Trends in Cell Biology
ReviewThe impact of p53 and p73 on aneuploidy and cancer
Introduction
p53, p63 and p73 are members of the p53 family of transcription factors [1]. First described in 1979 2, 3, p53 is still one of the most studied proteins in the cancer field. Its importance as a prognostic marker as well as in the comprehension of numerous tumorigenic processes is undeniable [4]. However, the discovery of two p53-related proteins, p63 [5] and p73 [6], further increased the level of complexity within this family, owing to their simultaneous, exclusive or consecutive physical interactions and ability to act as transcriptional regulators. These more recently discovered genes clearly show a strong ability to mimic many of the activities of p53 7, 8, 9. However, unlike the tumor-prone phenotype of p53 knockout mice, the phenotype of p63 and p73 null mice is developmental, involving defects in epithelial and neuronal maturation, respectively, and the function of p63 is more important in processes related to epithelial development 10, 11, 12 and stem cell maintenance 13, 14, 15. p63 appears to be the ancestral member of the family, whereas p53 seems to have evolved later 7, 9, 16. As we will demonstrate, both p53 and p73 can act as regulators of mitotic checkpoint proteins, and consequently they are linked to chromosomal instability and cancer. Although some evidence also links p63 with mitotic regulation, this is largely indirect, and the role of p63 will not be considered further in this review.
The p53 protein integrates multiple cellular stress signals, assessing cellular damage and responding by triggering transcription of genes involved in either cell cycle arrest or apoptotis [17]. These effects result predominantly from the ability of p53 to bind to DNA through its p53-responsive elements (p53REs). The high level of sequence similarity between the DNA-binding domains of p73 and p53 enables p73 to transactivate p53-responsive genes, also causing cell cycle arrest and apoptosis. Tumor protein p53 (TP53), in particular, is an important tumor suppressor gene. However, the evidence suggesting that p73 is a tumor suppressor gene remains controversial. To further complicate the analysis, TP73, as with TP53 [18], is also expressed as multiple protein variants with different activities (Box 1). The involvement of TP73 in tumorigenesis therefore remains debatable, despite strong evidence that p73 is a major regulator of cell death and proliferation.
The dominant–negative ΔNp73 isoform is the most abundant TP73-generated protein in various tumors [19], and this might mask any pro-apoptotic function of TAp73 (Box 1). Experimental evidence has also shown contrasting results in the p73-deficient mice: different groups reporting opposite results in terms of tumour incidence and inducibility. This supports the fact that p73 shares similarities but also differences with p53, possibly reflecting p73 numerous isoforms (Box 2). p53 and p73 are potent transcription factors, and so it is a convenient assumption that their involvement in cancer regulation is simply attributable to their ability to regulate gene expression. Analysis of their activities other than their function in regulating transcription could have an important impact on our understanding of how they are involved in the control of genomic stability and how aberration of this control can lead to cancer. But is the effect of p53 and p73 on cancer solely due to their functions in the cell cycle and apoptosis? Several recent publications have reported roles for p53 and p73 in another crucial defensive process against cancer: the regulation of mitosis either by modulation of mitotic checkpoint arrest or by involvement in mitotic cell death. Notably, the discovery that p53 has transcriptional-independent functions in centrosome duplication associated with aneuploidy is a first and important step in this area [20].
Mitosis is controlled by mitotic checkpoint proteins that sense defects in chromosomal segregation and microtubular attachment to kinetochores, and which delay mitotic progression by transiently inhibiting the anaphase-promoting complex (Figure 1) 21, 22. Studies of transgenic knockout mice revealed that partial or complete deletion of, as well as specific mutations within, mitotic checkpoint proteins can induce several phenotypes such as infertility, aging and, more pertinently, aneuploidy and/or cancer [23]. Indeed, as originally proposed by Boveri [24], aneuploidy can lead to cancer. Several reports have also revealed that spindle checkpoint mutations are associated with chromosomal instability (Box 3). For example, aneuploidy created in mice that are heterozygous for Mad2 (mitotic arrest-deficient 2), BubR1 (budding uninhibited by benzimidazoles) or Bub3;Rae1 (RNA export 1) is associated with tumor development 25, 26. However, although apparently strong experimental data in the mouse suggest a close relation between altered spindle checkpoint activity and tumorigenesis [27], more recent data indicate that a greater degree of complexity might exist in humans [23]. A more realistic hypothesis is that diminished rather than completely deleted spindle checkpoint activities could be important in tumor formation.
