRNA upon PGA2 treatment . In melanoma cells increased elevated levels of interleukin 10 (IL-10) resulted in decreased cytosolic AUF1 levels as compared with normal melanocytes .
Non-cancerous actions and disorders
The role and actions of AUF1 and HuR were also reported in other non-cancerous disorders. AUF1 proteins were identified as novel autoantigens in systemic lupus erythematosus (SLE) and other associated autoimmune rheumatic disorders. Autoantibodies to AUF1 were detected in 33% of SLE patients, 20% of patients with rheumatioid arthritis, 17% of patients with mixed connective tissue disorders and below 10% of patients with other related rheumatic diseases. Healthy controls were negative for AUF1 autoantibodies . The presence and the role of HuR autoantibodies are discussed in non-neuronal tissues .
The role of post-transcriptional gene regulation was also studied in the cells upon low oxygen levels. It has been demonstrated that in hypoxia conditions, HuR up-regulates the expression of two major hypoxia-inducible proteins, VEGF and HIF-1α. Furthermore, HuR also regulates the levels and/or translation of other ARE-containing mRNAs which encode hypoxia-inducible proteins such as GLUT1, TGF-β, c-myc and p53 . With regard to p53, HuR is able to bind Mdm2 mRNA, a critical negative regulator of p53. The authors suggest that by regulation of p53 levels HuR promotes the survival of hematopoietic progenitor cells . Until now the possible role of AUF1 in those processes remains undiscovered.
Both proteins were also identified as critical mediators of replicative senescence. It had been shown that reduction of AUF1 level occurred with replicative senescence and contributed to stabilization and elevated expression of ARE-bearing p16 mRNA in senescence-phenotype cells . Interestingly, exposure of the cells to hydrogen peroxide, which is related with TH production, led to reduced levels of AUF1. Furthermore, the cells overexpressing AUF1 were resistant to hydrogen peroxide-induced senescence. However whether AUF1 protective function against oxidative stress may be linked to thyroid function and disorders remains to be elucidated . HuR was found to interact with the 3′UTR of the HuR mRNA and elevated HuR translation by promoting the nuclear export of HuR mRNA. The authors propose that such a regulatory mechanism may be responsible for the loss of HuR during replicative senescence .
Nagaoka et al. showed that AUF1 may be implicated in mammary gland differentiation. It had been demonstrated that stimulation with lactogenic hormone decreased cytoplasmic, but increased nuclear AUF1 levels. Furthermore, depletion of AUF1 correlated with elevated expression of b-casein and decreased levels of c-myc mRNAs. Such a cytoplasmic-nuclear translocation of AUF1 allowed the cells initiation of differentiation followed by induction of milk production and inhibition of proliferation .
The possibility of functional interactions between AUF1 and HuR, and thyroid related mRNAs presented in this study is still speculative, but open new ways to investigate the unrevealed mechanisms, far beyond the known function of both proteins.
anaplastic lymphoma kinase
Adenylate-Uridylate rich RNA-binding Factor 1
D2, D3: deiodinases I, II, III
embryonic lethal abnormal vision
eyes absent homolog
glutathione S-transferase P
Hepatitis C virus
homebox protein HEX
heterogeneous nuclear ribonucleoprotein K
homebox protein Hox-A3
homebox protein Hox-A5
human telomerase reverse transcriptase
human antigen R
insulin-like growth factor 2 mRNA binding protein
internal ribosome entry site
methionine adenosyltransferase 1A
methionine adenosyltransferase 1A
methionine adenosyltransferase 2A
methionine adenosyltransferase 2A
monocarboxylate transporter 8
MutS homolog 2
pyruvate kinase isoenzymes M1/M2
peptidyl-prolyl cis-trans isomerase A
retinoic acid receptors
sarco(endo)plasmic reticulum calcium ATPase 2a
systemic lupus erythematosus
thyroid hormone receptor
tumor suppressor genes
thyroid stimulating hormone
thyroid stimulating hormone receptor.
