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Published ahead of print on September 21, 2006, doi:10.1165/rcmb.2006-0340TR
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American Journal of Respiratory Cell and Molecular Biology. Vol. 36, pp. 166-174, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2006-0340TR

HEME OXYGENASE-1: A MULTIFACETED TRIPLE-THREAT MOLECULE

How Many Transcription Factors Does It Take to Turn On the Heme Oxygenase-1 Gene?

Jawed Alam and Julia L. Cook

Department of Molecular Genetics, Ochsner Medical Center, New Orleans, Louisiana

Correspondence and requests for reprints should be addressed to Dr. Jawed Alam, Department of Molecular Genetics, Ochsner Medical Center, 1516 Jefferson Highway, New Orleans, LA 70121. E-mail: jalam{at}ochsner.org

Abstract

The ability to communicate with the environment and respond to changes—particularly those of an adverse nature—within that environment is critical for cell function and survival. A key component of the overall cellular stress response includes adjustments in the gene expression program in favor of proteins that manifest activities capable of frustrating and eventually eliminating the molecular constituents of the stress condition. One protein providing such cytoprotective activity is heme oxygenase-1 (HO-1), an enzyme that catalyzes the rate-limiting reaction in heme catabolism (i.e., the oxidative cleavage of b-type heme molecules to yield equimolar quantities of biliverdin IX{alpha}, carbon monoxide, and iron). Because of the potent antioxidant, anti-inflammatory, and signaling properties of the reaction products, the HO-1 gene (hmox1) is frequently activated under a variety of cellular stress conditions. Cells use multiple signaling pathways and transcription factors to fine-tune their response to a specific circumstance. Among these factors, members of the heat-shock factor, nuclear factor–{kappa}B, nuclear factor–erythroid 2, and activator protein-1 families are arguably the most important regulators of the cellular stress response in vertebrates. Although there is functional overlap between individual families, each broadly regulates different aspects of the cellular stress response and thus, with some exceptions, modulates the expression of different sets of targets genes. To the best of our knowledge, hmox1 is unique in that it is proposed to be directly regulated by all four of these stress-responsive transcription factors. In this article we provide a review and analysis of the data supporting this proposition.

Key Words: heme oxygenase-1 • transcription factors • HSF • AP-1 • NF-{kappa}B

Heme oxygenase-1 (HO-1), a microsomal membrane protein, catalyzes the oxidative cleavage of b-type heme molecules to yield equimolar quantities of biliverdin IX{alpha}, carbon monoxide (CO), and iron; biliverdin is subsequently reduced to bilirubin by the cytosolic enzyme biliverdin reductase. In its capacity as the rate-limiting enzyme in heme catabolism, HO-1 plays a critical role in at least two important physiologic processes: (1) recycling of iron molecules (primarily from senescent erythrocytes) for erythropoiesis and (2) maintenance of cellular homeostasis under stressful conditions. The latter property, a manifestation of the potent antioxidant, anti-inflammatory, and signaling activities of CO and the bile pigments, may be important in a wide range of human pathologies, including inflammatory diseases such as sepsis and asthma; cardiovascular diseases such as myocardial infarction, atherosclerosis, and hypertension; ischemia-reperfusion injury; and transplant graft rejection (1). Because the functional significance of HO-1 is dependent not only on its intrinsic enzyme activity but also on the ability of cells to potently stimulate, through transcriptional regulation of the hmox1 gene, such activity under stress conditions that to some degree mimic diseased states and because modulation of HO-1 activity is of potential therapeutic value (1), a detailed and thorough understanding of the mechanisms of hmox1 gene regulation is imperative.

We do not know how many transcription factors (TFs) it takes to turn on the hmox1 gene in part because of the seemingly endless inventory of pathologic states and stress-associated effectors that stimulate HO-1 expression, including the substrate heme, ultraviolet irradiation, hyperthermia, heavy metals, hydrogen peroxide, endotoxin, and inflammatory cytokines. Furthermore, because the ability to communicate with, and respond to changes within, their environment is critical for function and viability, cells use a sizeable number of signaling pathways and TFs to fine-tune their response to a specific circumstance. Among these TFs, members of the heat-shock factor (HSF), nuclear factor–{kappa}B (NF-{kappa}B), nuclear factor–erythroid 2 (NF-E2), and activator protein–1 (AP-1) families are arguably the most important, and among the best studied, regulators of the cellular stress response in vertebrates. Although a given stimulus can activate members of more than one (and even all four) of these TF groups and there is some functional overlap between individual families, each broadly regulates different aspects of the cellular stress response and thus is activated under differing sets of circumstances. For instance, HSF1 is activated under stress conditions characterized by significant intracellular accumulation of non-native proteins and consequently activates genes whose products are capable of alleviating this condition and restoring the integrity of damaged proteins. NF-{kappa}B is an important regulator of cytokines and other mediators of the immune and inflammatory responses that provide protection against bacterial and viral infections. Nrf2, an NF-E2 family member, is activated by various xenobiotics and oxidants and logically regulates genes encoding proteins with antioxidant and xenobiotic detoxification activities. Finally, AP-1 factors control cellular fate by regulating production of proteins that mediate cell growth or cell death, the latter being the most drastic (but sometimes necessary) decision by a cell under extreme stress.

