The tumor suppressor p53 represents a paradigm for gene regulation. Its rapid induction in response to DNA damage conditions has been attributed to both increased half-life of p53 protein and also increased translation of p53 mRNA. Recent advances in our understanding of the post-transcriptional regulation of p53 include the discovery of internal ribosome entry sites (IRESs) within the p53 mRNA. These IRES elements regulate the translation of the full length as well as the N-terminally truncated isoform, p53/47. The p53/47 isoform is generated by alternative initiation at an internal AUG codon present within the p53 ORF. The aim of this review is to summarize the role of translational control mechanisms in regulating p53 functions. We discuss here in detail how diverse cellular stress pathways trigger alterations in the cap-dependent and cap-independent translation of p53 mRNA and how changes in the relative expression levels of p53 isoforms result in more differentiated p53 activity.
The p53 protein is certainly one of the most intensely studied molecules in the history of biomedical sciences. It was originally discovered through its physical association with the transforming simian virus 40 (SV40) large T antigen around 30 years ago (Lane and Crawford, 1979; Linzer and Levine, 1979). Analogous to its interaction with the SV40 large T antigen, the interaction of p53 with other viral proteins important for cellular transformation were also reported. Subsequent studies highlighted the role of critical mutations within p53cDNA that are indispensable for its ability to induce cellular transformation. Thus, over a period of time the description of p53 changed from a viral-associated tumor antigen to an oncogene to a tumor suppressor protein. Years on, the p53 gene still continues to surprise researchers with its ever-increasing list of multiple functions and the enigmatic complexities involved in its regulation. The p53 protein is maintained at low levels during normal conditions through an autoregulatory feedback-loop involving its transcriptional target, mdm2 gene (Barak et al., 1993; Wu et al., 1993). In turn, Mdm2 functions as a p53-selective E3-ubiquitin ligase that promotes p53 polyubiquitination and targets it for proteasomal degradation (Haupt et al., 1997; Honda et al., 1997; Kubbutat et al., 1997). A very interesting study suggested that the expression levels of p53 and Mdm2 proteins oscillate in response to stress signals. These oscillations might allow cells to repair the damaged DNA, whereas avoiding the irreversible outcomes of excessive and continuous p53 activation (Lev Bar-Or et al., 2000). These findings further strengthen the fact that p53 levels are regulated at the post-transcriptional level. In 2002, a study showed that Mdm2 induces the translation of p53 mRNA from two initiation sites (Yin et al., 2002). Alternative translation initiation at an internal codon is responsible for the generation of the p53/47 isoform, also referred to as ΔN-p53, Δ40p53 (Courtois et al., 2004; Scrable et al., 2005; Bourdon, 2007; Halaby and Yang, 2007). Further, Mdm2 selectively targets full-length p53 protein for degradation because the p53/47 isoform lacks the N-terminus Mdm2 binding sites thereby, altering the relative levels of the two-p53 isoforms (Yin et al., 2002). Interestingly, several N-terminally deleted isoforms of relatives and evolutionary predecessors of p53, p63 and p73, have also been reported. It seems to be that diverse repertoire of protein isoforms might represent a ‘trademark’ of p53 protein family (Courtois et al., 2004; Bourdon, 2007). Analogous to this Mdm2, a focal regulator of the levels of the two-p53 isoforms, also possesses an N-terminally deleted isoform (Perry, 2004). A recent study has suggested that accumulation of Mdm2 at the polysome during p53 mRNA translation might lead to concomitant stimulation of p53 synthesis and inhibition of Mdm2 protein's E3 ligase activity. These findings indicate that the affinity of interaction between Mdm2 and p53 mRNA might act as a switch that controls the activity of Mdm2 toward p53 (Candeias et al., 2008). Another study concluded that Mdm2 also regulates p53 levels through its interaction with ribosomal protein, L26 (Ofir-Rosenfeld et al., 2008). Earlier L26 protein was shown to bind the 5′-untranslated region (UTR) of p53 mRNA and stimulate its translation during DNA damage conditions (Takagi et al., 2005). The recent study suggested that during unstressed conditions, Mdm2 binds and targets L26 for degradation. Thereby, it represses L26-mediated augmentation of p53 protein synthesis by constitutively tuning down the p53 translation (Ofir-Rosenfeld et al., 2008). These and other studies highlight that translation control form an important mechanism for regulating p53 activities (reviewed in Ewen and Miller, 1996; Giaccia and Kastan, 1998; Halaby and Yang, 2007). We intend to begin by discussing the role of cap-independent translation of p53 mRNA during stress conditions.