Brewer G: An A+U-rich element RNA-binding factor regulates c-myc mRNA stability in vitro. Mol Cell Biol 1991, 11: 2460–2466.
DeMaria CT, Brewer G: AUF1 binding affinity to A+U-rich elements correlaates with rapid mRNA degradation. J Biol Chem 1996, 271: 12179–12184. 10.1074/jbc.271.21.12179
Good PJ: A conserved family of elav-like genes in vetebrates. Proc Natl Acad Sci U S A 1995, 92: 4557–4561. 10.1073/pnas.92.10.4557
Ma WJ, Cheng S, Campell C, Wrignt A, Furneaux H: Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J Biol Chem 1996, 271: 8144–8151. 10.1074/jbc.271.14.8144
Loflin P, Chen CYA, Shyu AN: Unraveling a cytoplasmic rolr for hnRNPD in the in vivo mRNA destabilization directed by the AU-rich element. Genes Dev 1999, 13: 1884–1897. 10.1101/gad.13.14.1884
Zhang W, Wagner BJ, Ehrenmann K, Schaefer AW, DeMaria CT, Crater D, DeHaven K, Long L, Brewer G: Purification, characterization and cDNA cloning of an AU-rich element RNA-binding protein, AUF1. Mol Cell Biol 1993, 13: 7652–7665.
Wang W, Caldwell MC, Lin S, Furneaux H, Gorospe M: HuR regulated Cyclin A and cyclin B1 mRNA stability during cell proliferation. EMBO J 2000,19(10):2340–2350. 10.1093/emboj/19.10.2340
Suzuki M, Iijima M, Nishimura A, Tomozoe Y, Kamei D, Yamada M: Two separate regions essential for nuclear import of the hnRNP D nucleocytoplasmic shuttling sequence. FEBS J 2005, 272: 3975–3987. 10.1111/j.1742-4658.2005.04820.x
Fan XC, Steitz JA: HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc Natl Acad Sci U S A 1998, 95: 15293–15298. 10.1073/pnas.95.26.15293
David PS, Tanveer R, Port JD: FRET-detectable interactions between the ARE binding proteins, HuR and p37AUF1. RNA 2007, 13: 1453–1468. 10.1261/rna.501707
Moraes KC, Quaresma AJ, Maehnss K, Kobarg J: Identification and characterization of proteins that selectively interact with isoforms of the mRNA binding protein AUF1 (hnRNP D). Biol Chem 2003, 384: 25–37. 10.1515/BC.2003.004
Dignam JD, Lebovitz RM, Roeder RG: Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 1983, 11: 1475–1489. 10.1093/nar/11.5.1475
Li M, Makkinje A, Damuni Z: Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A. Biochemistry 1996, 35: 6998–7002. 10.1021/bi960581y
Zhu T, Matsuzawa S, Mizuno Y, Kamibayashi C, Mumby MC, Andjelkovic N, Hemmings BA, Onoé K, Kikuchi K: The interconversion of protein phosphatase 2A between PP2A1 and PP2A0 during retinoic acid-induced granulocytic differentiation and a modification on the catalytic subunit in S phase of HL-60 cells. Arch Biochem Biophys 1997, 339: 210–217. 10.1006/abbi.1996.9835
Millward TA, Zolnierowicz S, Hemmings BA: Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 1999, 24: 186–191. 10.1016/S0968-0004(99)01375-4
Chang N, Yi J, Guo G, Liu X, Shang Y, Tong T, Cui Q, Zhan M, Gorospe M, Wang W: HuR uses AUF1 as a cofactor to promote p16INK4 mRNA decay. Mol Cell Biol 2010, 30: 3875–3886. 10.1128/MCB.00169-10
Bakheed T, Frevel M, Williams BR, Greer W, Khabar KS: ARED: human AU-rich element containing mRNA database reveals an unexpectedly diverse functional repertoire of encoded proteins. Nucleic Acids Res 2001, 29: 246–254. 10.1093/nar/29.1.246
Gruber AR, Fallmann J, Kratochvill F, Kovarik P, Hofacker IL: AREsite: a database for the comprehensive investigation of AU-rich elements. Nucleic Acids Res 2011,39(Database issue):D66–9.