Functional overlap between the TF pathways arises in part because a given stimulus can simultaneously cause multiple types of "molecular" stress and because a given gene may be targeted by more than one of these TF families. For instance, promoters of genes encoding several chemokines, including IL-8, monocyte chemoattractant protein-1, and RANTES, contain binding sites for AP-1 and NF-{kappa}B factors. This configuration permits greater flexibility in gene regulation, allowing for stimulus- and cell-specific expression of the chemokines (2). To the best of our knowledge, hmox1 is unique in that it is proposed to be directly regulated by all four of these stress-responsive TFs. The function of Nrf2 and Bach1, an NF-E2 class repressor, in hmox1 gene regulation is the subject of several recent reviews (3–5); therefore, in this article, we focus attention on the contribution of HSF, NF-{kappa}B, and AP-1 factors in this process. The role of the mitogen-activated protein kinase (MAPK) signaling cascades in hmox1 gene regulation is also summarized.

HSFs

Characterization of the molecular mechanisms of hmox1 regulation began with the isolation and characterization of the rat gene in 1987 by Shibahara and colleagues (6). Primary structure analysis of the 5' flanking region revealed a motif similar to the consensus heat shock element (HSE) necessary for upregulation of a select set of genes in response to hyperthermia (Figure 1). HO-1 was already known to be induced by several nonheme agents but was not considered to be a heat shock protein (HSP). Subsequent analysis using cultured cells (7) and intact animals (8) confirmed that rat HO-1 is a bona fide HSP.


Figure 1
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  		Figure 1. Location of transcription factor binding sites in the 5' flanking region of a generic hmox1 gene. The relative position of binding sites for the NF-{kappa}B, HSF, AP-1, and NF-E2 families is indicated. The arrow marks the transcription initiation site, and distance from this site is given in kilobase pairs. The proximal promoter (PP) and distal enhancer (E1, E2) regions are designated. The function of some binding sites has largely been examined in a specific species: human (H), rat (R), or chicken (C).Other details are provided in the text.

 
The heat shock response (HSR) is a universal and evolutionary conserved biological mechanism used by organisms to preserve cellular function under adverse circumstances. Although elevated temperatures represent the prototypical stimulus, the HSR can be triggered by other stressors that affect cellular accumulation of non-native proteins, the common signal for HSR activation. The hallmark of the HSR is the rapid accumulation of HSPs, a conserved family of chaperone proteins that facilitate synthesis, folding, and assembly of nascent proteins; maintain proteins in their native folded form; assist in the intracellular transport of proteins; and promote proteolytic degradation or repair of misfolded or stress-damaged proteins. HSP expression is regulated primarily at the level of gene transcription, a process controlled by the HSF family of sequence-specific DNA binding proteins. In vertebrates, four HSFs have been identified, with HSF3 being unique to the avian lineage. Among family members, only HSF1 and HSF3 are activated by hyperthermia and are considered to be the primary regulators of the HSR. Gene activation results from the interaction of the HSF with the HSE, defined as a contiguous array of at least three copies of the 5-bp unit 5'-nGAAn-3' arranged in alternating orientations (9, 10).

In light of the evolutionary conservation of the HSR and the identification of rat HO-1 as an HSP, subsequent work by Shibahara and colleagues led to the unexpected finding that mouse and human HO-1s are apparently not HSPs. This conclusion was based on the observation that HO-1 protein or mRNA levels were not affected by elevated temperatures in several cultured cell lines (11, 12). Follow-up investigations (13–16) of additional human cell lines and cells derived from human tissues have largely confirmed the initial observations; the only convincing exception is the induction of HO-1 observed in Hep3B hepatoma cells (15). Similarly, the hmox1 gene is refractory to heat shock induction in multiple mouse cell lines, with the exception of another liver-derived cell line (i.e., Hepa cells) (J. Alam, unpublished observations). This species-dependent variation is unusual because classical HSPs do not exhibit such behavior. A reasonable explanation for this phenomenon can be found in comparing the sequences of the various hmox1 promoters.

