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First published online January 12, 2006
doi: 10.1242/10.1242/jcs.02815
Commentary |
Shriners Hospitals for Children and Department of Cell and Developmental Biology, Oregon Health and Science University, 3101 SW Sam Jackson Park Rd, Portland, OR 97239, USA
* Author for correspondence (e-mail: pjh{at}shcc.org)
Accepted 29 November 2005
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Summary |
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 Top Summary IntroductionThe ups and downs...Where do Mxd and...All Maxed outMnt smells like a...Conclusion and perspectivesReferences |
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Key words: Myc, Mnt, Mad, Mxd, Max, Cell cycle, Cancer
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Introduction |
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TopSummaryIntroductionThe ups and downs...Where do Mxd and...All Maxed outMnt smells like a...Conclusion and perspectivesReferences |
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; Nikiforov et al., 2000; Berns et al., 2000) but exhibit unique expression patterns in mammalian tissues (e.g. Hatton et al., 1996; Hurlin et al., 1997a). Each contains a basic helix-loop-helix leucine zipper (bHLHZip) motif at the C-terminus, which mediates heterodimerization with the small bHLHZip protein Max (Blackwood and Eisenman, 1991; Prendergast et al., 1991). Max serves as an obligate heterodimerization partner for Myc, allowing it to bind the sequence CACGTG and other related `E-box' sequences (Blackwood et al., 1992; Berberich and Cole, 1992; Kato et al., 1992; Littlewood et al., 1992; Blackwell et al., 1993) and activate transcription (Amati et al., 1992; Kretzner et al., 1992; Amin et al., 1993). Max also interacts with six other proteins containing bHLHZip motifs. Four of these, Mad1, Mxi1, Mad3 and Mad4 (Ayer et al., 1993; Zervos et al., 1993; Hurlin et al., 1995b), are very closely related; here, we refer to these proteins as Mxd1-Mxd4, respectively, to reflect the current nomenclature (http://www.gene.ucl.ac.uk/nomenclature/). Of the other two, Mnt (Hurlin et al., 1997a; Meroni et al., 1997) is distantly related to Mxd-family proteins and Mga is an unusual protein in that it contains both a bHLHZip motif and a T-domain DNA-binding motif (Hurlin et al., 1999). Like Myc-family proteins, Mnt, Mga and Mxd1-Mxd4 utilize Max as a cofactor for DNA binding at E-box sequences, but instead of activating transcription they appear to function as dedicated transcriptional repressors. For Mxd-family proteins and Mnt, repression is mediated by closely related domains that tether the co-repressor proteins Sin3A and Sin3B (Ayer et al., 1995; Schreiber-Agus et al., 1995; Hurlin et al., 1995b; Hurlin et al., 1997a). Sin3A and Sin3B function as scaffolds for the recruitment of several proteins involved in chromatin modification, including histone deacetylases (Alland et al., 1997; Hassig et al., 1997; Laherty et al., 1997). This is in contrast to c-Myc, which interacts with TRRAP and other co-activator proteins such as CBP/p300 that recruit histone acetyltransferases (McMahon et al., 2000; Frank et al., 2003; Vervoorts et al., 2003). Although Myc interacts with a variety of other co-activators that have different activities (reviewed by Adhikary and Eilers, 2005), a working model for transcriptional regulation by the `Max network' has emerged in which the activation state of shared target genes is governed, at least in part, by opposing effects on histone acetylation and chromatin conformation (Fig. 1). This antagonism model fits well with results showing that Mxd and Mnt can suppress Myc-dependent cell transformation (Zhou and Hurlin, 2001). Moreover, it predicts that antagonism of Myc by Mxd-family proteins and Mnt play significant roles regulating the various activities of Myc, including its role in tumorigenesis.