López de Silanes I, Zhan M, Lal A, Yang X, Gorospe M: Identification of a target RNA motif for RNA-binding protein HuR. Proc Natl Acad Sci U S A 2004, 101: 2987–2992. 10.1073/pnas.0306453101
Mazan-Mamczarz K, Kuwano Y, Zhan M, White EJ, Martindale JL, Lal A, Gorospe M: Identification of a signature motif in target mRNAs of RNA-binding protein AUF1. Nucleic Acids Res 2009, 37: 204–214. 10.1093/nar/gkn929
Gouble A, Morello D: Synchronous and regulated expression of two AU-binding proteins, AUF1 and HuR, throughout murine development. Oncogene 2000, 19: 5377–5384. 10.1038/sj.onc.1203910
Hambardzumyan D, Sergent-Tanguy S, Thinard R, Bonnamain V, Masip M, Fabre A, Boudin H, Neveu I, Naveilhan P: AUF1 and Hu proteins in the developing rat brain: implication in the proliferation and differentiation of neural progenitors. J Neurosci Res 2009, 87: 1296–1309. 10.1002/jnr.21957
Vázquez-Chantada M, Fernández-Ramos D, Embade N, Martínez-Lopez N, Varela-Rey M, Woodhoo A, Luka Z, Wagner C, Anglim PP, Finnell RH, Caballería J, Laird-Offringa IA, Gorospe M, Lu SC, Mato JM, Martínez-Chantar ML: HuR/methyl-HuR and AUF1 regulate the MAT expressed during liver proliferation, differentiation, and carcinogenesis. Gastroenterology 2010, 138: 1943–1953. 10.1053/j.gastro.2010.01.032
Sadri N, Schneider RJ: Auf1/Hnrnpd-deficient mice develop pruritic inflammatory skin disease. Auf1/Hnrnpd-deficient mice develop pruritic inflammatory skin disease. J Invest Dermatol 2009, 129: 657–670. 10.1038/jid.2008.298
Cunningham MJ, Zone JJ: Thyroid abnormalities in dermatitis herpetiformis. Prevalence of clinical thyroid disease and thyroid autoantibodies. Ann Intern Med 1985, 102: 194–196.
Artantas S, Gül U, Kiliç A, Güler S: Skin findings in thyroid diseases. Eur J Intern Med 2009, 20: 158–161. 10.1016/j.ejim.2007.09.021
Lu JY, Sadri N, Schneider RJ: Endotoxic shock in AUF1 knockout mice mediated by failure to degrade proinflammatory cytokine mRNAs. Genes Dev 2006, 20: 3174–3184. 10.1101/gad.1467606
Sadri N, Lu JY, Badura ML, Schneider RJ: AUF1 is involved in splenic follicular B cell maintenance. BMC Immunol 2010, 11: 1. 10.1186/1471-2172-11-1
Katsanou V, Milatos S, Yiakouvaki A, Sgantzis N, Kotsoni A, Alexiou M, Harokopos V, Aidinis V, Hemberger M, Kontoyiannis DL: The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development. Mol Cell Biol 2009, 29: 2762–2776. 10.1128/MCB.01393-08
Krane IM, Spindel ER, Chin WW: Thyroid hormone decreases the stability and the poly(A) tract length of rat thyrotropin beta-subunit messenger RNA. Mol Endocrinol 1991, 5: 469–475. 10.1210/mend-5-4-469
Staton JM, Leedman PJ: Posttranscriptional regulation of thyrotropin beta-subunit messenger ribonucleic acid by thyroid hormone in murine thyrotrope tumor cells: a conserved mechanism across species. Endocrinology 1998, 139: 1093–1100. 10.1210/en.139.3.1093
Goulart-Silva F, de Souza PB, Nunes MT: T3 rapidly modulates TSHβ mRNA stability and translational rate in the pituitary of hypothyroid rats. Mol Cell Endocrinol 2011, 332: 277–282. 10.1016/j.mce.2010.11.005
Leedman PJ, Stein AR, Chin WW: Regulated specific protein binding to a conserved region of the 3'-untranslated region of thyrotropin beta-subunit mRNA. Mol Endocrinol 1995, 9: 375–387. 10.1210/me.9.3.375
Murphy D, Pardy K, Seah V, Carter D: Posttranscriptional regulation of rat growth hormone gene expression: increased message stability and nuclear polyadenylation accompany thyroid hormone depletion. Mol Cell Biol 1992, 12: 2624–2632.