Contrary to initial observations (7), the rat hmox1 promoter contains two HSEs (Figure 2), both of which are required for optimal activation by hyperthermia (17). Both rat HSEs contain a single pentamer that deviates (by one residue) from the consensus unit 5'-nGAAn-3', but such mutations are tolerated and do not prevent heat shock responsiveness. Mouse HSE1 deviates from the rat ortholog at two positions, one of which is a substitution (G to A) at the most critical residue within the conserved GAA triplet of a pentamer unit. Unlike the analogous rat sequence, a synthetic copy of the mouse hmox1 HSE1/HSE2 locus is not activated by hyperthermia (18). Human HSE2 deviates from the consensus at three different positions in two adjacent pentamers and may not be a true HSE or bind to HSF1. Consequently, to the extent that productive heat shock activation requires cooperativity between HSF1 proteins bound to HSE1 and HSE2, human hmox1 is also likely to be unresponsive or only weakly responsive to hyperthermia. Chimpanzee (Pan troglodyte) HSEs are identical to those of the human and thus are likely to be inactive in the context of the native hmox1 gene. The cow (Bos taurus), dog (Canis familiaris), and chicken (Gallus gallus) HSEs deviate considerably and at critical residues from the consensus pentamer and are not likely to be functional elements. To the best of our knowledge, regulation of HO-1 by hyperthermia in cells derived from these species has not been examined, but it is reasonable to predict that HO-1 of these organisms is not an HSP.


Figure 2
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  		Figure 2. Comparison of the promoter proximal heat shock elements from hmox1 genes. Sequences were aligned by the Jotun Hein method (73) and manual adjustments. Nucleotides conserved in at least four species are highlighted in gray. The GAA/TTC consensus triplet of an HSE pentamer unit is marked in yellow. Single residue substitutions at either of the A/T positions of a given triplet are highlighted in green, indicating acceptable mutations. Substitutions at the critical G/C residue or at two or more positions within a triplet are marked in red, indicating potentially debilitating mutations. Numbers represent nucleotide distance from transcription start site. GenBank accession numbers for sequences are as follows: human (NT_011520.11), monkey (NW_121189), cow (NW_931574), dog (NW_876251), mouse (NT_078575), rat (NW_047532), and chicken (NW_060209). Other details are provided in the text.

 
If the HSE1/HSE2 loci in the mouse and human hmox1 genes are inactive, how does one explain the induction of HO-1 expression by hyperthermia in at least one cell line from each species? We suggest that such induction occurs via a recently identified distal HSE located within the Enhancer 1 (E1) region of the mouse hmox1 gene (Figure 1) (18). The distal HSE is conserved in the rat and human genes, and synthetic copies of each are as responsive to hyperthermia as the HSE from the well-studied hsp70 gene (18). Furthermore, targeted deletion of the E1 locus renders the full-length mouse hmox1 promoter unresponsive to heat shock in Hepa cells (J. Alam, unpublished observations), suggesting that the distal HSE is responsible for HO-1 induction in these cells. The location of a functional HSE at this distance is unusual because HSEs of the classical hsp genes are typically positioned immediately upstream of the transcription start site. Heat-shock responsiveness of a distal HSE may require the coordination of HSF1 with other, possibly cell-specific, factors, providing one potential explanation for hyperthermic induction of HO-1 in a limited number of mouse and human cells.

Although its role in hyperthermic gene activation may be restricted, the distal HSE may be more generally used during other cellular responses. For instance, HSF1 is known to be activated by other proteotoxic agents, including arsenite, cadmium, proteasome inhibitors, and amino-acid analogues, most of which induce expression of HO-1. Furthermore, the role of the distal HSE and its cognate binding proteins may not be limited to gene regulation under stress conditions. Recent studies, particularly those using HSF knockout cells and animals, have revealed unexpected roles of these factors in nonstress gene regulation, cell cycle progression, embryonic development, cellular differentiation, and spermatogenesis (10, 19). In particular, HSF1 is necessary for the constitutive expression of HSP70 and maintenance of redox homeostasis under basal conditions (20). Similarly, unstimulated hsf1–/– MEFs consistently exhibit reduced HO-1 levels compared with their wild-type counterpart (18). Furthermore, HSF1-deficient mice exhibit defects in the chorioallantoic placenta leading to increased prenatal lethality. Beyond the loss of the HSR and the inability to acquire thermotolerance, mice that survive to adulthood exhibit other pathologies, including decreased fertility, growth retardation, and increased sensitivity to endotoxins (21). Many of these abnormalities can be observed in HO-1–deficient mice (22).

NF-{kappa}B

Although initially identified as a specific transcription regulator of the {kappa} light-chain gene in B lymphocytes, NF-{kappa}B is now more of a generic term for a collection of transcription factors that regulate multiple genes involved in biological processes including the immune and inflammatory responses, cellular stress response, cellular proliferation, apoptosis, and embryonic development. NF-{kappa}B factors are generated by homo- or hetero-dimerization of members of the Rel family of proteins, five of which have been identified in vertebrates: RelA (p65), RelB, c-Rel, p52, and p50. RelA, RelB, and c-Rel harbor transcription activation domains, and dimers containing these species typically function as transcription activators, whereas homodimers of p52 and p50, which lack such domains, act primarily as repressors. The p65·p50 heterodimer is the first characterized, best studied, and generally the most abundant activator and, consequently, is frequently synonymous with NF-{kappa}B (23, 24).

