Review
The role of p53 in hypoxia-induced apoptosis

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Abstract

Hypoxia represents one of the most physiologically relevant stresses, having significant roles in both normal development and malignant progression. Exposure to severe hypoxia leads to the accumulation of p53 which can in turn lead to rapid apoptosis. In contrast to the response to DNA-damaging agents, hypoxia-induced p53 has little or no transcriptional transactivation capabilities and instead seems to function primarily as a transrepressor in order to induce apoptosis.

Section snippets

p53 induces apoptosis in hypoxic regions of tumors

The important role of p53 in mediating apoptosis in the hypoxic regions of tumors has been effectively demonstrated previously [14], [15], [16], [17], [18]. In particular, Graeber et al. showed that p53 positive tumors underwent significant hypoxia-induced apoptosis while matched p53 null tumors did not. This finding led to the conclusion that hypoxia acts as a selection pressure for cells with diminished apoptotic potential, for example a loss of p53 expression [8]. These findings offer an

Hypoxia-dependent stabilization of the p53 protein—how and why?

Before considering the complexities of the p53-dependent hypoxia-induced apoptosis signaling pathway, it is important to first consider how and why, p53 is stabilized in response to hypoxia. It should also be considered here that, although it is generally accepted that hypoxia does lead to an accumulation of p53, this has been disputed within the current literature [25], [26], [27], [28], [29]. It is highly likely that both the diversity of the cell lines studied, exact oxygen concentrations

Once stabilized, where does hypoxia-induced p53 accumulate?

Traditionally, p53 has been described as a nuclear protein, however, recent reports in the literature indicate a new role for p53 in the cytoplasm and specifically at the mitochondria [48], [49], [50], [51], [52]. These findings, combined with the data indicating a significant role for the mitochondria in p53-dependent hypoxia-induced apoptosis, raise several interesting possibilities [19]. For example, p53, once stabilized, acts directly at the mitochondria to affect the release of cytochrome c

Transactivation by hypoxia-induced p53

The role of p53 as a transcription factor has been extensively described, as have the many transcriptional target genes, which include Bax, Puma, Noxa, and Perp[56], [57], [58], [59]. Despite the number of p53-activated genes characterized to date, no one gene has been identified which can recapitulate quantitatively all the apoptosis induced by p53. Genetic studies from Yu et al. [57] indicate that p53-dependent, hypoxia-induced apoptosis is mediated via Puma and its effect on Bax. These data

Transrepression by hypoxia-induced p53

By the mid-to-late 1990s, evidence was mounting that p53 could also function as a transrepressor [64], [65], [66], [67], [68], [69]. For example, Murphy et al. [68] showed that p53 complexed with mSin3a in vivo. mSin3a is a corepressor molecule which forms a repression complex with histone deacetylases (HDACs) [70]. Subsequently, Koumenis et al. [33] demonstrated that, in response to hypoxia, p53 acts as a transrepressor, by complexing with mSin3a, and inducing apoptosis. This report also

Mechanism of repression

The association of p53 and corepressor molecules such as mSin3a and HDACs suggest that p53 forms a repression complex on the promoters of target genes, such as the survivin promoter [71], [72]. A p53 response element in the human survivin promoter was identified that was bound by both p53 and deacetylated histone H3. The identified p53 response element overlapped with an E2F-binding site, leading to the conclusion that p53-dependent repression of survivin is at least mediated in part by

How do repressed genes induce apoptosis?

The ability of HDAC inhibitors such as TSA to inhibit p53-dependent hypoxia-induced apoptosis indicates that this property/ability of p53 plays a critical role in hypoxia-induced death [33], [68]. It seems probable that, analogous to the DNA-damage response, many individual target genes will be involved. The list of identified p53-repressed genes is growing, although relatively few have been shown to play a direct role in apoptosis, and even fewer in hypoxia-induced apoptosis [79]. Survivin is

Why repression over activation?

The apoptotic response to many types of genotoxic stress relies on p53 transactivation and to a lesser extent transrepression. In contrast, hypoxia-induced p53 acts almost entirely as a transrepressor. The obvious remaining question is why. It is important to consider some of the factors involved in the hypoxic response which may also determine, at least in part, the p53 response. As previously mentioned, at the low oxygen concentrations required to induce p53 accumulation, DNA-synthesis stops.

Summary

In conclusion, hypoxia represents a unique stress response that it not only physiologically relevant to both normal development and tumorigenesis, but also offers insight into the many facets of p53. This has been effectively highlighted by the many elegant studies that demonstrate that hypoxic tumors are more aggressive, harder to treat, and exert a positive selection pressure for the loss of p53. In the traditional “guardian of the genome” role for p53 in response to irreparable

Acknowledgments

We thank Dr. Philip Lecane for critical reading of the manuscript and apologize to all those authors we weren’t able to cite due to space limitations. This work was supported by a NIH Grant (CA 88480) awarded to AJG.

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