p53 mRNA translation during stress conditions
Multiple features of p53 mRNA indicate that it might be regulated at the level of translation. The 5′ UTR preceding the open reading frame of the p53 mRNA is highly GC rich. In addition, the region of the p53 mRNA up to the alternative initiation codon that acts as the 5′ UTR for the p53/47 isoform is also GC rich. Earlier reports have suggested the presence of strong secondary stem-loop structures with significantly higher ΔG values in these regions (Mosner et al., 1995; Takagi et al., 2005; Ray et al., 2006). Consequently, the UTRs preceding the ORFs of p53, p53/47 would be expected to present a significant obstacle to translation initiation by conventional ribosome scanning mechanism (Gebauer and Hentze, 2004). An important step in controlling protein synthesis is translation initiation and hence it is also the target of diverse signaling pathways. Indeed, several mechanisms are used to repress cap-dependent initiation during stress conditions. For instance, the α-subunit of eukaryotic initiation factor, eIF2 is observed to be phosphorylated by a number of protein kinases that are activated in response to cellular stresses thereby, repressing global translation initiation (Wek et al., 2006). In addition, the integrity of the eIF4F cap-binding complex becomes increasingly compromised during stress conditions. An important mechanism regulating eIF4F integrity involves 4E-binding proteins (4E-BPs), which compete for the common binding sites on eIF4E with eIF4G. During the stress conditions, 4E-BPs can sequester eIF4E from eIF4F complex and eventually this ‘imprisonment of eIF4E’ leads to inhibition of cap-dependent translation (Clemens, 2001). In addition, proteolytic cleavage of eIF4G component of the eIF4F complex induced by caspases during apoptosis or viral proteases in the virus-infected cells renders eIF4F complex unable to associate with 5′ end of mRNA (Morley et al., 2005). Interestingly, multiple stress conditions that lead to a global translation inhibition are also activators of the p53 pathway. For instance, certain conditions like serum starvation and endoplasmic reticulum (ER) stress have actually shown to upregulate the levels of both the p53 isoforms (Candeias et al., 2006). The signaling cascades linking the ER stress to translational machinery are well documented in literature. One factor that plays crucial role in ER stress is transmembrane sensor protein kinase, RNA-activated protein kinase (PKR)-like ER kinase (PERK). PERK is shown to be activated in response to ER stress and is shown to phosphorylate eIF2 α-subunit, thereby inhibiting cap-dependent translation initiation (Harding et al., 1999). On the basis of these findings, it is highly tempting to speculate that PERK might be involved in cap-independent induction of p53 mRNA during ER stress conditions. In addition, an increase in p53 synthesis after treatment with the DNA-damaging agent etoposide has also been reported (Yang et al., 2006). Concomitantly, this increase was accompanied by an increase in the association of the translation initiation factor, eIF-4E, with its binding protein, 4E-BP1. This prevents the interaction of eIF-4E with eIF-4G and suppresses cap-dependent translation (Yang et al., 2006). Similarly, the translation of several pro- and anti-apoptotic messages continue during stress because they employ alternative mechanisms of translation initiation that do not involve the cap structure but direct recruitment of the ribosomes to structured regions in the mRNA known as internal ribosome entry sites (IRESs) (Spriggs et al., 2005). p53 could therefore serve as a good example of how alternative translation initiation mechanisms are employed during stress conditions.