During conditions of cellular homeostatis, NF-{kappa}B factors typically exist in an inactive state within the cytoplasm in association with the inhibitor protein I{kappa}B. In the classical mechanism of NF-{kappa}B activation, cellular stimulation triggers signaling pathways that lead to phosphorylation of I{kappa}B by I{kappa}B kinases (IKKs). Phosphorylated I{kappa}B is degraded by the 26S proteasome, permitting nuclear translocation of NF-{kappa}B and subsequent target gene activation. NF-{kappa}B activity is induced by a wide variety of stimuli typically associated with cellular stress or diseased states including inflammatory cytokines, bacterial and viral products such as lipopolysaccharide and double-stranded RNA, altered endogenous proteins, ultraviolet irradiation, and oxidants such as H2O2 (23, 24). Given the extensive overlap between the spectrum of NF-{kappa}B activators and HO-1 inducers, this transcription factor has been frequently and persistently implicated in hmox1 activation.

Multiple studies using a variety of stimuli and cell types have demonstrated costimulation of NF-{kappa}B activity and HO-1 expression (Table 1) with an implicit, and sometimes explicit, assertion of a direct causal relationship. Most HO-1 inducers generate cellular oxidative stress, a state that activates multiple transcription factors including, but not limited to, all those discussed in this article. Thus, co-stimulation of HO-1 expression and NF-{kappa}B activity provides only correlative information, and a causative role requires additional proof, including one or preferably both of the following: (1) identification of a hmox1 sequence motif that binds to NF-{kappa}B and confers inducer-dependent activation of a heterologous gene and (2) specific inhibition or ablation of the transcription factor, which attenuates induction of the hmox1 gene.


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  		TABLE 1. EVIDENCE SUPPORTING A ROLE FOR NF-{kappa}B IN HO-1 INDUCTION

 
Two potential NF-{kappa}B binding sequences were initially identified within the immediate 5' flanking region of the human hmox1 gene by a computer-assisted search for sequences similar to known regulatory sites. In vitro binding of purified NF-{kappa}B (p50 or p52 homodimer) to the proximal site and the induction of NF-{kappa}B DNA-binding activity (to a consensus element) in response to heme led to the suggestion that NF-{kappa}B is in part responsible for hmox1 activation by heme and possibly inflammatory cytokines and other stimuli (25). The full binding region was delimited by DNAase I footprint analysis using purified NF-{kappa}B and encompasses the sequence 5'-gactttgTTTCCCAAGGGtca-3', where the uppercase residues represent the core sequence identified by computer analysis. The core motif does not conform to the consensus NF-{kappa}B response sequence, 5'-GGGPuNNPyPyCC-3' (23) and more closely resembles the reverse (but not the reverse complement) of the consensus. Another disconcerting revelation is that the putative NF-{kappa}B response element is not well conserved in other mammalian hmox1 genes. Finally, although the role of the putative NF-{kappa}B site in gene activation by any stimuli has not been directly investigated, the mouse, rat, and human hmox1 promoter regions encompassing this putative response element have been consistently unresponsive to heme and several other HO-1 inducers in multiple cell types (7, 12, 26–28). Thus, despite its ability to bind purified NF-{kappa}B in vitro, it is unlikely that this site functions in such a capacity in vivo. A functional NF-{kappa}B binding site has not been identified in any hmox1 gene.

In contrast to the studies described previously, investigations with inhibitors provide a more compelling endorsement of NF-{kappa}B in hmox1 regulation. Chemical and gene-based inhibitors have been used for this purpose (Table 1). As an example of the former, coincubation with BAY 11–7082, an inhibitor of I{kappa}B phosphorylation and thus NF-{kappa}B activation, diminishes curcumin- or nordihydroguaiaretic acid–mediated HO-1 mRNA induction by > 90% in renal proximal tubule cells (29). Consistent with this observation, two other pharmacologic inhibitors of NF-{kappa}B, caffeic acid phenyl ester and Nap-tosyl-L-lysine chloromethyl ketone, attenuate rat hmox1 promoter activation in response to LPS in mouse macrophages (30). Chemical inhibitors lack sufficient specificity to permit unequivocal conclusions regarding the role of NF-{kappa}B in HO-1 induction. For instance, caffeic acid phenyl ester induces HO-1 expression in astroglial and renal epithelial cells (31, 32). An alternative, and presumably more specific, strategy is to use gene-based, dominant-negative mutants (DNMs) that target individual proteins within the NF-{kappa}B activation pathway. One such commonly used inhibitor is a mutant of I{kappa}B that is not a target for signal-induced phosphorylation and subsequent proteasomal degradation. Overexpression of the I{kappa}B DNM prevents nuclear translocation of NF-{kappa}B and has been shown to almost completely inhibit HO-1 induction by heme and cadmium in gastric (33) and papillary thyroid (34) cancer cells. Similarly, LPS activation of the rat hmox1 promoter is also significantly reduced in macrophages by coexpression of I{kappa}B or IKK DNMs (30). Thus, assuming that these DNMs inhibit the NF-{kappa}B pathway specifically, the latter studies provide the most persuasive evidence yet for a role for NF-{kappa}B in hmox1 regulation.