Silva FG, Giannocco G, Luchessi AD, Curi R, Nunes MT: T3 acutely increases GH mRNA translation rate and GH secretion in hypothyroid rats. Mol Cell Endocrinol 2010, 317: 1–7. 10.1016/j.mce.2009.12.005
Minamisawa S, Uemura N, Sato Y, Yokoyama U, Yamaguchi T, Inoue K, Nakagome M, Bai Y, Hori H, Shimizu M, Mochizuki S, Ishikawa Y: Post-transcriptional downregulation of sarcolipin mRNA by triiodothyronine in the atrial myocardium. FEBS Lett 2006, 580: 2247–2252. 10.1016/j.febslet.2006.03.032
Blum JL, Samarel AM, Mestril R: Phosphorylation and binding of AUF1 to the 3'-untranslated region of cardiomyocyte SERCA2a mRNA. Am J Physiol Heart Circ Physiol 2005, 289: H2543–2550. 10.1152/ajpheart.00545.2005
Zhou C, Vignere CZ, Levitan ES: AUF1 is upregulated by angiotensin II to destabilize cardiac Kv4.3 channel mRNA. J Mol Cell Cardiol 2008, 45: 832–838. 10.1016/j.yjmcc.2008.08.004
Steinsapir J, Harney J, Larsen PR: Type 2 iodothyronine deiodinase in rat pituitary tumor cells is inactivated in proteasomes. J Clin Invest 1998, 102: 1895–1899. 10.1172/JCI4672
Gereben B, Goncalves C, Harney JW, Larsen PR, Bianco AC: Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation. Mol Endocrinol 2000, 14: 1697–1708. 10.1210/me.14.11.1697
Curcio-Morelli C, Zavacki AM, Christofollete M, Gereben B, de Freitas BC, Harney JW, Li Z, Wu G, Bianco AC: Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation. J Clin Invest 2003, 112: 189–196.
Sagar GD, Gereben B, Callebaut I, Mornon JP, Zeöld A, da Silva WS, Luongo C, Dentice M, Tente SM, Freitas BC, Harney JW, Zavacki AM, Bianco AC: Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity. Mol Cell Biol 2007, 27: 4774–4783. 10.1128/MCB.00283-07
Martinez de Mena R, Scanlan TS, Obregon MJ: The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes. Endocrinology 2010, 151: 5074–5083. 10.1210/en.2010-0533
Navarro-Yubero C, Cuadrado A, Sonderegger P, Muñoz A: Neuroserpin is post-transcriptionally regulated by thyroid hormone. Brain Res Mol Brain Res 2004, 123: 56–65.
Mano H, Mori R, Ozawa T, Takeyama K, Yoshizawa Y, Kojima R, Arao Y, Masushige S, Kato S: Positive and negative regulation of retinoid X receptor gene expression by thyroid hormone in the rat. Transcriptional and post-transcriptional controls by thyroid hormone. J Biol Chem 1994, 269: 1591–1594.
Schmutzler C, Mentrup B, Schomburg L, Hoang-Vu C, Herzog V, Köhrle J: Selenoproteins of the thyroid gland: expression, localization and possible function of glutathione peroxidase 3. Biol Chem 2007, 388: 1053–1059. 10.1515/BC.2007.122
Naveh-Many T, Bell O, Silver J, Kilav R: Cis and trans acting factors in the regulation of parathyroid hormone (PTH) mRNA stability by calcium and phosphate. FEBS Lett 2002, 529: 60–64. 10.1016/S0014-5793(02)03259-3
Owen D, Kühn LC: Noncoding 3' sequences of the transferrin receptor gene are required for mRNA regulation by iron. EMBO J 1987, 6: 1287–1293.