Discovery of IRES elements within the p53 mRNA
Several studies have shown that cellular expression of both p53 and p53/47 increase sometimes independently in response to varied stress signals without an increase in either mRNA levels or alternative splice products (Fu et al., 1996; Yin et al., 2002; Candeias et al., 2006). These results indicate that translation of p53 mRNA plays an important role in changing the relative expression levels of p53 and p53/47 after cellular stress conditions. In addition, the studies suggest that translation initiation from the first and second AUGs in the p53 mRNA is regulated independently (Candeias et al., 2006). Strikingly, the changes in expression of the two-p53 isoforms were observed to be regulated through separate regions of p53 mRNA through distinct cell-stress induced pathways (Candeias et al., 2006). Stringent assays were performed to rule out the possibilities of cryptic promoter activity, scanning or alternative splicing within p53 mRNA using either synthetic bicistronic reporter constructs or p53 cDNA containing constructs (Candeias et al., 2006; Ray et al., 2006). Two internal ribosome entry sites have been shown to regulate synthesis of p53 and p53/47 in a cell-cycle phase-dependent manner (Ray et al., 2006). The IRES responsible for the translation of p53 was observed to be most active at the G2–M transition during which there is a global attenuation of cap-dependent translation. As p53 activity is required during this phase of the cell cycle, IRES-mediated translation might be required for maintaining basal levels of p53 protein. On the other hand, the activity of IRES responsible for the translation of p53/47 predominates at the G1–S transition (Ray et al., 2006). The increased IRES activity and consequent higher levels of p53/47 during G1–S transition is in line with the earlier observation (Courtois et al., 2002). Interestingly, an independent study has also shown the presence of IRES element within the p53 mRNA (Yang et al., 2006). A specific increase in p53 mRNA translation was observed on etoposide treatment (Yang et al., 2006). Etoposide is an inhibitor of topoisomerase II and could lead to tumorigenesis by causing accumulation of DNA double-strand breaks. The study concluded that the activity of p53 IRES element increases dramatically during etoposide-induced DNA damage conditions leading to increased p53 translation (Yang et al., 2006). The important question, yet to answer, is the molecular basis for this stress and cell-cycle phase-dependent regulation. It is possible that the interaction of different cellular proteins with the p53 IRES elements might be crucial for this regulation.
Role of IRES-interacting trans-acting factors in the regulation of p53 IRES function
The recruitment of ribosomes to viral IRES elements is mostly dependent on secondary and tertiary RNA structure (Baird et al., 2006; Pfingsten et al., 2007). However, the mechanisms by which cellular IRES elements recruit ribosomes are rather unclear. Cellular IRESs, unlike their viral counterpart, are relatively inefficient in the in vitro reconstituted systems, but can be induced by the addition of exogenous proteins (Mitchell et al., 2001; Pickering et al., 2003). Similarly, the IRES activities are known to vary in a cell-type specific manner, supporting the idea that non-canonical translation initiation factors are required for efficient IRES-mediated translation. A number of IRES-interacting trans-acting factors have been identified for both viral and cellular IRESs to date. These unusual non-canonical translation factors include DAP5, hnRNP I (PTB), hnRNPC1/C2, HuR, La autoantigen, unr and many others (Spriggs et al., 2005). Of these, the polypyrimidine tract-binding protein (PTB), also known as hnRNP I, is known to influence a wide spectrum of viral and cellular IRESs. The PTB protein was initially identified as a splicing factor associated with α-tropomyosin pre-mRNA. (Wagner and Garcia-Blanco, 2001). In addition, studies have suggested that the spatial-temporal regulations of PTB and other IRES-interacting trans-acting factors might play a critical role in regulating IRES-dependent translation of multiple cellular genes under physiological and stress conditions. In fact, treatment of cells with pro-apoptotic reagent (TRAIL) caused a cytoplasmic localization of PTB, which, in turn, modulated the expression of several IRES elements involved in apoptosis (Bushell et al., 2006). In addition, it was observed that treatment with DNA-damaging agent, doxorubicin, causes increased translocation of PTB protein from nucleus to cytoplasm (Grover et al., 2008). The study concluded that the increased cytoplasmic abundance of PTB protein, during DNA damage conditions, might contribute to increased p53 IRES activity leading to increased synthesis of p53 protein (Grover et al., 2008). The cytoplasmic level of PTB protein was observed to be maximum at the G2–M phase and low at the G1–S phase of the cell cycle (Kim et al., 2003). Correspondingly, it was shown that the activity of IRES element responsible for p53 synthesis is higher during G2–M phase (Ray et al., 2006). With the current findings, it is speculated that PTB protein might act as a chaperone by remodeling the IRES structure to attain correct conformation for ribosome recruitment as shown in case of Apaf-1 and Bag-1 IRES function (Mitchell et al., 2003; Pickering et al., 2004). On the basis of these findings, it is likely that PTB protein might also trigger conformational alteration in p53 IRES RNA structure that probably facilitates ribosome loading during internal initiation.
