Heterogeneity in Control of mRNA Stability by AU-rich Elements

AU-rich elements (AREs), located in the 3′-untranslated region of unstable cytokine and chemokine mRNAs, promote rapid decay of otherwise stable mRNAs and may mediate selective mRNA stabilization in response to stimulation with interleukin-1 (IL-1). AREs vary considerably, however, in both size and sequence context. To assess the heterogeneity involved in control of mRNA stability by ARE motifs, human mRNA sequences from IL-1α-stimulated HEK293 cells and T98G cells were screened for either instability or stability using both cDNA (950 ARE containing sequences) and Affymetrix oligonucleotide (U95Av2 GeneChip) array analysis. Although ARE-containing mRNAs exhibited a broad range of stability, IL-1α promoted stability in a subset of mRNAs that were unstable when transcriptionally induced by tumor necrosis factor α. Stabilization of granulocyte/macrophage-colony stimulating factor and IL-8 mRNAs by IL-1α was achieved only after 2 h of stimulation, required ongoing protein synthesis, and depended on the activation of p38 MAPK. In contrast, stabilization of Gro3 mRNA in response to IL-1α was achieved immediately and was insensitive to inhibitors of protein synthesis and p38 MAPK activation. In concert, these findings demonstrate that ARE sequences are functionally heterogeneous; only a subset of unstable mRNAs is sensitive to stabilization by IL-1α. Moreover, IL-1α promotes stabilization of unstable mRNAs through distinct mechanistic pathways that distinguish between specific mRNA sequences. AU-rich elements (AREs), located in the 3′-untranslated region of unstable cytokine and chemokine mRNAs, promote rapid decay of otherwise stable mRNAs and may mediate selective mRNA stabilization in response to stimulation with interleukin-1 (IL-1). AREs vary considerably, however, in both size and sequence context. To assess the heterogeneity involved in control of mRNA stability by ARE motifs, human mRNA sequences from IL-1α-stimulated HEK293 cells and T98G cells were screened for either instability or stability using both cDNA (950 ARE containing sequences) and Affymetrix oligonucleotide (U95Av2 GeneChip) array analysis. Although ARE-containing mRNAs exhibited a broad range of stability, IL-1α promoted stability in a subset of mRNAs that were unstable when transcriptionally induced by tumor necrosis factor α. Stabilization of granulocyte/macrophage-colony stimulating factor and IL-8 mRNAs by IL-1α was achieved only after 2 h of stimulation, required ongoing protein synthesis, and depended on the activation of p38 MAPK. In contrast, stabilization of Gro3 mRNA in response to IL-1α was achieved immediately and was insensitive to inhibitors of protein synthesis and p38 MAPK activation. In concert, these findings demonstrate that ARE sequences are functionally heterogeneous; only a subset of unstable mRNAs is sensitive to stabilization by IL-1α. Moreover, IL-1α promotes stabilization of unstable mRNAs through distinct mechanistic pathways that distinguish between specific mRNA sequences. tumor necrosis factor α AU-rich element actinomycin D cycloheximide untranslated region interleukin-1 granulocyte/macrophage-colony stimulating factor extracellular signal-regulated kinase 1 and 2 c-Jun N-terminal kinase In the course of an inflammatory response to injury or infection, both resident and infiltrating cells are subject to the action of a diverse collection of stimuli that produce dramatic changes in the pattern of gene expression (1Hamilton T.A. Lewis C. Burke B. 2nd. Ed. The Natural Immune System: The Macrophage. 2. Oxford University Press, Oxford2002: 73-102Google Scholar, 2Gordon S. Clarke S. Greaves D. Doyle A. Curr. Opin. Immunol. 1995; 7: 24-33Google Scholar, 3Nathan C.F. Cohn Z.A. Kelly W. Harris E. Ruddy S. Hedge R. Textbook of Rheumatology. W. B. Saunders, New York1995: 144-169Google Scholar). Although much attention has been directed at the role of transcription in the activation of inflammatory gene expression, post-transcriptional events, particularly the stability of specific mRNAs, have also been shown to be important in control of gene expression (4Guhaniyogi J. Brewer G. Gene (Amst.). 