Understanding the fate of mitotic cells delayed by checkpoints for long periods is crucial for understanding whether aneuploidy and the chromosomal instability phenotype are directly implicated in tumor formation. Concerning cell fate characterization, cells with a chromosomal instability phenotype should die as a result of one of two processes: by apoptosis in the next G1 phase following their earlier mitotic exit; or, as has recently been argued, by a form of non-apoptotic programmed cell death known as caspase-independent mitotic death (CIMD), which occurs during mitosis [28]. Currently, three types of death pathway have been described – apoptosis, mitotic catastrophe and CIMD – on the basis of morphological criteria; however, the molecular pathways involved in these processes have yet to be elucidated [29]. Moreover, the way these cell death processes interact with spindle checkpoint proteins and mitotic arrest mostly remains obscure. Several very recent studies have revealed the importance of p53 and p73 in these phenomena and have led to the hypothesis that these proteins are two of the missing links between mitotic arrest and cell death during mitosis.
Here, we focus on recent results that illustrate how p53 and p73 participate in the modulation of mitotic checkpoint regulatory activity and cell death during mitosis. In particular, we describe their role in the mitotic checkpoint response and cell death during mitosis, their impact on the control of ploidy, and the way that these processes cooperate to combat the chromosomal instability that leads to cancer. Finally, we evaluate p53 and p73 as key genes linking the chromosomal instability phenotype, mitotic arrest failure and cancer.
Section snippets
Mitotic checkpoint, the chromosomal instability phenotype and cancer
The major mitotic checkpoint that controls mitotic progression is known as the spindle assembly checkpoint (Figure 1) 30, 31. This signaling pathway ensures the proper alignment of the chromosomes at the metaphase plate before chromosomal segregation. The spindle assembly checkpoint is activated in every cell cycle immediately upon entry into mitosis, and it functions to delay anaphase until all chromosomes are properly attached to the microtubules [32]. The inhibitory signal comes from the
Existing links between p53 and the mitotic checkpoint
There is much evidence linking p53 and centrosome amplification 51, 52. Recently, it was shown that the transcriptional induction of p53 by mitotic checkpoint activation is essential in protecting cells from developing abnormal levels of chromosome ploidy caused by mitotic failure, as we explain below. Studies have shown that p53 deficiencies induce a insufficient mitosis arrest, compromise apoptosis, and can cause profound aneuploidy. Despite this, the molecular mechanisms implicating p53
p73 and mitotic regulation
Given that studies with p53 revealed the existence of a relationship between mitotic regulators and p53 during chromosomal instability, attention has also focused on a similar potential role for p73. The p73 proteins are modified during mitosis [64]. Indeed, Fulco and colleagues [64] showed that p73 is a physiological target of the p34Cdc2–cyclin B mitotic kinase complex in vivo. Both p73β and p73α isoforms are hyper-phosphorylated in normal mitotic cells and during mitotic arrest induced by
Involvement of p53 and p73 in the control of cellular ploidy
As reported above, the chromosomal instability phenotype is now regarded as a hallmark of certain types of cancer that have a specific signature involving mitotic regulators [45]. The discussion above suggests that a relationship exists among p53, p73 and mitotic regulators (see also [52]). It is therefore logical to investigate the involvement of p53 and p73 in the control of cellular ploidy and in the chromosomal instability phenotype. Besides the above studies, which clearly demonstrate the
Concluding remarks
As explained above, the observed effects of mitotic dysregulation in human cancer, in addition to new discoveries about the association between genetic alteration of mitotic regulators and chromosomal instability in human tumors, lend support to the view that p53 and p73 act as key modulators of pivotal mitotic proteins (Table 1). Proof of the involvement of p53 and p73 in the control of cellular ploidy – mainly through the regulation of mitotic checkpoint proteins and centrosomes – could act
Acknowledgements
We apologize to those colleagues whose work could not be cited, owing to space limitations. This work was funded by grants from l’Association de la Recherche Contre le Cancer (ARC) and la Ligue Contre le Cancer. In addition, funding was received from Telethon (GGPO4110 to G.M.), AIRC (2743), EU (LSGBH-2005–019067-Epistem; LSHC-CT-2004–503576-Active p53), FIRB-2001- RBNE01KJHT_004 (to G.M.) and RBNE01NWCH_008 (Rotilio), MIUR, MinSan (to G.M).
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