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The bHLHZip domain of Myc also mediates interaction with Miz1 (Peukert et al., 1997), which activates transcription by recruiting the co-activator CBP/p300. Binding of Miz1 to Myc prevents Miz1-dependent activation (Herold et al., 2002; Wu et al., 2003). Crucial targets of Miz1 activation include the cyclin-dependent kinase inhibitors p15INK4b and p21Cip1 (Herold et al., 2002; Seoane et al., 2001; Staller et al., 2001). By preventing activation of these genes, Myc expression relieves important control points that impede cell-cycle progression and sustained proliferation. Interestingly, interactions of Myc with Max and Miz1 are not mutually exclusive, and indeed binding of Max to Myc might facilitate Myc-Miz1 interaction and function (Peukert et al., 1997). Although Miz1 plays a crucial role in transcriptional regulation by Myc, at this time there is no evidence that Miz1 interacts with Mxd1-Mxd4, Mnt or Mga, or that that the latter proteins influence Miz1-dependent Myc activities.
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The ups and downs of Myc |
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TopSummaryIntroductionThe ups and downs...Where do Mxd and...All Maxed outMnt smells like a...Conclusion and perspectivesReferences |
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; Rabbitts et al., 1995) (Fig. 2B). Forced expression of Myc in quiescent cells stimulates entry into the cell cycle (Eilers et al., 1991), which suggests that mitogen-induced upregulation of Myc helps coordinate cell-cycle entry. The increase in Myc levels occurs during G1 phase, but these then rapidly decline to low levels by S phase (Kelly et al., 1983; Rabbitts et al., 1985). So how does the transient increase in Myc expression levels promote cell-cycle entry? The recent use of chromatin immunoprecipitation (ChIP) together with microchips containing DNA arrays representing whole chromosomes (`ChIP-on-chip') indicates that c-Myc binds to many thousands of sites in the human genome, including sites that appear to be involved in the regulation of noncoding microRNAs (Cawley et al., 2004; O'Donnell et al., 2005). These findings support previous results using a more directed ChIP approach that showed that c-Myc binds to a large number of sites (Fernandez et al., 2003) and results using a methylation-tagging approach that showed that the sole Myc protein in Drosophila (dMyc) binds to a large number of sites in the Drosophila genome (Orian et al., 2003).
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Although the degree of correspondence between Myc binding and gene regulation at most of these sites remains largely unknown, numerous genes have been rigorously defined as Myc (usually c-Myc) target genes (a comprehensive list is available from the Myc Target Gene Database, http://www.myccancergene.org/site/mycTargetDB.asp; see also http://genomebiology.com/2003/4/10/R69). Some of the best-defined Myc targets encode proteins that function directly in cell-cycle control, including cyclin D2 (Bouchard et al., 1999; Bouchard et al., 2001; Bouchard et al., 2004), cyclin-dependent-kinase (CDK)4 (Hermeking et al., 2000) and the CDK inhibitors p15INK4b and p21Cip1 mentioned above. In addition, genes encoding proteins that regulate metabolism, ribosome biogenesis and protein translation have been identified as Myc targets (Patel et al., 2004) (reviewed by Adhikary and Eilers, 2005) (see below).
Myc-dependent promotion of ribosome biogenesis and protein translation, and the consequent effects on cell size (accumulation of cell mass) have emerged as a key activity underlying Myc function, including promotion of cell-cycle entry and sustained cell proliferation. In fact, c-Myc can engage the basal transcriptional machinery associated with RNA polymerase III to stimulate transcription of tRNAs and 5S rRNA (Gomez-Roman et al., 2003), and binds to and regulates rRNA genes in concert with RNA polymerase I (Grandori et al., 2005; Arabi et al., 2005; Grewal et al., 2005). These activities probably explain why ectopic c-Myc expression increases cell size (Iritani and Eisenman, 1999; Johnston et al., 1999; Schuhmacher et al., 1999; Beier et al., 2000) and loss of N-Myc or c-Myc causes a reduction in cell size (Knoepfler et al., 2002; Zanet et al., 2005) (see also Trumpp et al., 2001). Moreover, the ability of Myc-family proteins to promote not only cell-cycle entry and cell proliferation but also oncogenesis is probably largely a result of their effects on ribosome biogenesis (reviewed by White, 2005), together with their regulation of genes encoding proteins that directly impinge on the restriction checkpoint in G1 phase.
