Deciphering p53 signaling in tumor suppression

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Highlights

  • p53 responses to acute DNA damage signals are dispensable for tumor suppression.

  • p53 transcriptional activity is critical for tumor suppression.

  • p53 responds to diverse stresses and regulates a variety of cellular processes.

  • Tumor suppression likely relies on p53 coordinately regulating various processes.

The p53 transcription factor is mutated in over half of human cancers, and p53-null mice are highly predisposed to cancer, highlighting p53s essential role in tumor suppression. Studies in mouse models have revealed that p53 cell cycle arrest and apoptosis responses to acute DNA damage signals are dispensable for tumor suppression, prompting a search for new mechanisms underlying p53-mediated cancer suppression. p53 responds to other types of stress signals and regulates a host other cellular processes, including maintenance of genomic stability, metabolism, stemness, non-apoptotic cell death, migration/invasion, and cell signaling, any or all of which could be fundamental for suppressing carcinogenesis. The ability of p53 to govern numerous transcriptional programs and cellular functions likely explains its potent tumor suppressor activity.

Introduction

The gene encoding the p53 transcription factor is mutated in over half of all human cancers, reflecting its crucial role in preventing cancer [1]. This key role as a tumor suppressor is supported by observations from mouse models, where p53 inactivation results in a rapid, fully-penetrant tumor predisposition [2]. Early studies on p53 revealed that it plays a fundamental role in stress responses, especially in triggering cell cycle arrest or apoptosis in response to acute DNA damage signals [1, 3]. The p53-mediated cell cycle arrest response was envisaged to allow cells an opportunity to arrest to repair DNA damage before proceeding through the cell cycle and to thereby prevent the propagation of oncogenic mutations, while the apoptotic response was proposed to eliminate damaged or neoplastic cells. p53 was shown to trigger these responses by inducing specific downstream target genes including the CDK inhibitor p21, and the pro-apoptotic Bcl-2 family members Puma and Noxa, which are important for DNA-damage-induced cell cycle arrest and apoptosis, respectively [1, 3]. These responses provided reasonable initial explanations for the mechanisms underlying p53-mediated tumor suppression. In support of such mechanisms, evidence from various mouse tumor models has suggested that p53 restricts proliferation and triggers apoptosis in developing tumors [1, 3]. As will be described in this review, however, the picture of p53-mediated tumor suppression is much more complex than envisaged originally.

Section snippets

p53 acute DNA damage responses are dispensable for tumor suppression

In recent years, a series of studies interrogating the requirement of p53 acute DNA damage programs for cancer suppression has challenged the importance of these responses for p53-mediated tumor suppression. The first set of such studies used mice expressing temporally-regulatable versions of p53 to demonstrate that the presence of p53 during exposure to acute DNA damage is dispensable for inhibiting tumorigenesis, and that instead the ability of p53 to respond to oncogenic signals as tumors

If not acute DNA damage responses, then what?

If the p53 pathways important for acute DNA damage responses are nonessential for tumor suppression, then how does p53 work? As mentioned, there is ample evidence from various mouse tumor models that p53 inhibits cell division and induces apoptosis in tumors in vivo, yet the aforementioned studies suggest that p53-dependent acute DNA damage responses and tumor suppression can be uncoupled. How can these discrepancies be reconciled? We will consider several potential explanations, which are not

An array of cellular functions regulated by p53

Beyond inducing cell cycle arrest, senescence, and apoptosis in response to acute DNA damage, p53 also regulates various other aspects of cellular behavior (Figure 2). Given the plethora of target genes that p53 regulates, the ability of p53 to control many cellular processes is anticipated, and the coordinate regulation of many different gene expression programs presumably underlies p53s potent tumor suppressor activity. Specifically, p53 has been implicated in the following processes:

Integrating the pieces of the puzzle

The aforementioned studies demonstrate that p53 regulates many processes that could in principle contribute to tumor suppression (Figure 3). Understanding the relative contributions of these different effects of p53 to tumor suppression requires the identification of specific p53 target genes involved in each of these pathways and a genetic interrogation of such components for cancer suppression. Adding to the complexity of deciphering tumor suppression pathways is the notion that p53 governs a

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Anthony Boutelle, Kathryn Bieging-Rolett, Alyssa Kaiser, and Liz Valente for critical reading of the manuscript. We apologize to those whose work was not cited due to space constraints. This work was supported by an NCI R35 CA197591 grant to LDA.

References (48)

  • K.T. Bieging et al.

    Unravelling mechanisms of p53-mediated tumour suppression

    Nat Rev Cancer

    (2014)
  • G. Hinkal et al.

    Timed somatic deletion of p53 in mice reveals age-associated differences in tumor progression

    PLoS ONE

    (2009)
  • A. Efeyan et al.

    Tumour biology: policing of oncogene activity by p53

    Nature

    (2006)
  • M.A. Christophorou et al.

    The pathological response to DNA damage does not contribute to p53-mediated tumour suppression

    Nature

    (2006)
  • J. Valente Liz et al.

    p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa

    Cell Rep

    (2013)
  • M.T. Hemann et al.

    Suppression of tumorigenesis by the p53 target PUMA

    Proc Natl Acad Sci U S A

    (2004)
  • L.J. Valente et al.

    Combined loss of PUMA and p21 accelerates c-MYC-driven lymphoma development considerably less than loss of one allele of p53

    Oncogene

    (2016)
  • S. Sengupta et al.

    p53: traffic cop at the crossroads of DNA repair and recombination

    Nat Rev Mol Cell Biol

    (2005)
  • J. Ganem Neil et al.

    Cytokinesis failure triggers hippo tumor suppressor pathway activation

    Cell

    (2014)
  • C.Q. Yeo et al.

    p53 maintains genomic stability by preventing interference between transcription and replication

    Cell Rep

    (2016)
  • A.J. Levine et al.

    P53 and the defenses against genome instability caused by transposons and repetitive elements

    Bioessays

    (2016)
  • C. Dudgeon et al.

    The evolution of thymic lymphomas in p53 knockout mice

    Genes Dev

    (2014)
  • A. Tovy et al.

    p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity

    Genes Dev

    (2017)
  • I.Y. Park et al.

    Deregulation of DNA methyltransferases and loss of parental methylation at the insulin-like growth factor II (Igf2)/H19 loci in p53 knockout mice prior to tumor development

    J Cell Biochem

    (2005)
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