Mittag J, Behrends T, Hoefig CS, Vennström B, Schomburg L: Thyroid hormones regulate selenoprotein expression and selenium status in mice. PLoS One 2010, 5: e12931. 10.1371/journal.pone.0012931
Sela-Brown A, Silver J, Brewer G, Naveh-Many T: Identification of AUF1 as a parathyroid hormone mRNA 3'-untranslated region-binding protein that determines parathyroid hormone mRNA stability. J Biol Chem 2000, 275: 7424–7429. 10.1074/jbc.275.10.7424
Bermano G, Arthur JR, Hesketh JE: Selective control of cytosolic glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase mRNA stability by selenium supply. FEBS Lett 1996, 387: 157–160. 10.1016/0014-5793(96)00493-0
Riese C, Michaelis M, Mentrup B, Götz F, Köhrle J, Schweizer U, Schomburg L: Selenium-dependent pre- and posttranscriptional mechanisms are responsible for sexual dimorphic expression of selenoproteins in murine tissues. Endocrinology 2006, 147: 5883–5892. 10.1210/en.2006-0689
Serrano-Nascimento C, Calil-Silveira J, Nunes MT: Posttranscriptional regulation of sodium-iodide symporter mRNA expression in the rat thyroid gland by acute iodide administration. Am J Physiol Cell Physiol 2010, 298: C893-C899. 10.1152/ajpcell.00224.2009
Trojanowicz B, Brodauf L, Sekulla C, Lorenz K, Finke R, Dralle H, Hoang-Vu C: The role of AUF1 in thyroid carcinoma progression. Endocr Relat Cancer 2009, 16: 857–871. 10.1677/ERC-08-0234
Braun J, Hoang-Vu C, Dralle H, Hüttelmaier S: Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas. Oncogene 2010, 29: 4237–4244. 10.1038/onc.2010.169
Trojanowicz B, Fu T, Gimm O, Sekulla C, Finke R, Dralle H, Hoang-Vu C: Relationship between RKIP protein expression and clinical staging in thyroid carcinoma. Open Endocrinology Journal 2008, 2: 16–20. 10.2174/1874216500802010016
Trojanowicz B, Winkler A, Hammje K, Chen Z, Sekulla C, Glanz D, Schmutzler C, Mentrup B, Hombach-Klonisch S, Klonisch T, Finke R, Köhrle J, Dralle H, Hoang-Vu C: Retinoic acid mediated down-regulation of ENO1/MBP-1 gene products caused decreased invasiveness of the follicular thyroid carcinoma cell lines. J Mol Endocrinol 2009, 42: 249–260.
Chen Z, Mustafa T, Trojanowicz B, Brauckhoff M, Gimm O, Schmutzler C, Köhrle J, Holzhausen HJ, Kehlen A, Klonisch T, Finke R, Dralle H, Hoang-Vu C: CD82, and CD63 in thyroid cancer. Int J Mol Med 2004, 14: 517–527.