Following the strong upregulation of c-Myc during entry into the cell cycle, it is rapidly downregulated and stays at constant low levels throughout the proliferative cell cycle (Hann et al., 1985; Rabbitts et al., 1985; Thompson et al., 1985) (Fig. 2B). When mitogens are withdrawn, Myc levels decline to very low levels and proliferating cells exit the cell cycle (Kelly et al., 1983; Rabbitts et al., 1985). Myc levels also typically decline to very low levels during cell-cycle exit associated with the differentiation of various cell types (reviewed by Grandori et al., 2000). Myc downregulation is a crucial event in cell-cycle exit since a very similar response (i.e. cell-cycle exit) is observed following conditional deletion of c-Myc in cultured cells (Trumpp et al., 2001; deAlboran et al., 2001; Walker et al., 2005). However, some cell types might be less sensitive to loss of Myc than others. For example, epithelial cells of the skin (Zanet et al., 2005) and gut (Bettess et al., 2005) continue to proliferate following conditional deletion of c-Myc in vivo, and the Rat1 fibroblast cell line lacking c-Myc continues to proliferate, albeit at a much reduced rate (Mateyak et al., 1997). Although the Rat1 cell line does not produce any Myc protein (Mateyak et al., 1997), in other settings it is not entirely clear whether expression of N-Myc or L-Myc compensates for loss of c-Myc. Similarly, c-Myc or L-Myc expression, even at low levels, might compensate for the loss of N-Myc in neuronal cells (Knoepfler et al., 2002) and slow their exit from the cell cycle.
The rapid downregulation of c-Myc following its induction during cell-cycle entry, even in the continuous presence of mitogens, suggests that high levels of Myc trigger a dedicated negative-feedback mechanism. Indeed, ectopic Myc expression effectively shuts down Myc transcription (Cleveland et al., 1988) and this system can operate in trans among Myc-family members (Rosenbaum et al., 1989). Downregulation of Myc is clearly a crucial feature of its regulation, since sustained high levels of Myc are catastrophic for cells under most conditions and can lead to tumor formation. Indeed, negative Myc autoregulation is lost in at least some tumors (Grignani et al., 1990). Negative Myc autoregulation, as well as other transcriptional mechanisms that control Myc levels (reviewed by Spencer and Groudine, 1991), are probably lost or disrupted in the many tumors in which Myc genes are amplified, translocated or affected by viral integration. It is also becoming increasingly clear that mechanisms that disrupt pathways responsible for the short half-life of the Myc protein might also contribute to Myc-dependent tumorigenesis (for reviews, see Sears, 2004; Adhikary and Eilers, 2005). The outcome of these events is the uncoupling of Myc expression from mitogenic signaling and the general nullification of mechanisms that keep it at proper and/or tolerable levels.
Deregulation of Myc expression has other consequences more immediate than tumor formation in many primary cell types. Myc sensitizes cells to apoptosis and, in the absence of `survival factors', overexpression of Myc is lethal (Askew et al., 1991; Evan et al., 1992) (for reviews, see Pelengaris et al., 2002; Nilsson and Cleveland, 2003). These survival factors can be mitogenic factors, such as platelet-derived growth factor (PDGF), which normally upregulate Myc (Harrington et al., 1994). Thus, cells appear to have evolved a sensing mechanism that detects the uncoupling of Myc from factors that normally stimulate its expression. Moreover, the ability of elevated or deregulated Myc to induce apoptosis may have evolved as a protective mechanism to eliminate cells that have the potential to give rise to cancer (Lowe et al., 2004). Consistent with this idea is an abundance of data showing that counteracting the apoptotic activity of Myc, either through disruption of downstream effector molecules (Nilsson et al., 2004) or by specific mutations in Myc (Hemann et al., 2005), can profoundly accelerate Myc-dependent tumor progression.
Given the dire consequences of Myc deregulation (e.g. death of cells or the eventual death of the organism) and the important role Myc-family genes play in development (Grandori et al., 2000), it is clear that there is not much room for error in the regulation of Myc. Whereas cellular levels of Myc are tightly regulated by transcriptional and post-transcriptional mechanisms, Mnt- and Mxd-family proteins provide an additional level of regulation. Below, we discuss in more detail how these proteins might function as Myc antagonists.