2001; 265: 11-23Google Scholar, 5Mitchell P. Tollervey D. Curr. Opin. Genet. Dev. 2000; 10: 193-198Google Scholar). Indeed many mRNAs encoding inflammatory gene products are inherently unstable, although decay may be controlled selectively in response to extracellular stimulus. The importance of these mechanisms is illustrated in studies of the post-transcriptional control of TNFα1 mRNA wherein both mRNA stability and translation have been shown to be critical determinants of the magnitude of the inflammatory response (6Kontoyiannis D. Pasparakis M. Pizarro T.T. Cominelli F. Kollias G. Immunity. 1999; 10: 387-398Google Scholar, 7Carballo E. Lai W.S. Blackshear P.J. Science. 1998; 281: 1001-1005Google Scholar). Adenosine uridine-rich elements (AREs) found in the 3′-untranslated regions (3′-UTRs) of many inflammatory cytokines and growth factors are well known to promote rapid mRNA degradation (8Caput D. Beutler B. Hartog K. Thayer R. Brown-Shimer S. Cerami A. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 1670-1674Google Scholar, 9Shaw G. Kamen R. Cell. 1986; 46: 659-667Google Scholar). Furthermore, multiple studies have shown that rates of mRNA decay can be modified in response to extracellular stimulation (10Lasa M. Mahtani K.R. Finch A. Brewer G. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2000; 20: 4265-4274Google Scholar, 11Stoeckle M.Y. Nucleic Acids Res. 1991; 19: 917-920Google Scholar, 12Holtmann H. Winzen R. Holland P. Eickemeier S. Hoffmann E. Wallach D. Malinin N.L. Cooper J.A. Resch K. Kracht M. Mol. Cell. Biol. 1999; 19: 6742-6753Google Scholar). For example, IL-1α has been shown to enhance the stability of a variety of cytokine and chemokine mRNAs that otherwise exhibit short half-lives, and this depends, at least in part, upon the presence of ARE motifs in the 3′-UTRs (10Lasa M. Mahtani K.R. Finch A. Brewer G. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2000; 20: 4265-4274Google Scholar, 11Stoeckle M.Y. Nucleic Acids Res. 1991; 19: 917-920Google Scholar, 12Holtmann H. Winzen R. Holland P. Eickemeier S. Hoffmann E. Wallach D. Malinin N.L. Cooper J.A. Resch K. Kracht M. Mol. Cell. Biol. 1999; 19: 6742-6753Google Scholar). A recent search of human sequence databases has identified over 900 human mRNAs that contain one or more ARE motifs (13Bakheet T. Frevel M. Williams B.R. Greer W. Khabar K.S. Nucleic Acids Res. 2001; 29: 246-254Google Scholar), and it seems unlikely that all such mRNAs will exhibit comparable sensitivity to regulatory mechanisms governing their stability. Indeed, studies using mRNAs with defined ARE sequences have demonstrated sequence-specific functional heterogeneity that reflects the differential participation of distinct ARE binding proteins (14Chen C.Y. Xu N. Shyu A.B. Mol. Cell. Biol. 2002; 22: 7268-7278Google Scholar, 15Xu N. Chen C.Y. Shyu A.B. Mol. Cell. Biol. 2001; 21: 6960-6971Google Scholar, 16Chen C.-Y.A. Shyu A.-B. Trends Biochem. Sci. 1995; 20: 465-470Google Scholar). To further evaluate the functional heterogeneity of AREs, we determined the sensitivity of a set of ARE-containing mRNAs to IL-1α-induced stabilization. We also assessed the mechanistic diversity of IL-1α-mediated mRNA stabilization with respect to the pathways through which stimulus and mRNA decay mechanism are coupled. As a first step, we examined the expression of multiple ARE containing mRNAs using cDNA and oligonucleotide array analysis. The results demonstrate that, although many IL-1α-inducible, ARE-containing mRNAs are unstable, a subset of the mRNAs are stabilized by the stimulus. This effect is specific for IL-1α, because TNFα induces transcription of many of the same genes but does not lead to stabilization of their mRNAs. Finally, within the set of IL-1α-inducible and stabilized mRNAs, there appear to be multiple intracellular pathways through which the stabilization end point can be achieved. Dulbecco's modified Eagle's medium, Dulbecco's phosphate-buffered saline, antibiotics, glutamine, agarose, guanidine isothiocyanate, and cesium chloride were obtained from PerkinElmer Life Sciences (Rockville, MD). Anhydrous ethanol, Sarkosyl, and formamide were obtained from International Biotechnologies, Inc. (New Haven, CT). Magna nylon transfer membrane was obtained from Micron Separations