Lengfelder E, Saussele S, Weisser A, Buchner T, Hehlmann R: Treatment concepts of acute promyelocytic leukemia. Crit Rev Oncol Hematol 2005, 56: 261–274. 10.1016/j.critrevonc.2004.08.009
Hansen LA, Sigman CC, Andreola F, Ross SA, Kelloff GJ, De Luca LM: Retinoids in chemoprevention and differentiation therapy. Carcinogenesis 2000, 21: 1271–1279. 10.1093/carcin/21.7.1271
Simon D, Körber C, Krausch M, Segering J, Groth P, Görges R, Grünwald F, Müller-Gärtner HW, Schmutzler C, Köhrle J, Röher HD, Reiners C: Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study. Eur J Nucl Med Mol Imaging 2002, 29: 775–782. 10.1007/s00259-001-0737-6
Handkiewicz-Junak D, Roskosz J, Hasse-Lazar K, Szpak-Ulczok S, Puch Z, Kukulska A, Olczyk T, Piela A, Paliczka-Cieslik E, Jarzab B: 13-cis-retinoic acid re-differentiation therapy and recombinant human thyrotropin-aided radioiodine treatment of non-Functional metastatic thyroid cancer: a single-center, 53-patient phase 2 study. Thyroid Res 2009, 2: 8. 10.1186/1756-6614-2-8
Fernández CA, Puig-Domingo M, Lomeña F, Estorch M, Camacho Martí V, Bittini AL, Marazuela M, Santamaría J, Castro J, Martínez de Icaya P, Moraga I, Martín T, Megía A, Porta M, Mauricio D, Halperin I: Effectiveness of retinoic acid treatment for redifferentiation of thyroid cancer in relation to recovery of radioiodine uptake. J Endocrinol Invest 2009, 32: 228–233.
Schmutzler C, Kohrle J: Retinoic acid redifferentiation therapy for thyroid cancer. Thyroid 2000, 10: 393–406. 10.1089/thy.2000.10.393
Schmutzler C, Hoang-Vu C, Rüger B, Kohrle J: Human thyroid carcinoma cell lines show different retinoic acid receptor repertoires and retinoid responses. Eur J Endocrinol 2004, 150: 547–556. 10.1530/eje.0.1500547
Trojanowicz B, Sekulla C, Lorenz K, Köhrle J, Finke R, Dralle H, Hoang-Vu C: Proteomic approach reveals novel targets for retinoic acid-mediated therapy of thyroid carcinoma. Mol Cell Endocrinol 2010, 325: 110–117. 10.1016/j.mce.2010.05.022
Gouble A, Grazide S, Meggetto F, Mercier P, Delsol G, Morello D: A new player in oncogenesis: AUF1/hnRNPD overexpression leads to tumorigenesis in transgenic mice. Cancer Res 2002, 62: 1489–1495.
Blaxall BC, Dwyer-Nield LD, Bauer AK, Bohlmeyer TJ, Malkinson AM, Port JD: Differential expres-sion and localization of the mRNA binding proteins, AU-rich element mRNA binding protein (AUF1) and Hu antigen R (HuR), in neoplastic lung tissue. Mol Carcinog 2000, 28: 76–83. 10.1002/1098-2744(200006)28:2<76::AID-MC3>3.0.CO;2-0
Yuan Z, Sanders AJ, Ye L, Jiang WG: HuR, a key post-transcriptional regulator, and its implication in progression of breast cancer. Histol Histopathol 2010, 25: 1331–1340.
Kakuguchi W, Kitamura T, Kuroshima T, Ishikawa M, Kitagawa Y, Totsuka Y, Shindoh M, Higashino F: HuR knockdown changes the oncogenic potential of oral cancer cells. Mol Cancer Res 2010, 8: 520–528. 10.1158/1541-7786.MCR-09-0367
Fawal M, Armstrong F, Ollier S, Dupont H, Touriol C, Monsarrat B, Delsol G, Payrastre B, Morello D: A "liaison dangereuse" between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK. Blood 2006, 108: 2780–2788. 10.1182/blood-2006-04-014902
Paek KY, Kim CS, Park SM, Kim JH, Jang SK: RNA-binding protein hnRNP D modulates internal ribosome entry site-dependent translation of hepatitis C virus RNA. J Virol 2008, 82: 12082–12093. 10.1128/JVI.01405-08