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Where do Mxd and Mnt fit in? |
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TopSummaryIntroductionThe ups and downs...Where do Mxd and...All Maxed outMnt smells like a...Conclusion and perspectivesReferences |
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) and one gene related to Mnt and Mxd [dMnt (Bourbon et al., 2002)]. Studies examining DNA binding by dMyc, dMnt and dMax indicate that these proteins have shared and unique binding sites, and that binding is strongly affected by protein concentration (Orian et al., 2003). Studies in Drosophila also indicate that dMnt and dMyc have opposing activities in the control of cell growth (Loo et al., 2005) and therefore argue that they function as antagonists in the regulation of at least some pathways.
Although mammalian Mxd-family members and Mnt exhibit similar biochemical properties (Zhou and Hurlin, 2001), it is now apparent that Mxd proteins probably have somewhat specialized roles as Myc antagonists, whereas Mnt probably serves a more general role antagonizing or regulating Myc activities. This conclusion is based primarily on the phenotypes of mice and cells that lack Mxd-family proteins or Mnt. Mice lacking Mxd1, Mxd2 and Mxd3 are viable, fertile and, with the possible exception of Mxd2-null mice, not tumor prone (Foley et al., 1998; Schreiber-Agus et al., 1998; Queva et al., 2001). By contrast, Mice lacking Mnt typically die within 24 hours of birth (Toyo-oka et al., 2004) and conditional deletion of Mnt in breast epithelium and in other cell types has severe consequences, including tumor formation (Hurlin et al., 2003) (S. Dezfouli, A. Bakke, A. Wynshaw-Boris and P.J.H., unpublished observation). Moreover, mouse embryo fibroblasts (MEFs) lacking Mnt and cells depleted of Mnt by RNA interference (RNAi) appear largely to phenocopy cells that overexpress c-Myc (Hurlin et al., 2003; Nilsson et al., 2004; Walker et al., 2005).
One potential explanation for the relatively mild phenotypes of mice lacking Mxd-family genes is that Mxd-family proteins regulate or antagonize Myc only to a limited extent. For example, some Mxd proteins can interact with other bHLHZip proteins besides Max (Billin et al., 1999; Meroni et al., 2000) and therefore might have activities independent of Myc antagonism (Zhou and Hurlin, 2001). In addition, the bHLHZip regions of Mxd- and Myc-family proteins are not functionally equivalent (O'Hagan et al., 2000; James and Eisenman, 2002), which suggests that they have both unique and overlapping sets of target genes and biological activities. Importantly, however, Mxd-Max complexes have been clearly identified in cells, and alternative Mxd complexes containing the bHLHZip protein Mlx are predicted to have activities similar to those of Mxd-Max (Billin et al., 1999; Meroni et al., 2000). Moreover, studies examining the effects of Mxd1 deletion and Mxd1 overexpression in vivo indicate that it is involved in the suppression of key Myc-associated activities such as cell proliferation, cell growth and apoptosis (Foley et al., 1998; Queva et al., 1999; Queva et al., 2001; Rudolf et al., 2001; Iritani et al., 2002; Poortinga et al., 2004). Thus, because there is abundant evidence that Mxd-family proteins can antagonize Myc, the subtle phenotypes resulting from Mxd gene deletion in mice might primarily be a consequence of strong functional redundancy in this family.
This latter explanation is bolstered by results showing extensive overlap in the expression patterns of the Mxd genes during mouse embryonic development and in different adult tissues (Hurlin et al., 1995b; Queva et al., 1998; Vastrik et al., 1995). Furthermore, with the exception of Mxd3, Mxd-family gene expression is preferentially, but not exclusively, found in more-differentiated cell populations in vivo and in cell culture model systems (Ayer et al., 1993; Hurlin et al., 1995a; Hurlin et al., 1995b; Vastrik et al., 1995; Queva et al., 1998). Multiple Mxd-family genes are also expressed in senescent cells and cells in G0 phase (Marcotte et al., 2003) (W. L. Walker and P.J.H., unpublished observation). This is in contrast to the close association of Myc expression with proliferating cells, and to the consistent and apparently ubiquitous expression of Mnt in proliferating, quiescent and differentiating cells (see Fig. 2A, and below).