Inc. (Westboro, MA). Fetal bovine serum was purchased from BioWhittaker (Walkersville, MD). Actinomycin D (ActD) and cycloheximide (CHX) were purchased from Sigma-Aldrich (St. Louis, MO). Recombinant human IL-1α and TNFα were purchased from R&D Systems (Minneapolis, MN). PerkinElmer Life Sciences (Boston, MA) was the source of [α-32P]dCTP. SB203580 was purchased from Calbiochem (San Diego, CA). HEK293 cells and T98G glioblastoma cells were obtained from Dr. Xiaoxia Li and Dr. George Stark, respectively (Lerner Research Institute). Both cell lines were maintained in Dulbecco's modified Eagle's medium containing 107 fetal bovine serum, penicillin, and streptomycin in humidified 57 CO2. Total cellular RNA was extracted by the guanidine thiocyanate-cesium chloride method (17Chirgwin J.M. Pryzbyla R.J. MacDonald R.J. Rutter W.J. Biochemistry. 1979; 18: 5295-5299Google Scholar). Northern hybridization analysis was done as previously described (18Tebo J.M. Kim H.S. Gao J. Armstrong D.A. Hamilton T.A. Blood. 1998; 92: 4742-4749Google Scholar). RNA labeling and hybridization were carried out according to the protocol supplied by Affymetrix. In brief, RNA was isolated by the guanidine/CsCl method (17Chirgwin J.M. Pryzbyla R.J. MacDonald R.J. Rutter W.J. Biochemistry. 1979; 18: 5295-5299Google Scholar), and 10 ॖg of total RNA per sample was converted to double-stranded cDNA using an oligo(dT) primer containing a T7 polymerase site. The resulting cDNA was then used as template forin vitro transcription with biotinylated CTP and UTP to generate cRNA. 15 ॖg of fragmented cRNA was hybridized to Affymetrix U95Av2 GeneChips. The arrays were washed and stained according to supplied protocols and scanned using an Affymetrix GeneChip scanner. Raw image data was processed and normalized using Microarray Analysis suite 4.0. cDNA array and hybridization were carried out as previously described (19Frevel M.A.E. Bakheet T. Silva A.M. Hisong J.G. Khabar K.S.A. Williams B.R.G. Mol. Cell. Biol. 2003; 23: 425-436Google Scholar). The ARE cDNA array used in this study was composed of ∼950 ARE-containing genes defined in the ARED data base (13Bakheet T. Frevel M. Williams B.R. Greer W. Khabar K.S. Nucleic Acids Res. 2001; 29: 246-254Google Scholar), 18 genes potentially involved in AU-directed mRNA decay, and 50 housekeeping for array from and cells were with and The and were and hybridized to the array a in a hybridization for were washed and scanned on a Raw data were with the and the for further analysis. To evaluate the functional heterogeneity of ARE-containing mRNAs with respect to instability and the decay of multiple mRNAs were determined in IL-1α-stimulated cells using both oligonucleotide and cDNA array HEK293 cells and T98G glioblastoma cells were used to RNA for 2 h with IL-1α, or for 2 h with IL-1α by of for an The total RNA from cell were used for of cRNA and to array analysis using either the Affymetrix U95Av2 or a cDNA array using the sequences defined in the ARED data base of ARE-containing mRNAs (13Bakheet T. Frevel M. Williams B.R. Greer W. Khabar K.S. Nucleic Acids Res. 2001; 29: 246-254Google Scholar). The analysis of IL-1α-inducible mRNAs to after 2 h of The IL-1α of mRNAs between cell lines a subset were identified in both and T98G were as either stable decay over stable decay over or unstable decay over The mRNAs identified using these are in of mRNAs. within all the of mRNAs contain an ARE as at least one within the Although mRNAs in not one of or AU-rich regions may also mRNA have been C.-Y.A. Shyu A.-B. Trends Biochem. Sci. 1995; 20: 465-470Google Scholar). it is that ARE-containing mRNAs exhibit heterogeneity in of their rates of decay in the presence of IL-1α from stable to of mRNAs as stable or stable AREs, and these be unstable mRNAs that are stabilized in response to of these mRNAs however, be inherently because decay was not assessed in the of IL-1α, we that IL-1α a in their of to to that sequence be found in mRNAs 10 stable mRNAs 10 for mRNAs to that sequence be found in in a To the of specific mRNAs in array of HEK293 and T98G cells were with IL-1α for 2 and were further with for an Total RNA was and the of mRNAs were determined by Northern hybridization analysis. In cell we