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Department of Animal Science, Texas A&M University, College Station, Texas 77843-2471
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONAUTOREGULATION OF THE...REGULATION OF STABILITIES OF...CONCLUSIONS AND FUTURE...REFERENCES |
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gene regulation, mechanisms of hormone action, steroid hormones, steroid hormone receptors
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONAUTOREGULATION OF THE...REGULATION OF STABILITIES OF...CONCLUSIONS AND FUTURE...REFERENCES |
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Posttranscriptional Regulation of Gene Expression
Genome studies of diverse species indicate that mammalian physiology is unique not because of greater numbers of genes but rather because of greater complexity of the regulation of genes [6, 7]. Posttranscriptional regulation of gene expression (including mRNA translation and stability) is one of the ways organisms control and modify the flow of genetic information into the proteome [8]. Within the continuum of gene expression, from transcription to protein degradation, regulated mRNA stability is increasingly being recognized as a major effector of gene regulation. It has been established that the rate of mRNA degradation is as important as the rate of synthesis in regulating the steady-state concentration of the mRNA [9]. In comparisons of transcriptional and posttranscriptional upregulation of gene expression, the latter (mRNA stabilization) may be advantageous to organisms because it lacks the lag phase and increased energetic costs that occur for responses that increase rates of gene transcription.
Physiological changes that affect mRNA stability occur during development, nutritional stress, hypoxia, inflammation, cancer, and aging [10–14]. Therefore, it should not be surprising that a number of different hormones regulate concentrations of various gene products primarily by altering mRNA stability [3, 4]. Steroid hormones are among these hormones. This posttranscriptional regulation joins other effects of steroid hormones on gene expression [15]. While it is clear that steroid hormones regulate the expression of many genes at the level of transcription, there are numerous cases where those effects are inadequate to account for the magnitude of the change in the steady-state concentration of the mRNA. There are additional cases where steroid hormones regulate the concentration of an mRNA purely via posttranscriptional regulation of the stability of that message. These will be discussed after a brief digression to introduce the molecular mechanisms that govern mRNA stability.
Pathways of mRNA Degradation
Different regions of mRNAs contain sequences and structures for diverse functions. The average nascent mammalian mRNA has a 7mGpppN "cap" on the 5' end and approximately 200 adenosine residues in a "poly(A) tail" on the 3' end. The 5' untranslated region (UTR) is usually short (100–200 bases long). The 5'UTR is scanned by ribosomes, which initiate translation at an AUG codon within an optimal Kozak sequence and proceed to translate the coding sequence until they reach a stop codon. The length of 3'UTRs is highly variable between different mRNAs: from a few hundred bases for glyceraldehyde 3-phosphate dehydrogenase mRNA to 
3000 bases for the mRNAs encoding steroid hormone receptors. Although they do not contain coding sequences, the 3'UTR sequences of an mRNA are well conserved across species [16, 17]. The 3'UTR sequences are predicted to form stable structures with algorithms such as MFOLD [18] that may bind proteins. The 3'UTR is the only region of the mRNA in which RNA structure:binding protein complexes remain uninterrupted by ribosome transit. The 3'UTR sequences, structures, and binding proteins confer its function: regulating the life span of the mRNA. The average mRNA half-life in mammalian cells is 24 h, with short-lived messages such as c-fos (FOS) mRNA having 20-min half-lives and long-lived RNAs, like 28S and 18S rRNAs having 4-day-long half-lives [19]. The half-life of an RNA is important in determining how long each mRNA acts as a template for translation of proteins. In addition, the half-life of the mRNA also controls how rapidly its steady-state concentrations can be altered: expression of genes with short half-lived mRNAs are rapidly regulated by changes in transcription and degradation rates, while long-lived mRNAs may take days to achieve a new steady-state level in response to a cell signal.