The expression of multiple Mxd genes and Mnt in differentiated cells could in theory enforce a non-proliferative state when Myc levels are low by augmenting repression of Myc target genes. However, in the absence of Mxd1 alone, granulocyte differentiation in vitro is delayed, and these cells undergo additional divisions before exiting the cell cycle (Foley et al., 1998; Poortinga et al., 2004). Similarly, Mxd2 deficiency appears to cause ectopic cell divisions in certain cell types (Schreiber-Agus et al., 1998). These latter results raise the possibility that sensitivity to deletion of single Mxd genes reflects the number and expression level of other family members. For example, cells that express only a single Mxd-family protein in differentiating cells would theoretically be more sensitive to its deletion.
In contrast to other Mxd-family members, Mxd3 is preferentially expressed in cells that are in S phase of the cell cycle (Hurlin et al., 1995a; Queva et al., 1998; Queva et al., 2001; Fox and Wright, 2001). Although this expression pattern is clearly distinct from that of other Mxd-family members, there is a common theme: Mxd proteins are typically upregulated when Myc levels are downregulated. For example, whereas Mxd1 is upregulated when c-Myc is downregulated in association with cell-cycle exit and differentiation (as discussed above), Mxd3 induction at S phase follows the decline in Myc levels from their transient peak during G1 phase following cell-cycle entry (depicted in Fig. 2B). Conversely, Mxd3 is also induced at S phase during the proliferative cell cycle (Fox and Wright, 2001) when c-Myc levels are constant (Hann et al., 1985). The relationship between c-Myc and Mxd3 during the proliferative cell cycle suggests that Mxd3 imparts phase-specific regulation of Myc targets during the cell cycle. However, mice lacking Mxd3 appear generally healthy, and Mxd3-deficient cells do not seem to have defective cell-cycle entry or exit (Queva et al., 2001). Instead, Mxd3 deficiency sensitizes thymocytes and neuronal cells to radiation-induced apoptosis. It is not clear whether cells sensitized to apoptosis by loss of Mxd3 are actively cycling, as might be predicted. However, one possibility is that cells in S phase are particularly vulnerable to Myc-induced apoptosis, and expression of Mxd3 during this period might orchestrate the transient downregulation of apoptosis-related Myc target genes and render the cells less sensitive to Myc-dependent apoptosis. Because Mnt expression is independent of the cell cycle (Hurlin et al., 2003), and Mnt is therefore co-expressed with Mxd3 in S phase (Fig. 2B), this model predicts that the increased experimentally induced apoptosis in cells lacking Mxd3 should be exacerbated in the absence of both Mnt and Mxd3. Indeed, the issue of Mxd redundancy in general will be best addressed by characterization of mice containing multiple Mxd gene deletions and/or combinations of Mxd and Mnt deletions.
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All Maxed out |
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TopSummaryIntroductionThe ups and downs...Where do Mxd and...All Maxed outMnt smells like a...Conclusion and perspectivesReferences |
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; Hurlin et al., 1997b; Sommer et al., 1998; Sommer et al., 1999; Pulverer et al., 2000). Moreover, the DNA-binding studies suggest that Mnt-Max and Myc-Max complexes are the most abundant Max complexes in proliferating cells. Max has a long half-life [>24 hours (Blackwood et al., 1992)] compared with the rapid turnover (15-20 minutes) of Myc, Mxd1 and Mnt (Hann et al., 1985; Rabbitts et al., 1995; Ayer and Eisenman, 1993; Hurlin et al., 1997b), and it has been assumed that Max is in such excess that its abundance is not a rate-limiting factor in the formation of the various heterodimeric complexes (Fig. 2). This is an important supposition, considering the importance of Max for the function of Myc and its other dimerization partners. It is based primarily on studies indicating that all of the newly synthesized c-Myc in a proliferating chicken B-cell line forms complexes with Max (Blackwood and Eisenman, 1991). However, Myc levels are induced to high levels during cell-cycle entry and can be extremely high in tumors. In addition, although Max has a long half-life, it appears not to be a particularly abundant protein. Max may therefore be limiting in certain settings where it is downregulated or where its dimerization partners are expressed at particularly high levels, such as during cell-cycle entry.