Given the absence of a clearly identified, functional NF-{kappa}B binding site, how NF-{kappa}B promotes hmox1 gene transcription becomes a matter of speculation. It is conceivable that future studies may identify such sequences and demonstrate direct gene activation. Based on current information, we suggest that such activation occurs not by mechanisms involving direct NF-{kappa}B–DNA interaction but rather by indirect mechanisms in which NF-{kappa}B insinuates itself into the transcription machinery of the hmox1 gene through its association with other DNA-binding proteins directly or indirectly within a larger complex containing other transcription modulators, such as coactivators (23). This type of mechanism has been postulated for the regulation of several NF-{kappa}B–dependent genes. In the case of the keratin 6b gene, induction by TNF-{alpha} requires NF-{kappa}B and the transcription factor C/EBPbeta because downregulation of either factor abolishes the response. K6b gene activation does not require a putative NF-{kappa}B recognition sequence in the promoter but is strictly dependent on three tandem C/EBP binding sites that serve as targets for a presumptive NF-{kappa}B·C/EBPbeta complex (35). C/EBPbeta seems to be a common partner of NF-{kappa}B because a similar mechanism has been proposed for induction of C-reactive protein in response to IL-6 (36) and for constitutive expression of IL-6 in prostate cancer cells for which IL-6 serves as an autocrine growth and survival factor (37). The latter mode of regulation seems to be cell type dependent because NF-{kappa}B uses c-Jun, a member of the AP-1 family of transcription factors, and its cognate binding site for control of IL-6 expression in multiple myeloma cells (38). The mouse hmox1 distal enhancer 1 contains multiple binding sites for AP-1 and C/EBP factors, and these sites are necessary for optimal gene activation by cadmium in hepatoma cells (39). Given these findings and the structural conservation of these response elements between the mouse and human genes (3), it is tempting to speculate that the NF-{kappa}B–dependent induction of HO-1 by cadmium observed in gastric and thyroid carcinomas (33, 34) occurs via an NF-{kappa}B binding site–independent mechanism involving activator complexes containing NF-{kappa}B and C/EBPbeta, c-Jun, or possibly Nrf2, which has also been implicated in hmox1 activation by cadmium (40, 41).

AP-1

Like NF-{kappa}B, the term AP-1 originally defined a distinct transcription factor but is now synonymous with a large group of dimeric proteins generated by intra- and interfamily associations between the Jun and Fos families of DNA binding proteins. Like NF-{kappa}B/Rel, Jun and Fos family members are widely distributed and regulate multiple cellular processes, including proliferation, differentiation, apoptosis, and the adaptive response to stress. Given their prominent role in the latter process in particular, AP-1 proteins have long been proposed to regulate activation of the hmox1 gene by multiple stimuli. Many of these propositions, however, have been based solely upon correlative data, which are insufficient to draw definite conclusions.

Unlike the case with NF-{kappa}B, multiple AP-1 binding sites have been identified within hmox1 genes from several species (Figure 1), and their functional responsiveness to one or more HO-1 inducers has been experimentally verified. Nonetheless, implicating AP-1 proteins in these responses is not as straight-forward as one may assume.

One difficulty is that many of the hmox1 AP-1 binding sites are composite elements that also bind to members of the NF-E2 and CREB/ATF families of transcription factors. Consequently, in addition to demonstrating inducer-dependent responsiveness, it is necessary to carry out studies to discriminate between the multiple proteins that can potentially bind to the composite site and mediate the observed effect. Some such studies have demonstrated that the role of AP-1 proteins in hmox1 activation is limited. For instance, inhibition of transcription factor activity by DNMs and discriminating mutation of the composite elements revealed that induction of the mouse gene by several agents, including cadmium and heme, is mediated primarily by Nrf2 rather than AP-1 proteins (40–43). Nonetheless, relatively convincing evidence exists for a role of AP-1 factors in HO-1 induction by some agents, including arsenite, inflammatory mediators, and TPA.