In mammalian cells, some pathways of mRNA degradation initiate with removal of the poly(A) tail (deadenylation), while others do not [20, 21]. In the former, poly(A)-specific ribonuclease progressively shortens the original 
200-base-long poly(A) tail of mRNAs. The shortened "tails" bind fewer poly (A) binding proteins and other proteins in ribonucleoprotein complexes that are associated with stable mRNAs. The deadenylation precedes decapping and degradation of the body of the mRNA by exonucleases. Hormones may affect the lengths of the poly(A) tails of mRNAs and thereby impact the decay of specific mRNAs by the deadenylation pathway [22, 23]. However, in the best characterized cases of hormonally regulated mRNA stability, mRNA degradation appears to occur via a "deadenylation-independent" pathway [20, 21]. Instead of shortening of the poly(A) tail, endoribonucleolytic cleavage is the initial event in decay of the message. Because the cleavage by the endoribonuclease usually occurs within the 3'UTR, it functionally deadenylates the coding sequence, leaving it susceptible to rapid 3' to 5' decay by the "exosome," as well as decapping, and 5' to 3' degradation by exonucleases [24]. In the example of estrogen stabilization of vitellogenin mRNA (discussed later), estrogen lowers the rate of the cleavage of the mRNA within its 3'UTR to enhance vitellogenin gene expression (discussed later). While most products of mRNA cleavage are short lived, the 3' fragment of insulin-like growth factor-II (IGF2) mRNA is a stable and easily detected indicator of its regulated endonucleolytic cleavage [25, 26].
Few endoribonucleases (RNases) and proteins that bind and inhibit them (RNasins) have been characterized in vertebrate animals [27]. The identified RNases appear to have little or no specificity in the RNA sequences they cleave. For example, RNase A (produced by the pancreas and other tissues) cleaves single-stranded regions of RNA molecules. RNase L (induced by interferon in tissues as part of an antiviral response) destabilizes a large population of mRNAs by cleaving single-stranded RNA sequences [28]. RNasins, such as those available commercially, bind to and inactivate several such endoribonucleases. Some studies of the rat vaginal epithelium and uterus have indicated that estrogen treatment alters the ratio of these general endoribonuclease and RNasin activities [29–31]. However, there is disagreement about the direction of the effect: toward increased endoribonuclease activity or its inhibition. Our more recent study found no effect of low-dose estrogen treatment on the half-life of poly(A)+ RNA in endometrium [32]. In the hormonal regulation of the stability of an mRNA, there is a balance between cleavage and protection of specific sites within the mRNA sequence/structure. The sequence specificity may reside within the endoribonuclease or within RNA-binding proteins that protect exposed sites of the mRNA against nonspecific endoribonuclease activities [33].
Cis-Elements and Transacting Factors
As in the case of mRNA synthesis (transcription) in the nucleus, rates of mRNA degradation in the cytoplasm are regulated by the sequences of the nucleic acid (cis-elements on the mRNA) and the proteins that bind them (trans-acting factors [21]). The most well-characterized mRNA cis-elements are AU-rich sequences. These were first identified as instability elements in the 3'UTRs of oncogene and cytokine mRNAs, for example, those encoding c-fos (FOS) and tumor necrosis factor (TNF [24, 34]). There are distinct classes of AU-rich elements (AREs), ranging from arrays composed of several AUUUA elements in oncogene mRNAs to individual AUUUA elements scattered in 3'UTR sequences of FSH ß-subunit (FSHB) and epidermal growth factor receptor (EGFR) mRNAs [16, 35, 36]. There are multiple families of proteins that bind AREs, including AU-binding factors (e.g., HNRNPD, also known as AUF1), zinc-finger proteins (e.g., tristetraprolin, the ZFP36 gene product), and relatives of the Drosophila RNA-binding ELAV protein (e.g., ELAV1, which is also known as HuR [4, 36]). While some ARE-binding proteins (such as tristetrapolin) destabilize the ARE-bearing mRNA, others (such as HuR) have stabilizing effects, and AUF1 can serve in either function. Most are commonly expressed, although there is some degree of tissue specificity in their distribution [10, 13, 34, 37]. Interestingly, the expression of some ARE-binding protein genes are regulated by steroid hormones [38–40].
There are many different trans-acting factors and cis-elements that are involved in the regulation of mRNA stabilities. For example, the poly(C)-binding proteins -1 and -2 bind C-rich elements of LH receptor (Lhcgr) mRNA [41]. The binding of the poly(C)-binding proteins destabilizes the LH receptor mRNA and contributes to its down-regulation during an LH response. However, individual cis-elements and binding proteins do not work in isolation. The androgen receptor (AR) mRNA bears a C-rich element in its 3'UTR that binds a poly(C)-binding protein as well as HuR [42, 43]. These two proteins cooperate in a cell-type-specific manner to determine whether androgen stimulation stabilizes or destabilizes the AR mRNA. In this way, the regulation of mRNA stability resembles that of transcription; the ultimate effect on gene expression depends on the interplay of various trans-acting factors bound to multiple cis-elements.