It should be pointed out that several other proteins were shown to interact with p53 5′ UTR and implicated in the control of p53 mRNA translation. Many of these proteins such as ribosomal protein L26, nucleolin, hnRNP U and autoantiantigen La might be potential p53 IRES-interacting trans-acting factors (Takagi et al., 2005). Interestingly, p53 protein has been shown to bind to 5′ UTR of its own mRNA and inhibit translation (Mosner et al., 1995). It is possible that during normal conditions, the binding of certain negative regulatory proteins such as nucleolin, p53 might promote the double-strand RNA stem loop structure of p53 5′ UTR for maintainence of basal low levels of p53 protein (Mosner et al., 1995; Takagi et al., 2005). However, during the stress conditions, concomitant displacement of these negative regulatory factors and the binding of positive regulatory factors such as L26, PTB might unwind the stem loop structure and contribute to cap-independent translation (summarized in Figure 1; Takagi et al., 2005; Grover et al., 2008).
Finally, we will discuss the possible physiological relevance of co-existence of the two-p53 isoforms.
p53 brothers talk and decide the activity
In 2002, a study reported that p53/47 impairs the ability of p53 to trans-activate certain target genes such as p21 and hence, p53 was unable to induce G1 arrest in the presence of p53/47 (Courtois et al., 2002). In addition, in the same study, it was observed that the ratio between the levels of two p53 isoforms varies during cell cycle. On the basis of these findings, it was proposed that p53/47 might function as a transient negative regulator of p53 to allow progression through cell cycle (Courtois et al., 2002). However, the recent findings suggest that the role of p53/47 is most likely more complicated than anticipated. For instance, p53-null human-lung carcinoma cells, H1299 cells transfected with either p53 or p53/47 were observed to undergo similar levels of apoptosis (Zhu et al., 1998; Yin et al., 2002). In addition, p53/47 was observed to induce many apoptosis-related genes that were not induced by p53, such as P53BP2 (ASPP2) and TIAL1 (Ohki et al., 2007). The apoptosis induction by p53/47 might be explained by the induction of these pro-apoptotic genes (Taupin et al., 1995; Samuels-Lev et al., 2001). In addition, in an independent study, p53/47 expression in transgenic mice was observed to induce senescence and premature ageing even when the level of p44 (mouse form of p53/47) was only slightly elevated (Maier et al., 2004). Taken together, these studies highlight that p53/47 is not solely a negative regulator of p53. A more recent study has investigated the influence of p53/47 on p53 activity under normal and during stress conditions. The results showed that both p53 and p53/47 isoform exhibit diverse and unique trans-activation features when expressed individually and that an excess of p53/47 in addition to p53 leads to further differentiation of the p53-dependent gene expression pattern (Powell et al., 2008). Not only does p53/47 have unique trans-activation properties, but it also seems to be that it is modified differently as compared with p53. Intriguingly, the p53/47 isoform does not harbor most of the first trans-activation domain, and it also lacks the Mdm2-binding site but retains the capacity to oligomerise with p53. Consequently, p53/47 can form homo- and hetero-oligomer complexes with the full-length p53 protein. It has been shown that p53 exhibits a stronger affinity for the p53/47 isoform than for itself (Ghosh et al., 2004; Powell et al., 2008). The fact that p53/47 alters p53 activity in the cell can probably be explained by changes in the recruitment of co-activators (Candeias et al., 2006; Powell et al., 2008). The probable cause of difference in the employment of these co-activators could be altered post-translational modification profile of p53 complexes that is imposed on by p53/47. These changes would in turn influence the binding to promoter sequences and the interaction with the transcription machinery and eventually alter the pattern of induction of the target genes (Powell et al., 2008). This would suggest that expression of p53/47 results in a differentiated and more specific downstream gene expression pattern (Figure 2).