Independent studies have implicated AP-1 factors in arsenite-mediated activation of the mouse, rat, and chicken hmox1 genes in liver-derived cells (44–47). Non-orthologous AP-1 binding sites have been proposed to mediate this response: The mouse arsenite-responsive elements are located in the distal enhancers, whereas those of the rat and chicken genes are more proximal to the transcription start site but distinct from each other (Figure 1). Because the studies in rat and chicken cells used promoter constructs lacking the distal enhancers, it is conceivable that the conserved AP-1/NF-E2 composite elements in the latter regions of these genes contribute to the overall induction by arsenite. The discrepancy between the specific response elements notwithstanding, studies with all three genes used multiple strategies, including analysis of promoter mutants, immuno-identification of DNA-binding proteins, and TF DNMs, to confirm the role of AP-1 proteins in this process. In all three cases, TFs, in addition to AP-1 proteins, were required for maximal induction by arsenite. With the mouse gene, Nrf2 and CREB proteins, which function via the composite AP-1/NF-E2 elements, contributed to gene activation (44), whereas for the rat (47) and chicken (46) genes, Myc/Max transcription factors or other bHLH proteins are potential co-regulators of the response. The use of multiple TFs for optimal hmox1 stimulation is not necessarily surprising because arsenite is a pleiotropic activator of numerous signaling pathways. HSF1 also contributes to mouse hmox1 induction by arsenite (18).

LPS and inflammatory cytokines have long been recognized as potent inducers of HO-1 expression, and several studies have linked AP-1 factors in this response (48–51). Treatment of rat aortic smooth muscle cells with IL-1beta stimulates protein binding to the hmox1 AP-1 composite element in a time-dependent manner. c-Jun and Fos polypeptides, but not Nrf1 or Nrf2, are detected in these DNA-protein complexes, specifically implicating AP-1 factors in HO-1 induction by this cytokine (50). In mouse RAW 264.7 macrophages, LPS also causes a time-dependent increase in AP-1 DNA-binding activity. Additionally, it stimulates the transcription activity of the mouse E1 and E2 enhancers, and mutation of the AP-1 composite elements abolishes this response (48, 49). In this case, a contributory role of Nrf2 can not be ruled out because recent studies demonstrate that LPS also stimulates Nrf2 DNA-binding activity and that overexpression of a Nrf2 DNM diminishes LPS-stimulated enhancer activity (52) and HO-1 mRNA accumulation (53). Finally, pharmacologic inhibition of AP-1 attenuates IL-1{alpha}– and TNF-{alpha}–mediated induction of HO-1 mRNA in human umbilical vein endothelial cells (51), although the validity of this approach and the conclusions drawn from these results are debatable.

The AP-1 binding site is commonly referred to as the TPA-response element because of an early recognition of the similarity between these sequences and the stimulation of AP-1 DNA-binding activity by TPA. AP-1 proteins probably mediate hmox1 activation by TPA in certain settings because both enhancers from the mouse gene are activated by TPA, this compound increases protein binding to the composite elements, and mutation of these elements abolishes TPA responsiveness (27). The DNA–protein interaction and mutation analyses did not specifically discriminate between the various bZIP proteins that can bind to the composite element, leaving in doubt the identity of the activating factor. Nonetheless, given the established role of AP-1 proteins in mediating the cellular effects of TPA, it is reasonable to conclude that such factors also mediate the induction of HO-1.

MAPK SIGNALING PATHWAYS

Although heme is proposed to enhance hmox1 gene transcription in part by directly binding to Bach1 (5), it is generally accepted that most, if not all, HO-1 inducers regulate transcription factor activity indirectly through activation of signaling cascades that are dependent on protein (de)phosphorylation, reduction-oxidation (redox) reactions, or both. Given the multitude of HO-1 inducers, it should come as no surprise that a variety of protein kinases, including protein kinases A and G, tyrosine kinases, and the enzymes of the PI3K/AKT and JAK/STAT pathways, have been implicated in the regulation of hmox1 gene activation (54). Accumulating evidence points to the MAPK cascades as one of the principle mediators of this response.

MAPKs belong to an evolutionary conserved and ubiquitous signal transduction supersystem that regulates countless cellular programs, including growth and apoptosis, motility, differentiation, and responses to environmental signals and stresses. The MAPK supersystem is subdivided into three primary signaling pathways identified by their resident MAPKs: the extracellular regulated kinases (ERK pathway), the c-Jun N-terminal kinases or stress-activated kinases (JNK/SAPK pathway), and the p38 subfamily of kinases (p38 pathway). Each cascade contains a central three-tiered "core signaling module" of the following general structure: MAP3K-MAPKK-MAPK. Because each tier of the general module is composed of multiple, functionally related kinases, the three primary pathways can be further divided into a larger repertoire of distinct MAPK signaling cascades. Signal sensing and transmission involves sequential phosphorylation and activation of the components that constitute a specific module. The terminal, activated MAPKs phosphorylate their target proteins, including various transcription factors, and thus are responsible for the regulation of many genes (55, 56).