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AUTOREGULATION OF THE STABILITIES OF mRNAs ENCODING HORMONE RECEPTORS |
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TOPABSTRACTINTRODUCTIONAUTOREGULATION OF THE...REGULATION OF STABILITIES OF...CONCLUSIONS AND FUTURE...REFERENCES |
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One of the most striking observations about regulated mRNA stabilities is that hormones commonly use this mechanism to autoregulate the expression of the mRNAs that encode their own receptor proteins. In general, hormone receptor mRNAs are designed to be unstable: they carry long 3'UTR sequences with a large number of ARE instability sequences. This is true for the mRNAs encoding steroid hormone receptors listed in Table 1 as well as for the mRNAs encoding G-protein-coupled receptors for oxytocin, FSH, LH, epidermal growth factor (EGF), and ß-adrenergic agonists (FSHR, LHCGR, EGFR, Adrb2). The last three mRNAs are well characterized for their autoregulated stabilities [5, 16, 35, 44, 45]. The instability of receptor mRNAs makes their concentrations very sensitive to changes in rates of transcription and degradation of mRNAs. Another notable point is that while hormones uniformly down-regulate concentrations of their receptor proteins, autoregulation of the stability of their receptor mRNAs may be positive or negative [15, 46]. Positive posttranscriptional autoregulation, demonstrated by EGF, can augment the recovery of receptor concentrations and responsiveness to EGF, while negative autoregulation, demonstrated by LH and ß-adrenergic receptors, can increase the refractory period after a response to those hormones [5, 35, 44, 45].
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Estrogen Receptor
Estrogen is a steroid hormone that autoregulates the stability of the mRNA encoding its receptor. Estrogens stabilize estrogen receptor (ESR1) mRNA in fish liver during the initiation of oogenesis and in mammalian endometrium during the preovulatory surge of estrogen [17, 47] (Table 1). In both cases, the stabilization and resultant upregulation of ESR1 mRNA are dependent on ESR1 protein because estrogen antagonists block the effect. The conservation of this estrogen action across these diverse species implies that it is an important mechanism for augmenting further estrogen responses. In sheep endometrium, a single physiological dose of estradiol upregulates ESR1 mRNA concentrations 5-fold in 24 h, during which time there is no increase in the transcription rate of the ESR1 gene [48]. That the primary mechanism of ESR1 mRNA upregulation occurs by increasing ESR1 mRNA stability was directly demonstrated in vivo with pulse-chase labeling and ex vivo using explants cultured with a transcription inhibitor [32].
The molecular mechanism by which estrogen stabilizes ESR1 mRNA is unknown. Human and sheep ESR1 mRNAs carry numerous ARE elements in their 3'UTRs that are probably involved in the instability of the ESR1 messages and of heterologous mRNAs on transfer of the 3'UTR to them [17, 49]. Using an in vitro stability assay developed with cytoplasmic extracts from endometrial samples from control and estradiol-treated ewes, two discrete (82-base-long) Minimal Estradiol-Modulated Stability Sequences (MEMSSs) were identified in the vast (>4000-base-long) 3'UTR of the sheep ESR1 mRNA [17]. These MEMSSs confer estradiol-enhanced stability to heterologous mRNAs. The endometrial proteins that bind the MEMSS are currently being identified. Estrogen has also been reported to destabilize ESR1 mRNA in the MCF7 breast cancer cell line [50]. The explanation of these contrasting effects of estrogens may become clear when the molecular mechanism(s) that regulate ESR1 mRNA stability are elucidated.