Weinlich S, Hüttelmaier S, Schierhorn A, Behrens SE, Ostareck-Lederer A, Ostareck DH: IGF2BP1 enhances HCV IRES-mediated translation initiation via the 3'UTR. RNA 2009, 15: 1528–1542. 10.1261/rna.1578409
Kang X, Chen W, Kim RH, Kang MK, Park NH: Regulation of the hTERT promoter activity by MSH2, the hnRNPs K and D, and GRHL2 in human oral squamous cell carcinoma cells. Oncogene 2009, 28: 565–574. 10.1038/onc.2008.404
Lin S, Wang W, Wilson GM, Yang X, Brewer G, Holbrook NJ, Gorospe M: Down-regulation of cyclin D1 expression by prostaglandin A(2) is mediated by enhanced cyclin D1 mRNA turnover. Mol Cell Biol 2000, 20: 7903–7913. 10.1128/MCB.20.21.7903-7913.2000
Brewer G, Saccani S, Sarkar S, Lewis A, Pestka S: Increased interleukin-10 mRNA stability in melanoma cells is associated with decreased levels of A + U-rich element binding factor AUF1. J Interferon Cytokine Res 2003, 23: 553–564. 10.1089/107999003322485053
Skriner K, Hueber W, Süleymanoglu E, Höfler E, Krenn V, Smolen J, Steiner G: AUF1, the regulator of tumor necrosis factor alpha messenger RNA decay, is targeted by autoantibodies of patients with systemic rheumatic diseases. Arthritis Rheum 2008, 58: 511–520. 10.1002/art.23306
Nabors LB, Furneaux HM, King PH: HuR, a novel target of anti-Hu antibodies, is expressed in non-neural tissues. J Neuroimmunol 1998, 92: 152–159. 10.1016/S0165-5728(98)00196-9
Masuda K, Abdelmohsen K, Gorospe M: RNA-binding proteins implicated in the hypoxic response. J Cell Mol Med 2009, 13: 2759–2769. 10.1111/j.1582-4934.2009.00842.x
Ghosh M, Aguila HL, Michaud J, Ai Y, Wu MT, Hemmes A, Ristimaki A, Guo C, Furneaux H, Hla T: Essential role of the RNA-binding protein HuR in progenitor cell survival in mice. J Clin Invest 2009, 119: 3530–3543. 10.1172/JCI38263
Wang W, Martindale JL, Yang X, Chrest FJ, Gorospe M: Increased stability of the p16 mRNA with replicative senescence. EMBO Rep 2005, 6: 158–164. 10.1038/sj.embor.7400346
Guo GE, Ma LW, Jiang B, Yi J, Tong TJ, Wang WG: Hydrogen peroxide induces p16(INK4a) through an AUF1-dependent manner. J Cell Biochem 2010, 109: 1000–1005.
Yi J, Chang N, Liu X, Guo G, Xue L, Tong T, Gorospe M, Wang W: Reduced nuclear export of HuR mRNA by HuR is linked to the loss of HuR in replicative senescence. Nucleic Acids Res 2010, 38: 1547–1558. 10.1093/nar/gkp1114
Nagaoka K, Tanaka T, Imakawa K, Sakai S: Involvement of RNA binding proteins AUF1 in mammary gland differentiation. Exp Cell Res 2007, 313: 2937–2945. 10.1016/j.yexcr.2007.04.017
Klonisch T, Hoang-Vu C, Hombach-Klonisch S: Thyroid stem cells and cancer. Thyroid 2009, 19: 1303–1315. 10.1089/thy.2009.1604
We would like to thank Ms. Kathrin Hammje for excellent technical assistance in creation of this manuscript. This study was partly supported by Deutsche Forschungsgemeinschaft (DFG) and Deutsche Krebshilfe. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.
This article has been published as part of Thyroid Research Volume 4 Supplement 1, 2011: New aspects of thyroid hormone synthesis and action. The full contents of the supplement are available online at http://www.thyroidresearchjournal.com/supplements/4/S1
The authors declare that they have no competing interests.
About this article
Cite this article
Trojanowicz, B., Dralle, H. & Hoang-Vu, C. AUF1 and HuR: possible implications of mRNA stability in thyroid function and disorders. Thyroid Res 4, S5 (2011). https://doi.org/10.1186/1756-6614-4-S1-S5
- Thyroid Hormone
- Thyroid Stimulate Hormone
- Anaplastic Lymphoma Kinase
- mRNA Stability