Deciphering p53 signaling in tumor suppression
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)
- et al.
Illuminating p53 function in cancer with genetically engineered mouse models
Semin Cell Dev Biol
(2014) - et al.
Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression
Cell
(2011) - et al.
Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence
Cell
(2012) - et al.
p53 activity results in DNA replication fork processivity
Cell Rep
(2016) - et al.
p53 genes function to restrain mobile elements
Genes Dev
(2015) - et al.
Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations
Nature
(2017) - et al.
A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial–mesenchymal transition
J Cell Biol
(2011) - et al.
Non-cell-autonomous tumor suppression by p53
Cell
(2013) - et al.
An oncogene-induced DNA damage model for cancer development
Science
(2008) - et al.
p53 research: the past thirty years and the next thirty years
Cold Spring Harb Perspect Biol
(2010)
Unravelling mechanisms of p53-mediated tumour suppression
Nat Rev Cancer
Timed somatic deletion of p53 in mice reveals age-associated differences in tumor progression
PLoS ONE
Tumour biology: policing of oncogene activity by p53
Nature
The pathological response to DNA damage does not contribute to p53-mediated tumour suppression
Nature
p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa
Cell Rep
Suppression of tumorigenesis by the p53 target PUMA
Proc Natl Acad Sci U S A
Combined loss of PUMA and p21 accelerates c-MYC-driven lymphoma development considerably less than loss of one allele of p53
Oncogene
p53: traffic cop at the crossroads of DNA repair and recombination
Nat Rev Mol Cell Biol
Cytokinesis failure triggers hippo tumor suppressor pathway activation
Cell
p53 maintains genomic stability by preventing interference between transcription and replication
Cell Rep
P53 and the defenses against genome instability caused by transposons and repetitive elements
Bioessays
The evolution of thymic lymphomas in p53 knockout mice
Genes Dev
p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity
Genes Dev
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
Cited by (167)
19q13.12 KRAB zinc-finger protein ZNF383 represses p53 signaling pathway by interacting with p53
2022, Cellular SignallingDistinct p53 isoforms code for opposing transcriptional outcomes
2022, Developmental CellCombined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice
2024, Cell Death and DifferentiationP53 together with ferroptosis: a promising strategy leaving cancer cells without escape
2024, Acta Biochimica et Biophysica SinicaNeoadjuvant pyrotinib plus trastuzumab and chemotherapy for HER2-positive breast cancer: a prospective cohort study
2023, World Journal of Surgical Oncology