Transcription, apoptosis and p53: catch-22

doi:10.1016/j.tig.2005.01.001

Trends in Genetics

Volume 21, Issue 3, March 2005, Pages 182-187

https://doi.org/10.1016/j.tig.2005.01.001 Get rights and content

The tumor suppressor p53 is a transcription factor and is activated in response to DNA damage or oncogenic transformation through modification of its interaction with regulatory proteins. The transcription factor activity of p53 is thought to mediate its primary functions of cell-cycle arrest and apoptosis through the gene expression it regulates, and evidence to support this interpretation continues to accumulate. However, reports of transcription-independent activities of p53, especially in the induction of apoptosis, persist. In particular, recent studies suggest that cytosolic p53 directly interacts with members of the BCL-2 family of apoptosis regulators, thereby triggering mitochondrial outer membrane permeabilization and apoptosis. In this article, we examine the possible relationships between the transcription-dependent activity of p53 and its transcription-independent activity, and we propose ways in which both might regulate apoptosis.

Introduction

Once in a while, an old friend reveals an unexpected new facet. At first, this might be ignored. However, if it persists, it becomes difficult to overlook. Finally, it forces us to re-evaluate our opinion. This is particularly true of p53, which is more complex than was first acknowledged.

The tumor suppressor protein p53 has been viewed exclusively as a transcription factor that exerts its many functions by transactivating an ever-growing list of target genes [1]. Consensus sequences for p53-responsive elements were defined [2], which, in the post-genomic era, enable the detection of new p53 targets, sometimes before actual ‘wet’ experimentation [3]. The two major outcomes of a p53 response, cell-cycle arrest and cell death, seem to be achieved by inducing the expression of genes, whose products then execute the function. Prominent examples of such p53-target genes are p21 for arrest 4, 5, 6, p53 upregulated modulator of apoptosis [PUMA; also known as BCL2 binding component 3 (BBC3)], phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, also known as NOXA), BH3 interacting domain death agonist (BID), BCL-2-associated X protein (BAX) and death receptor 5 (DR5) for apoptosis 7, 8, 9, 10, 11, 12. In the context of apoptosis, p53 was also shown to act as a sequence-specific transcriptional repressor 13, 14, 15, 16, 17. In addition, p53 controls its own abundance via the induction of MDM2 and additional proteins that regulate its degradation by the proteasome 18, 19, 20. How could one expect more wizardry from such a ‘smart’ little molecule (Figure 1)?

Nevertheless, during the past ten years, a small but persistent set of papers attributed additional, transcription-independent functions to p53. One obvious transcription-independent activity (TIA) of mutant p53 in the heterozygous state is the inactivation of wild-type p53 molecules. This is thought to result from conformational changes in p53 tetramers containing mutant proteins, thus severely impairing transactivation of p53 targets. Interestingly, this TIA of p53 mutants seems not to be restricted to p53 itself, because mutant p53 proteins can also inactivate the p53 homologues p63 and p73, which themselves are rarely targets of somatic mutations 21, 22, 23, 24. However, the most striking claims of TIA of p53 relate to the pro-apoptotic function of the molecule. Can p53 trigger cell death independently of its own transactivating activity?

Section snippets

Evidence for a transcription-independent pro-apoptotic activity of p53

Early studies performed in cancer cell lines that used artificial p53 mutants or fusion proteins demonstrated induction of apoptosis, either in the presence of inhibitors of transcription and translation or by p53 mutants with abrogated transactivation activity 25, 26, 27, 28. However, those studies were criticized for not reflecting a physiological situation, and they were recently challenged by transgenic ‘knock in’ mice bearing inactivating germ line mutations of the p53 transactivation

Transcription-independent activities of p53 in the context of genetic mouse models

The acid test for a proposed function of a molecule is its confirmation in vivo in a genetic model. Thymocytes or oncogene-transformed fibroblasts from p53-deficient mice exhibit a profound protection against apoptotic cell death induced by growth-factor withdrawal or DNA damage 53, 54, 55. This rapid apoptosis is executed largely via the mitochondrial pathway of caspase activation – cells derived from mice deficient in apoptotic protease activating factor-1 (APAF-1) or caspase-9 display at

Integrating transcription-dependent and –independent functions of p53

It is generally agreed that the physiological relevance of p53 TIA will only be proven by a genetic model in which a transcriptionally incompentent p53 displays tumor-suppressor activity and/or apoptotic responses to DNA damage. However, such a genetic model of the TIA of p53 is confounded by what we call the ‘p53 catch-22.’ A ‘catch-22’ is any rule that is impossible to apply because of its inherent contradictions. (In the novel, Catch-22, Yosarian cannot use insanity as an excuse to avoid

Concluding remarks

To play devil's advocate, so far there is no conclusive evidence that the transcription-dependent induction of apoptosis by p53 can proceed independently of TIA. It has been shown by several groups that mutations in the crucial ‘proline-rich’ N-terminal domain of p53 abrogates its pro-apoptotic activity 41, 42, 43, 46. However, these mutants were capable of transactivating p53-dependent target genes, including those that are involved in the induction of apoptosis. Hence, a valuable genetic

Acknowledgements

We thank Jerry Chipuk and the members of our laboratories for their input on this article. M.S. is supported by the Deutsche Krebshilfe and by MAIFOR. D.R.G. receives grant support from the National Institutes of Health and Gemini Science.

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