examined unstable mRNAs and stable mRNAs. The results the data in the mRNAs were induced by IL-1α, and either binding or were stable in the presence of IL-1α To unstable mRNAs in which stability was by IL-1α we of a that, although TNFα and IL-1α can both transcription of the chemokine only IL-1α promotes stabilization Hamilton T.A. Biochem. Res. Scholar, J. S. R. M. J.A. Hamilton T.A. J. Biol. 2000; Scholar). of the mRNAs induced by IL-1α also be induced in response to TNFα but in this all exhibited rapid decay and is that mRNAs that are stabilized by IL-1α exhibit in response to IL-1α as with that are unstable in both comparable expression in response to either stimulus. In with TNFα to of the of IL-1α with also in the stabilization of Gro3 and in T98G cells and IL-8 and Gro3 in the mRNAs, although were not stabilized findings that these specific mRNAs are inherently unstable but can be stabilized in response to with IL-1α. The findings that ARE-containing mRNAs are functionally with respect to their sensitivity to IL-1α-mediated stabilization. To assess there further heterogeneity within the set of mRNAs that are subject to such we the stabilization of and Gro3 mRNAs in IL-1α-stimulated T98G cells with respect to their on protein synthesis, and p38 MAPK activation. As a first we determined stability of mRNA is immediately only after stimulation T98G cells were for or h with IL-1α by the of for a further to assess decay 1 h after stimulation both IL-8 and mRNAs 2 h of stimulation, however, both these mRNAs exhibited stability. In contrast, Gro3 although only induced at 1 was stable and exhibited decay at of the The for stabilization of and IL-8 the that synthesis of a protein be required as of the stabilization induced by IL-1α. To T98G cells were with IL-1α in the presence or of the protein synthesis cycloheximide (CHX) for 2 h and washed to the to the of medium containing were at and of specific mRNA were determined The stabilization of both and IL-8 mRNAs was when the stimulation was carried out in the presence of In the stability of Gro3 was in IL-1α can mRNAs immediately in the of stabilization of IL-1α-induced and IL-8 mRNAs protein To this we that TNFα a to the protein synthesis which is upon the of IL-1α. To evaluate this the effect of on the of IL-1α to mRNA was T98G cells were first with TNFα for 2 h in the presence or of to the the cells were with IL-1α and and mRNA were determined further Gro3 and mRNAs were both unstable in the of IL-1α and were stabilized when IL-1α was the decay of the stimulation with TNFα the of both mRNAs but not decay rates as with cells In cells with and however, IL-1α not mRNA but the to Gro3 mRNA was not results demonstrate that the stabilization of mRNAs in response to IL-1α protein synthesis and that there are at least pathways that control mRNA IL-1α-induced stabilization of mRNAs is to upon activation of the p38 MAPK (10Lasa M. Mahtani K.R. Finch A. Brewer G. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2000; 20: 4265-4274Google Scholar, R. Kracht M. B. A. Chen C.Y. Shyu A.B. M. M. Resch K. H. J. 1999; 18: Scholar, A. D. A. Winzen R. R. H. Kollias G. M. J. Biol. 2002; Scholar). This has been demonstrated in multiple through the of the specific p38 protein kinase SB203580 and by of of both and and in the p38 kinase To IL-1α-mediated mRNA stabilization is we examined the decay of mRNAs in cells with or the of the kinase of T98G cells were with IL-1α for 2 h to the of with or Although the stability of was by of p38 kinase Gro3 mRNA stable Gro3 and mRNAs were both unstable when induced by TNFα and both were stabilized IL-1α was at the same as The of IL-1α to was by the stabilization of Gro3 mRNA was not This further the that and Gro3 mRNA sequences are controlled by distinct mRNA decay This differential reflects cell and because recent findings using demonstrate that Gro3 mRNA stability induced in cells by is sensitive to the of the p38 (19Frevel M.A.E. Bakheet T. Silva A.M. Hisong J.G. Khabar K.S.A. Williams B.R.G. Mol. Cell. Biol. 2003; 23: 425-436Google Scholar). The protocol used in the involved the of the p38 2 h after the IL-1α stimulus when mRNA been In many the activation of p38 MAPK in response to IL-1α or TNFα stimulation is rapid and and has to within a M. C. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2002; 22: Scholar, J. J. Finch A. Biochem. 1999; Scholar). In with the findings in 2 a selective in the of stability for IL-8 and mRNAs, this that p38 kinase on stabilization of these mRNAs only after the Indeed, of T98G cells with SB203580 for the of IL-1α not the of or Gro3 mRNA at 2 h and As when SB203580 was to cells with 2 h after IL-1α, there was a in the of and IL-8 mRNA a further Gro3 mRNA was insensitive to the p38 as previously findings that it is not the of p38 IL-1α stimulation kinase in the activation that is required for stabilization of sensitive mRNAs. A the which p38 kinase mRNA stability has been M. C. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2002; 22: The importance of AREs in the of decay of mRNAs is well and the of extracellular stimuli to mRNA is (8Caput D. Beutler B. Hartog K. Thayer R. Brown-Shimer S. Cerami A. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 1670-1674Google Scholar, 9Shaw G. Kamen R. Cell. 1986; 46: 659-667Google Scholar, M. Mahtani K.R. Finch A. Brewer G. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2000; 20: 4265-4274Google Scholar, 11Stoeckle M.Y. Nucleic Acids Res. 1991; 19: 917-920Google Scholar, 12Holtmann H. Winzen R. Holland P. Eickemeier S. Hoffmann E. Wallach D. Malinin N.L. Cooper J.A. Resch K. Kracht M. Mol. Cell. Biol. 1999; 19: 6742-6753Google Scholar, 16Chen C.-Y.A. Shyu A.-B. Trends Biochem. Sci. 1995; 20: 465-470Google Scholar). The of mRNAs containing such sequences within their 3′-UTRs that there is to be heterogeneity in their (13Bakheet T. Frevel M. Williams B.R. Greer W. Khabar K.S. Nucleic Acids Res. 2001; 29: 246-254Google Scholar). The study was to assess the of this diversity with on sensitivity to IL-1α-mediated stabilization. This has been by the of ARE-containing mRNAs in IL-1α-stimulated cells using a of cDNA and oligonucleotide arrays and by the intracellular with the stabilization of a set of mRNAs. The results demonstrate first that there is a broad range of decay rates for ARE-containing mRNAs induced in response to IL-1α. only a subset of unstable ARE-containing mRNAs stability the action of IL-1α. Finally, IL-1α to at least pathways to stabilization of mRNAs. The one or more mechanisms governing stabilization of and IL-8 mRNAs are on protein synthesis, and the activation of p38 MAPK. In contrast, the stabilization of Gro3 mRNA immediately and is insensitive to inhibitors of protein synthesis and p38 kinase these mechanisms on the mRNA are upon functionally distinct regulatory sequences within the mRNAs the range in decay rates for ARE-containing mRNAs is the of mRNAs stability is subject to in response to IL-1α the to the of decay in the of IL-1α. of the IL-1α-induced mRNAs are also induced transcriptionally in response to TNFα but are not stable in this The of IL-1α to such mRNAs in the presence of the the stabilization mRNAs, however, unstable in the presence of IL-1α, and this the of heterogeneity for ARE-containing sequences with respect to stimulus the subset of ARE-containing mRNAs that are also stabilized in response to IL-1α, at least of mRNA can be upon their for of stability. Although Gro3 mRNA to be stabilized both and IL-8 mRNAs not exhibit stability in T98G cells 2 h after the to IL-1α. This to a for ongoing protein synthesis, because of protein synthesis with this their stabilization. Although IL-1α can mRNA stabilization immediately in the presence of this only in cells that have been with TNFα and the of TNFα to promote this also sensitivity to findings that IL-1α or TNFα can expression of one or more gene products that are to the mRNA stabilization may a for the of one or more proteins from mRNAs. The differential of TNFα and IL-1α to stability of the same mRNAs is in of the and response exhibited by these stimuli J. J. Finch A. Biochem. 1999; Scholar). Both have in the activation of multiple protein kinase and p38 MAPK has been shown to be for IL-1α-induced mRNA stabilization (10Lasa M. Mahtani K.R. Finch A. Brewer G. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2000; 20: 4265-4274Google Scholar, R. Kracht M. B. A. Chen C.Y. Shyu A.B. M. M. Resch K. H. J. 1999; 18: Scholar, A. D. A. Winzen R. R. H. Kollias G. M. J. Biol. 2002; Scholar), the of TNFα to promote mRNA stability that and p38 activation are not or that p38 activation is but not for stabilization. The for p38 MAPK activation in the IL-1α-induced stabilization of and IL-8 mRNAs, as by R. Kracht M. B. A. Chen C.Y. Shyu A.B. M. M. Resch K. H. J. 1999; 18: G. P. M. C. RNA 2001; 7: Scholar), is in T98G cells in the study through the of the p38 IL-1α-mediated stabilization of Gro3 mRNA was insensitive to the p38 further that there is more one through which mRNA stability can be by this stimulus. sensitivity to the p38 with mRNAs, the mechanisms upon the of the decay to between the mRNA sequences. The activation of p38 MAPK that is for stabilization of and IL-8 mRNAs only after the of IL-1α. This is by the that p38 inhibitors not the of specific mRNAs the first 2 h of stimulation but the stabilization response after the the of p38 activation that is well as of the response to many stimuli may not to mechanisms involved in mRNA This is with a recent that a but activation of p38 in cells is to stabilization of mRNA M. C. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2002; 22: Scholar). Moreover, this the that the between TNFα and IL-1α with respect to the stabilization of mRNA in differential to promote a activation findings lead to a that there are at least in the to stabilization of both and IL-8 mRNAs. The first to be the either or from mRNAs, of one or more proteins required for in the stabilization response to IL-1α. The be a and activation of p38 MAPK. Indeed, the p38 kinase can IL-1α-induced stabilization of IL-8 mRNA at from 2 through h after stimulation of the cells not is to that these are functionally the protein the cell for the activation of p38 This an effect on the activation of the kinase or the of a for the p38 kinase that in the RNA degradation this is distinct from the stabilization of Gro3 mRNA that is of both protein synthesis and p38 MAPK activation. The functional in of ARE-containing mRNAs are to be within the ARE sequences but the specific that instability as with stimulus sensitivity are not ARE motifs have been previously at least in upon the of C.-Y.A. Shyu A.-B. Trends Biochem. Sci. 1995; 20: 465-470Google Scholar). AREs contain multiple isolated motifs, AREs contain at least and AREs contain motifs but contain or AU-rich that the stability of mRNAs containing or AREs are controlled by the action of ARE binding proteins that and these sequences in in a cell (14Chen C.Y. Xu N. Shyu A.B. Mol. Cell. Biol. 2002; 22: 7268-7278Google Scholar, 15Xu N. Chen C.Y. Shyu A.B. Mol. Cell. Biol. 2001; 21: 6960-6971Google Scholar). and IL-8 mRNAs both contain AREs, the Gro3 ARE can be as these mRNAs be by distinct ARE binding proteins that are by the pathways A of stimulus sensitivity with ARE for a of the unstable ARE-containing mRNAs identified in this however, between ARE and sensitivity to IL-1α-induced stabilization stimulus sensitivity is within the ARE per is not for using defined ARE motifs have shown that short sequence from mRNAs growth are to both instability and stimulus sensitivity that such sequence elements both R. Kracht M. B. A. Chen C.Y. Shyu A.B. M. M. Resch K. H. J. 1999; 18: Scholar, H. J. Biol. 2002; Scholar). Indeed, in at least one the sensitivity to stimulus was in only a of the ARE these to be H. J. Biol. 2002; and sensitivity to stabilization by IL-1α are not is upon of known sequences using the defined by Chen and Shyu mRNAs are stabilized by IL-1α as shown either in the study or in mRNAs ARE is upon of known sequences using the defined by Chen and Shyu C.-Y.A. Shyu A.-B. Trends Biochem. Sci. 1995; 20: 465-470Google mRNAs are stabilized by IL-1α as shown either in the study or in in a is that diversity within ARE-containing mRNAs with to of their stability by extracellular This functional heterogeneity is upon sequence between mRNAs and in a that can vary with respect to cell and intracellular the of in mRNA stability can produce dramatic changes in the of mRNAs and their protein this diversity of mechanism will be important to in and may lead to important for of inflammatory gene expression in human

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