Progesterone, Androgen, and Glucocorticoid Receptors
Similar to estrogen, other steroid hormones (progestins, androgens, and glucocorticoids) also autoregulate the expression of their receptor genes by altering mRNA stabilities (Table 1). Messages encoding progesterone receptor (PGR), AR, and glucocorticoid receptors (NR3C1) are similar to ESR1 mRNA in that they carry very long 3'UTRs that, with the exception of AR mRNA, include numerous AREs [42, 43, 51, 52]. In contrast to the bidirectional autoregulation of ER mRNA by estrogen, progestins have only been reported to stabilize PGR mRNA [51]. The progestin medroxyprogesterone acetate increased the PGR mRNA half-life from 6 to 12 h in primary cultures of stromal cells from human endometrium [50]. Androgens, like estrogens, autoregulate the stability of their receptor's mRNA in both positive and negative directions [42, 43]. The effect depends on dose and the tissue or cell line examined. For instance, androgens stabilize AR mRNA in a prostate cancer cell line but destabilize it in the MDA453 breast cancer cell line. As mentioned previously, differential binding of novel HuR and poly(C)-binding proteins to a conserved C-rich sequence in the 3'UTR is believed to be responsible [43]. Some controversy exists over whether glucocorticoids regulate the stability of the mRNA that encodes the predominant glucocorticoid receptor (NR3C1). While glucocorticoids transcriptionally repress the NR3C1 gene, they also rapidly destabilize NR3C1 mRNA in many cell types [52]. We can conclude that steroid hormones demonstrate a variety of posttranscriptional effects on their receptor mRNAs: upregulation or down-regulation with some cell specificity of the effect. Because they affect the concentration of the receptor proteins, these steroid hormone actions can either enhance or limit the responses of a tissue to hormonal stimuli.
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REGULATION OF STABILITIES OF OTHER mRNAs BY STEROID HORMONES |
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TOPABSTRACTINTRODUCTIONAUTOREGULATION OF THE...REGULATION OF STABILITIES OF...CONCLUSIONS AND FUTURE...REFERENCES |
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Estrogen is the hormone that is best known for its effects on mRNA stabilities. The most complete studies of estrogen regulating mRNA stabilities were performed with frog and chicken liver, which is a primary target organ for estrogen action in oviparous species. Interestingly, at the initiation of egg production, estrogen destabilizes mRNAs encoding serum proteins (e.g., albumin mRNA) while stabilizing mRNAs encoding proteins that will be packaged into the eggs (e.g., vitellogenin and apolipoprotein II mRNAs [2, 3, 53–55]; Table 2). In frog liver, estrogen activates polysomal ribonuclease 1 (an endoribonuclease with some sequence specificity for A[C/U]UGA sequences) to degrade albumin (ALB) mRNA more rapidly [33]. However, estrogen simultaneously induces production of vigilin (HDLBP), a 119-kDa protein with 15 RNA-binding domains. Vigilin binds and protects cis-elements within the 3'UTR of vitellogenin mRNA to extend its half-life from 16 to 600 h [3]. These data illustrate how estrogen has distinct negative and positive effects on the stabilities of different mRNAs in one tissue. However, estrogen stabilization of apolipoprotein II appears to occur via a different mechanism in chicken liver. Estrogen induces production of a 25-kDa protein (unlike vigilin) that binds a discrete region within the 3'UTR of apolipoprotein II mRNA to stabilize the message [53, 55]. Further in-depth characterizations of the cis-elements and binding proteins involved in estrogen regulation of mRNA stabilities will allow us to compare them between species and tissues and, ultimately, to explore the breadth of the estrogen effects on other coregulated mRNAs.
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In mammals, estrogen regulates the stabilities of several mRNAs in many diverse tissues [56–61] (Table 2). In the pituitary, estrogen stabilizes some mammalian mRNAs (e.g., thyroid hormone-releasing hormone receptor [Trhr] mRNA) while destabilizing others (e.g., peptidylglycine 
-amidating mono-oxygenase [Pam] mRNA [59, 61]). Most of these studies provide little mechanistic information, so it will be interesting to learn how estrogen affects the stabilities of mRNAs in mammals. This includes whether estrogen affects the expression and/or activities of mammalian homologues of the RNA-binding proteins involved in the regulation of albumin, vitellogenin, and apolipoprotein II mRNAs in frog and chicken livers [3, 55].