A substantial amount of data supports a role for the MAPK cascades in signal-mediated hmox-1 gene activation (54). Several general conclusions can be derived from this accumulated data. (1) Many structurally and functionally diverse HO-1 inducers activate one or more of the three major MAPK cascades in multiple cell types. Some, such as arsenite and cadmium, activate all three pathways (40, 45), whereas others may exhibit a more restricted response. The JNK MAPKs are less frequently activated than the ERK and p38 kinases. (2) Activation of a particular MAPK does not automatically lead to hmox-1 induction. For instance, treatment of A549 pulmonary epithelial cells with TGF-beta1 activates ERK1, ERK2, and p38{alpha} MAPKs, but pharmacologic inhibition of p38{alpha}, and not of the ERK pathway, attenuates HO-1 mRNA accumulation (57). (3) Under certain circumstances, as exemplified by ischemia-reperfusion-mediated HO-1 induction in rat pulmonary artery endothelial cells (58), multiple MAPK pathways may be required for an optimal response. (4) For a given inducer, the MAPK(s) used may be dependent on the cell type or species of origin. For example, the ERK pathway promotes HO-1 induction by cadmium in human gastric cancer cells (33) but not in breast cancer cells (40). Additionally, the ERK and p38 MAPKs are implicated in hmox-1 activation by arsenite in liver-derived cells from chicken (45), but JNK and p38 enzymes are required for the same response in rat hepatocytes (47). (5) Finally, of the three major subfamilies, the p38 cascade is most frequently used for hmox-1 induction. Where directly tested, in only one case (induction by prostaglandin E2 in RAW264.7 macrophages) did inhibition of p38 not affect HO-1 expression. The most commonly used pharmacologic inhibitor of p38, SB203580, inactivates only the {alpha} and beta isozymes but not the other isoforms, and thus one must exercise caution in interpreting results from these type of studies. Treatment of rat hepatocytes with SB203580 does not alter HO-1 mRNA accumulation in response to arsenite, but the use of isoform-specific DNMs reveals that p38{gamma} positively regulates rat hmox-1 promoter activity (47).

The identities of the transcription factors involved in MAPK-dependent hmox-1 activation have been explored in a subset of the studies noted previously. Where examined, Nrf2 and AP-1 proteins are the most commonly implicated TFs in these responses (31, 40, 45, 47, 59–61). Although phosphorylation of AP-1 constituents is well documented (55, 56), direct phosphorylation of Nrf2 by MAPKs remains to be demonstrated. Mutation of potential MAPK phosphorylation sites of Nrf2 does not affect its transcription activity (62, 63), and MAPKs seem to regulate Nrf2-dependent transcriptional responses indirectly, possibly by phosphorylating proteins that affect subcellular localization of Nrf2 (62) or by its interaction with coactivators (63). Similarly, MAPK-dependent hmox-1 gene transcription by NF-{kappa}B is not likely to involve direct phosphorylation by MAPKs because IKKs are primarily responsible for NF-{kappa}B activation. Unlike Nrf2 and NF-{kappa}B, HSF1 is known to be directly phosphorylated by all three of the major MAPKs, but this modification generally leads to suppression of transcription activity (64, 65). Nevertheless, induction of HSF1 target genes, particularly in response to chemical stressors, is often dependent on activation of one or more MAPKs (66, 67), again suggestive of a mechanism involving MAPK-mediated phosphorylation—not of the transcription factor (i.e., HSF1), but of an accessory or upstream protein in the signaling pathway.

CONCLUSIONS

As summarized here and elsewhere (3–5), convincing evidence exists for hmox1 regulation by members of the NF-E2, HSF, AP-1, and NF-{kappa}B families of transcription factors, although in the latter case, such regulation may be indirect, requiring the cooperation of other sequence-specific DNA binding proteins. Regulation by all four classes of stress-responsive TFs—possibly unique to the hmox1 gene—should permit induction of HO-1 expression under a greater array of stressful settings and disease conditions (Figure 3) than typically observed with other stress proteins, a possibility that seems to be supported by the extensive list of known HO-1 inducers (1, 68). Why is it necessary to activate the hmox1 gene under such wide-ranging conditions? One possibility is that hemoproteins, which are present in all cells, may be particularly susceptible to denaturation under suboptimal environments, necessitating a system to contend with the accumulating free heme molecules that are detrimental to cellular structures and processes. Conversely, the cell may find it tactically expedient to temporarily sacrifice the activities of some hemoproteins to activate defensive mechanisms that are essential to survival. Regardless of the reason, regulation of the hmox1 gene by all four of these major TFs further highlights the critical importance of HO-1 in the cellular stress response.


