Reviewp53 translational control: A new facet of p53 regulation and its implication for tumorigenesis and cancer therapeutics
Introduction
The tumor suppressor p53 is a transcription factor that plays a key role in both cell cycle arrest and apoptosis. While p53 levels are kept low in unstressed cells, they rapidly increase in response to stressors, such as DNA damage. p53 will then become activated through posttranslational modifications and tetramerization following genotoxic or cytotoxic stress (Vogelstein et al., 2000, Bode and Dong, 2004). The inability of p53 to accumulate and become activated in the cell in response to stressful stimuli is the main underlying cause of tumorigenic transformation (Vogelstein et al., 2000, Oren, 2001–2002). The increase in p53 levels is therefore a key component of the p53 response to stress, and understanding the mechanisms leading to p53 accumulation in the cell can open up new avenues for cancer therapy.
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Importance of p53 translation in the response to DNA damage
It is now well established that in response to DNA damage, p53 accumulates in the cell mainly as a result of either increased p53 half-life or increased p53 translation. It is well known that the half-life of p53 is mainly regulated by the ubiquitin ligase MDM2, which can bind to p53 and target it for degradation in the proteasome. In contrast, the mechanisms of p53 translational regulation are still poorly understood despite major advances in this field in the last two decades (Ewen and
Regulation of p53 translation at the 5′-UTR
The 5′-UTRs of both human and murine p53 are predicted to form stable stem–loop secondary structures that are capable of inhibiting translation (Mosner et al., 1995, Takagi et al., 2005). When wild type murine p53 was incubated with biotinylated RNA corresponding to either the full-length p53, p53 5′-UTR, p53 coding region or the SV40 T-antigen, it was found that p53 can bind specifically to the 5′-UTR of its own mRNA. Moreover, addition of increasing amounts of wild type p53 protein to an in
Regulation of p53 translation at the 3′-UTR
In addition to the regulation at the 5′-UTR, p53 translation can also be regulated by the 3′-UTR. The human p53 3′-UTR is 1176 nucleotides long and contains an Alu-like sequence of about 470 nucleotides. This region is predicted to form a secondary structure that is capable of inhibiting p53 translation (Fu et al., 1996). Using deletion analysis, a repressor element was further mapped to a 66 nucleotide U-rich stretch within the Alu-like sequence. UV-crosslinking of proteins from MCF-7 cells to
Discovery of the p53 IRES and its implication for p53 translational control
In recent years, major progress has been made in the field of protein translation. Currently, there are two recognized forms of eukaryotic translation, cap-dependent translation and cap-independent translation (Hellen and Sarnow, 2001). The recognition of the 7-methylguanosine cap located at the 5′-end of eukaryotic mRNAs by the eukaryotic initiation factor eIF4E, which is part of a greater initiation complex eIF4F, is a crucial step of cap-dependent protein translation (Gingras et al., 1999).
Importance of IRES trans-acting factors (ITAFs) in p53 translation following DNA damage
Using the mfold algorithm (Zuker, 2003), it has been predicted that the human p53 5′-UTR contains complex stem–loop structures that can inhibit p53 translation (Takagi et al., 2005, Ray et al., 2006). This is in accordance with the assumption that all IRESs have complex secondary structures. The role of secondary structure in the function of IRESs is just starting to be understood. In both viral and cellular IRESs, it is thought that the structural domains of the IRES can serve as anchoring
Possible cooperation between the p53 IRES and 3′-end
Despite the discovery of the p53 IRES, there are still many unanswered questions in terms of translational regulation of p53 following DNA damage. For one, the 3′-UTRs of mRNAs are typically longer and more complex than the 5′-UTR sequences, suggesting that 3′-UTRs may be important regulatory sites for mRNA translation (Mazumder et al., 2003). It is thought that in many instances, the 3′-UTR and its binding proteins can regulate poly(A) tail length and therefore mRNA stability. In addition, the
Potential implication of p53 IRES in tumorigenesis and cancer therapeutics
Constant exposure to DNA damage can lead to genomic instability, which predisposes the cell to tumorigenic transformation. p53 is necessary to protect the cells against such events. It does so by inducing either cell cycle arrest, allowing cells to repair damaged DNA, or apoptosis, a last resort option that allows organisms to get rid of irreparably damaged cells (Attardi, 2005). Therefore, understanding the mechanisms behind p53 induction, the initial event leading to p53 activation following
Summary
In summary, the discovery of the p53 IRES may provide new insights into the mechanism underlying the translational regulation of p53 in response to DNA damage and the process of tumorigenesis in many types of cancer, such as breast and prostate cancer, that harbor the wild type p53 coding region. Identification of p53 IRES mutations or abnormal expression of p53 ITAFs in cancer cells will lead to further advances in the fields of cancer detection, diagnosis and therapeutics.
Acknowledgements
We would like to thank Dr. Keith Weaver and Dr. Keith Miskimins at the University of South Dakota, Sanford School of Medicine for their critical reading of this review article. We would also like to thank Katie Connors for her technical assistance. In addition, we would like to express our gratitude to Oncogene for allowing us to use a previously published figure.
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