Internal ribosome entry sites-mediated translation represents cellular backup plan to allow continued synthesis of extremely vital pools of proteins during conditions when canonical cap-dependent translation is globally repressed. The recent landmark in the field of translational regulation is the discovery of IRES elements regulating the translation of p53 and its little brother, p53/47. In this review, we have summarized the current understanding of IRES-mediated translation regulation mechanisms underlying coordinated synthesis of p53 brothers. It is noted that the little brother, p53/47, can have a significant impact on p53 activities and hence cellular outcomes. This is probably because of the fact that p53/47 isoform can form oligomer complexes more readily as compared with p53 protein. In addition, it has been shown that the p53/47 isoform supports the conformation of p53 protein that is associated with a more active state. It is thus possible that the combination of changes in inter- and intra-molecular conformation and altered post-translational modification pattern allows p53/47 to mediate a more differentiated p53 activity profile, both in terms of promoter binding as well as in the recruitment of transcriptional co-activators (Yin et al., 2002; Candeias et al., 2006; Powell et al., 2008). In the perspective of results showing that p53 and p53/47 are independently translated from the same p53 mRNA in a stress- and cell-cycle-dependent manner (Candeias et al., 2006; Ray et al., 2006), it is conceivable that changes in the relative expression levels of p53 and p53/47 forms an important part in deciding how the cells orchestrate an appropriate and differentiated p53-dependent response to specific stress signaling pathways. We do not know yet the molecular pathway(s) underlying stress-induced regulation of IRES-mediated translation of p53 mRNA. It is probable that deregulation of these pathways might be one of the mechanisms leading to tumor development in some types of cancers.
An additional consideration is the recently described complex expression pattern of p53 gene, like its other family members. The human p53 gene encodes at least nine different isoforms (Bourdon, 2007). The pattern of expression of p53 isoforms is tissue-specific and hence can be specifically regulated. Moreover, p53 isoforms are expressed at lower level than full-length p53 protein and have distinct subcellular localizations within cells suggesting distinct biochemical activities. Experiments involving co-transfection of p53 protein with individual p53 isoforms suggest that wild-type p53 activity is modulated by its isoforms (Bourdon et al., 2005). This can provide a probable justification for the multiple functions played by p53 protein within the cell. The experimental data also suggests an abnormal expression of p53 isoforms in head and neck cancers (Boldrup et al., 2007), acute myeloid leukemia (Anensen et al., 2006) and cell lines (Goldschneider et al., 2006). Thus, suggesting altered p53 isoforms expression pattern could disrupt p53 function and also be fundamental to tumor formation. Therefore, an integrated and complex analysis of p53 isoforms’ expression pattern, including p53/47, is essential in clinical studies to help diagnosis and design appropriate treatments. For instance, a distinct activation profile of p53 and p53/47 in both time- and drug dependent-manner provided molecular explanation for the efficacy of a novel drug, LA-12, in treating cells resistant to a related drug (Hrstka et al., 2008).
In general, it is likely that this concept of regulating properties of an oligomeric transactivator by expression of isoforms generated through alternative initiation mechanism from the same transcript might also apply to other families. For instance, the mRNAs encoding the CCAAT/enhancer-binding proteins (c/EBPα and c/EBPβ) also give rise to alternatively initiated isoforms (Ossipow et al., 1993). Interestingly, these isoforms also lack parts of trans-activation domains, however, they retain oligomerization domain as p53/47. Consequently, these isoforms can interact with their full-length counterparts and result in modulation of downstream gene expression pattern. Hence, it seems to be a widespread mechanism, by which the activation repertoire of a transcription factor is enhanced, although the molecular mechanisms that are involved might be different.
Conflict of interest
The authors declare no conflict of interest.
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This study is supported by a research grant from the Indo-French (IFCPAR) to SD and RF. RG is supported by pre-doctoral fellowship from Council of Scientific and Industrial Research, India.
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Grover, R., Candeias, M., Fåhraeus, R. et al. p53 and little brother p53/47: linking IRES activities with protein functions. Oncogene 28, 2766–2772 (2009). https://doi.org/10.1038/onc.2009.138
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