Figure 3
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  		Figure 3. Regulation of the hmox1 gene. The major mammalian stress-responsive transcription factors, Nrf2, HSF1, AP-1, and NF-{kappa}B, all regulate the HO-1 gene although the latter may do so indirectly through cooperation with unknown DNA-binding proteins (X). MAPK enzymes modulate the transcription factor responses, possibly through direct phosphorylation of the TF (single arrow) or indirectly (multiple arrows) by phosphorylation of other proteins in the signaling cascades. The multiplicity of hmox1 regulators permits gene activation by numerous different stimuli and stress conditions (gray sphere), and consequently HO-1 is expressed at high levels, presumably as part of an adaptive response, in a variety of diseased states (yellow sphere). Although not indicated (for reasons of illustrative clarity), there is considerable crosstalk and overlap at all stages of the gene response pathway. For example, inflammatory mediators frequently cause imbalances in redox homeostasis (i.e., oxidative stress), which can also lead to accumulation of non-native proteins (i.e., imbalances in protein homeostasis). Oxidative stress alters the activities of all the TFs described herein. See text for additional details. Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; MI, myocardial infarction.

 
Another valid answer to the question posed by the title is: "A lot more than four!" Vertebrate cells use many other TFs beyond those discussed in this article to coordinate an appropriate stress response. Several of these proteins, including HIF1, STAT proteins, C/EBP factors, ETS, and USF family members, are known to regulate inducer-dependent hmox1 transcription under specific circumstances and may work in conjunction with the principal factors discussed in this article (1, 54, 68–70). Furthermore, beyond the stress response, the hmox1 gene is transcribed under homeostatic conditions, and this activity is modulated in a tissue-dependent manner during development and differentiation and by stress-independent stimuli, such as growth factors (71). Such regulation is likely to be mediated, at least in part, by transcription factors distinct from those used during the stress response, as exemplified by the cooperativity between hepatocyte nuclear factor-4 and specificity protein 1 or 3 (Sp1/Sp3) in conferring basal and liver cell-specific enhancer activity to the human hmox1 promoter (72). The hmox1 gene is subjected to complex regulatory controls, and a detailed understanding of these mechanisms, including delineation of the precise signaling pathways and their target transcription factors, may provide unique opportunities for a more refined modulation of a therapeutically important enzyme.

Acknowledgments

The authors regret any omissions of relevant studies or acknowledgment of primary sources resulting from neglect or design due to space limitations.

Footnotes

Originally Published in Press as DOI: 10.1165/rcmb.2006-0340TR on September 21, 2006

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form September 8, 2006

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C.-C. Lin, X.-M. Liu, K. Peyton, H. Wang, W.-C. Yang, S.-J. Lin, and W. Durante
Far Infrared Therapy Inhibits Vascular Endothelial Inflammation via the Induction of Heme Oxygenase-1
Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 739 - 745.
[Abstract] [Full Text] [PDF]

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 Pharmacol. Rev.Home page
N. G. Abraham and A. Kappas
Pharmacological and Clinical Aspects of Heme Oxygenase
Pharmacol. Rev., March 1, 2008; 60(1): 79 - 127.
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 Antimicrob. Agents Chemother.Home page
K. El Fadili, M. Imbeault, N. Messier, G. Roy, B. Gourbal, M. Bergeron, M. J. Tremblay, D. Legare, and M. Ouellette
Modulation of Gene Expression in Human Macrophages Treated with the Anti-Leishmania Pentavalent Antimonial Drug Sodium Stibogluconate
Antimicrob. Agents Chemother., February 1, 2008; 52(2): 526 - 533.
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 Nucleic Acids ResHome page
A. Meiller, S. Alvarez, P. Drane, C. Lallemand, B. Blanchard, M. Tovey, and E. May
p53-dependent stimulation of redox-related genes in the lymphoid organs of {gamma}-irradiated mice identification of Haeme-oxygenase 1 as a direct p53 target gene
Nucleic Acids Res., November 29, 2007; 35(20): 6924 - 6934.
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 Circ. Res.Home page
H. P. Kim and A. M.K. Choi
A New Road to Induce Heme Oxygenase-1 Expression by Carbon Monoxide
Circ. Res., October 26, 2007; 101(9): 862 - 864.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
L. Villacorta, J. Zhang, M. T. Garcia-Barrio, X.-l. Chen, B. A. Freeman, Y. E. Chen, and T. Cui
Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway
Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H770 - H776.
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 Am. J. Respir. Cell Mol. Bio.Home page
M. A. Perrella
Heme Oxygenase-1: A Multifaceted Triple-Threat Molecule
Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 137 - 137.
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