Progesterone
Progesterone, like estrogen, has stabilizing and destabilizing effects on mRNAs. In cultures of anterior pituitary cells, progesterone stabilizes the mRNA encoding the ß-subunit of LH (Lhb [62]). That stabilizing effect is augmented by estrogen treatment. Others, using a similar model system, noted that progesterone treatment altered the length of the poly(A) tails on the messages encoding the - and ß-subunits of LH (CGA, LHB), which might impact their stability [22]. In breast cancer cells, progesterone stabilizes fatty acid synthetase (FASN) mRNA from a 6-h to a 24-h half-life while it concurrently increases the transcription of the gene [63]. In myometrial cells, progesterone destabilizes interleukin-1 (IL1A) mRNA via a PR-dependent mechanism [64]. Interestingly, the destabilization of interleukin-1 mRNA by progesterone also dominantly prevents its upregulation by phorbol esters.
Androgens
Androgens posttranscriptionally regulate the expression of two genes that are critical to reproduction: Egf and Fshb [65–67] (Table 2). Androgens stabilize both Egf and Fshb mRNAs in rodents. There is still some controversy on the mechanism of the gender differences seen in steady-state concentrations of Egf mRNA in the submaxillary gland. However, testosterone appears to enhance the stability, polyadenylation, and translation of the Egf message [23, 65, 67]. These effects are concurrent with increased binding of a 47-kDa protein to a discrete, conserved sequence within the 3'UTR of Egf mRNA. As is the case for progesterone, there are few reports of androgens destabilizing mRNAs, with the exception of androgen destabilizing AR mRNA in breast cancer cells [42].
Glucocorticoids
Glucocorticoids, like estrogens, have effects on most tissues. Perhaps for that reason, glucocorticoids also affect the stabilities of many different mRNAs [68–77] (Table 2). They increase the stabilities of growth hormone (GH1) mRNA in the pituitary and fatty acid synthase (Fasn) in fetal lung [68, 69]. However, the majority of the effects reported for glucocorticoids on mRNA stabilities are of its destabilization of messages [14]. This group of mRNAs includes those encoding many inflammatory response proteins, including cytokines (e.g., interleukins-1ß, -6, and -8 [IL1B, Il6, IL8], tumor necrosis factor- [TNF], and monocyte chemoattractant protein [Ccl2]) and generators of inflammatory mediators (e.g., cyclooxygenase-2 [PTGS2] and nitric oxide synthase [NOS2]) [14, 70–72]. In addition, the adhesion proteins and metalloproteinases that may also be involved in inflammation are coordinately regulated [74, 76, 77]. During inflammation, p38 mitogen-activated protein kinase (MAPK1) stabilizes the mRNAs encoding inflammatory response proteins by reducing the binding of tristetraprolin to their AREs [14]. Glucocorticoids interfere by inducing sustained expression of MAPK phosphatase 1 (DUSP1), which inactivates MAPK and, indirectly, destabilizes the same set of mRNAs [70]. Whether glucocorticoids destabilize all the mRNAs listed in Table 2 by this mechanism remains to be determined. The destabilization of these inflammatory response mRNAs is an important mechanism in the anti-inflammatory actions of glucocorticoids. It also indicates a mechanism for cross talk of steroid hormone and MAPK-signaling pathways at the posttranscriptional level of gene regulation.
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CONCLUSIONS AND FUTURE DIRECTIONS |
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TOPABSTRACTINTRODUCTIONAUTOREGULATION OF THE...REGULATION OF STABILITIES OF...CONCLUSIONS AND FUTURE...REFERENCES |
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A continuing challenge facing reproductive biology is to understand how hormones regulate specific genes within responsive tissues and to apply that knowledge usefully. Mechanistic information about steroid hormone-regulated mRNA stability (RNA sequence elements and the transacting binding proteins) may provide new targets for therapeutic control of expression of those genes. Some investigators are already attempting to interrupt crucial mRNA-protein interactions for therapeutic interventions [78, 79]. Alternatively, expression or function of the trans-acting factor (such as a steroid hormone-induced RNA-binding protein) could be individually singled out for inhibition. Such innovative therapies could spare some actions of steroid hormones while limiting others to tailor gene expression for a desired outcome, such as enhanced control of reproduction.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received: 14 January 2005.
First decision: 14 February 2005.
Accepted: 18 February 2005.
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TOPABSTRACTINTRODUCTIONAUTOREGULATION OF THE...REGULATION OF STABILITIES OF...CONCLUSIONS AND FUTURE...REFERENCES |
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