Supporting this idea is the observation that the abundance of Mnt-Max complexes declines during the window of peak c-Myc induction that accompanies cell-cycle entry, even though Mnt levels remain relatively constant (Walker et al., 2005) (depicted in Fig. 2B). These results suggest that, as c-Myc levels rise above a specific threshold level, c-Myc successfully competes with Mnt for a limited supply of Max. Alternatively, some other mechanism might be responsible for the transient decline in Mnt-Max levels. For example, Mnt might be transiently modified during cell-cycle entry in a way that interferes with Mnt-Max heterodimerization. However, although Mnt phosphorylation appears to influence interaction with Sin3 (Popov et al., 2005), there is no evidence that its interaction with Max is regulated in such a manner.
If Max can become limiting during cell-cycle entry, it might also be limiting in tumors, in which Myc is often expressed at exceedingly high levels. For example, neuroblastomas sometimes have up to several hundred copies of the N-Myc gene, which results in exceedingly high N-Myc levels (Schwab, 1993). Thus, under these conditions, N-Myc might severely deplete the amount of Max available for dimerization with other Max partner proteins (see Fig. 2C). At the least, these other Max partners might be at a severe competitive disadvantage for forming functional Max complexes. Since Mnt and Mxd can suppress Myc-dependent cell transformation, the ability of high levels of Myc to swamp the competition might significantly contribute to its oncogenic activity. If Max is limiting in tumors that express high levels of Myc, then ectopic expression of Max might impede tumor growth. Indeed, there appears to be evidence for such activity of Max, because the rate of Myc-dependent lymphomagenesis is reduced in transgenic mice that overexpress Max (Lindeman et al., 1995).
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Mnt smells like a tumor suppressor |
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TopSummaryIntroductionThe ups and downs...Where do Mxd and...All Maxed outMnt smells like a...Conclusion and perspectivesReferences |
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; Nilsson et al., 2004; Walker et al., 2005). Several genes known to be Myc targets are upregulated in Mnt-deficient cells. Moreover, in the context of cell-cycle entry, upregulation of several of the genes surveyed is most pronounced at the point at which induction of c-Myc peaks (Walker et al., 2005). In the absence of c-Myc, MEFs essentially fail to re-enter the cell cycle upon serum stimulation following quiescence, but MEFs lacking both c-Myc and Mnt re-enter the cell cycle with kinetics similar to those of wild-type cells (Walker et al., 2005). Furthermore, several Myc and Mnt target genes are expressed with cell-cycle entry kinetics similar to those of wild-type cells following simultaneous deletion of c-Myc and Mnt. These results are consistent with the findings of Nilsson et al. (Nilsson et al., 2004), who showed that RNAi-mediated knockdown of Mnt rescues the slow proliferation phenotype of Rat1 fibroblasts that lack Myc and causes upregulation of the Myc target gene ornithine decarboxylase (Odc). Note that Odc does not seem to be deregulated following Cre-mediated deletion of Mnt in primary MEFs (Walker et al., 2005). Moreover, RNAi-mediated knockdown of Mnt has effects on the expression of several Myc targets that are not observed following Cre-mediated deletion of Mnt (Nilsson et al., 2004; Walker et al., 2005). Nonetheless, the phenotypes of Mnt-deficient cells in these studies are very similar and strongly argue that Mnt-Max and Myc-Max share at least an overlapping subset of target genes in mammalian cells.
