ReviewThe transcriptional targets of p53 in apoptosis control
Section snippets
p53 and apoptosis
Expression of the wildtype p53 was found to cause rapid loss of cell viability with morphological characteristics of apoptosis [9]. The evidence for p53-mediated apoptosis in vivo came from studying the p53-null mice and cells. The p53-null thymocytes and intestinal stem cells are more resistant to radiation-induced apoptosis than their normal counterparts, and p53-null mouse embryonic fibroblast cells (MEFs) are resistant to apoptosis induced by oncogene overexpression and chemotherapeutic
Transactivation by p53 and apoptosis
Transcriptional activation is the best described biochemical function ascribed to p53. p53 binds to DNA in a sequence-specific manner to activate its downstream targets [21], [22]. The great majority of tumor derived mutants are defective in transactivation [23], [24]. The structural studies revealed that the amino acid residues in the mutation hot spots of p53 are involved in DNA binding [25]. In animal models, transcription impaired mutants of p53 are defective in apoptosis induced by DNA
In search of the p53 apoptotic targets
Apoptosis is an evolutionarily conserved process for an organism to remove unwanted or damaged cells. Two major apoptotic pathways are defined in mammalian cells. The extrinsic pathway is mediated by the death receptor family of proteins. Upon ligand binding to the receptor on the cell surface, recruitment of the adaptor molecules results in caspase 8 activation and subsequent activation of other caspases [32], [33]. The intrinsic pathway is engaged when the cells are challenged by stress and
Apoptotic targets of p53
It has been suggested that the intrinsic apoptotic pathway is primarily utilized in p53-mediated apoptosis, while the extrinsic pathway is used to augment the apoptotic response [42]. The p53 apoptotic targets can be divided into several categories based on their functions in these pathways. It is notable that both positive and negative feedback regulations are common between p53 and its apoptotic targets.
Modulation of transcriptional activity of p53 in apoptosis
As a key transducer of the signaling pathways evoked by various stresses, p53 activity is highly governed through complex networks of posttranslational modifications, including phosphorylation, acetylation, ubiquitination, sumoylation, neddylation, and cytoplasmic sequestration, etc. [6], [7]. MDM2 plays a key role in regulating p53 stability [7]. Several recently identified regulators of p53 appear to exert their influence on p53 through MDM2, such as the positive regulator PML [86], [87], the
Decision on cell cycle arrest vs. apoptosis by p53 targets
In response to DNA damage and other stresses, p53 induces either cell cycle arrest or apoptosis depending on specific cellular contexts. Important questions have been raised on how the cell fate, i.e., the choice between cell cycle arrest and apoptosis, is determined by the differential regulation of the distinct classes of p53 targets, and whether these two mechanisms are related to each other.
Recent studies indicate that cell cycle arrest is not only an arm of the p53 response, but also a
Transcription-independent mechanisms
Transcription-independent mechanisms of p53-dependent apoptosis are reviewed by others in this issue and elsewhere [113]. Several provocative models are proposed to explain how p53 induces apoptosis outside of the nucleus. The wildtype p53 and some transactivation-deficient mutants can directly signal the mitochondria to activate BAX in the cytoplasm, much like what BH3-only proteins do [114]. p53 also accumulates at the mitochondria in some tissues following DNA damage, and mitochondrial p53
p53 apoptotic targets in therapeutic manipulation
Loss of apoptotic response by inactivating the p53 pathway appears to be consistently required for malignant progression and also contribute to chemoresistance. Learning how p53 controls apoptosis through its targets might help us devise better cancer therapeutics and prognostic tests. For example, the expression of p53 apoptotic targets might predict the prognosis in p53 gene therapy or other therapies designed to reactivate p53 in tumor cells. Unlike p53, the p53 apoptotic targets are rarely
Conclusions
Transcriptional control by p53 is important for apoptosis induction. How does p53 precisely control apoptosis through its targets to keep malignancy at bay? The answer is unlikely to be a simple one given the enormous complexity in the regulation of p53 and its targets. In many occasions, the activation of the targets and the final decision on life and death are out of the hand of p53 itself. Different experimental systems employing normal and transformed cells often give very different answers
Acknowledgments
We apologize for not being able to cite many excellent original papers by our colleagues due to space limitation. We thank the members in our laboratories for their helpful comments. The work in author’s laboratories is supported in part by Flight Attendant Medical Association, the Hillman Foundation, NIH Grant CA106348, the General Motors (GM) Cancer Research Foundation, the Edward Mallinckrodt Jr. Foundation, the V Foundation for Cancer Research, and the Elsa U. Pardee Foundation.
References (118)
- et al.
Cell
(1979) - et al.
Mutat. Res.
(1999) - et al.
Cell
(1993) - et al.
Cell
(1994) - et al.
Cancer Cell
(2002) - et al.
Curr. Biol.
(2001) - et al.
Curr. Opin. Cell Biol.
(2002) Semin. Cancer Biol.
(1998)- et al.
Curr. Biol.
(2003) - et al.
Mol. Cell
(2001)