It is important to recognize that even if Myc-Max and Mnt-Max bound to and regulated the same target genes, the effect of loss of Mnt would not necessarily be functionally equivalent to that caused by deregulated overexpression of Myc. This is because, in the absence of Mnt, Myc levels are still constrained by the same stringent regulatory mechanisms that normally control its levels (Fig. 2D). For example, in the absence of Mnt, Myc levels should still increase and decrease in response to mitogen levels, and to factors and conditions such as cell density that normally control cell proliferation. Accordingly, loss of Mnt-Max repression should increase the basal expression levels of its target genes, and perhaps increase their sensitivity to activation by Myc, but these should still largely depend on the regulated expression of Myc. Indeed, this seems to be the case during cell-cycle entry in the absence of Mnt (Walker et al., 2005).
The idea that loss of Mnt and deregulated overexpression of Myc are not equivalent is supported by in vivo studies of breast epithelium. Here, conditional deletion of Mnt results in tumor formation (Hurlin et al., 2003) that is less penetrant and takes longer than that caused by ectopic overexpression of c-Myc (Stewart et al., 1984). It is not yet clear whether this is also the case in other cell types and tissues. It is important to recognize that current models of the functional relationship between Myc, Mnt and Mxd are based on a very limited number of cell types in which Myc-Max, Mxd-Max (usually Mxd1) and Mnt-Max complexes have been examined (Zhou and Hurlin, 2001). Thus, although breast cancer caused by loss of Mnt in breast epithelium might be a manifestation of a loss of Mnt-dependent Myc antagonism, the situation in other tissues might differ, depending on the unique composition and regulation of Myc-Max and other Max complexes. Indeed, conditional deletion of Mnt in T cells ultimately leads to tumor formation but also disrupts T-cell development and causes an inflammatory disease that resembles autoimmune disorders (S. Dezfouli, A. Bakke, A. Wynshaw-Boris and P.J.H., unpublished observation). This is in contrast to ectopic c-Myc expression in T cells, which leads to tumor formation but otherwise appears not to affect T-cell development strongly (Stewart et al., 1993).
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Conclusion and perspectives |
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TopSummaryIntroductionThe ups and downs...Where do Mxd and...All Maxed outMnt smells like a...Conclusion and perspectivesReferences |
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Do Mnt- and Mxd-family members regulate RNA polymerases and the same genes and processes regulated by Myc? Initial studies of the effects of Mnt and Mxd1 deficiency on cultured mouse fibroblasts and other cells suggest that this might be the case. However, it is important to emphasize that, whereas dMnt and dMyc appear to play reciprocal roles in the regulation of cell size in Drosophila (Loo et al., 2005), they have both unique and overlapping binding sites (Orian et al., 2003). Moreover, genetic experiments indicate that loss of Mnt in mice does not rescue the lethality caused by either loss of c-Myc or loss of N-Myc (Z.-Q. Zhou and P.J.H., unpublished observation). Finally, a major point of diversion is Myc-dependent transcriptional repression (Wanzel et al., 2003), which might not be influenced by Mnt or Mxd-family proteins. Thus, the available evidence indicates that Myc, Mnt and Mxd-family proteins affect both unique and overlapping pathways.
Clearly, we are in the early stages of elucidating mechanisms whereby Mnt and Mxd-family proteins impinge on the various activities of Myc, activities that have been uncovered only after decades of work. Moreover, since these proteins function within the context of a network, understanding their relationship requires that all of the individual components of this network be identified and their activities ultimately accounted for in any given biological setting. This level of understanding will hopefully lead to the identification of specific mechanisms that can be targeted to attenuate Myc activities in cancers.
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Acknowledgments |
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Footnotes |
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References |
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TopSummaryIntroductionThe ups and downs...Where do Mxd and...All Maxed outMnt smells like a...Conclusion and perspectivesReferences |
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Amati, B., Dalton, S., Brooks, M. W., Littlewood, T. D., Evan, G. I. and Land, H. (1992). Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max. Nature 359, 423-426.[CrossRef][Medline]
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Blackwell, T. K., Huang, J., Ma, A., Kretzner, L., Alt, F. W., Eisenman, R. N. and Weintraub, H. (1993). Binding of Myc proteins to canonical and noncanonical DNA sequences. Mol. Cell. Biol. 13, 5216-5224.
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