New plays in the p53 theater
Introduction
Humans with germline p53 mutations are affected by the Li-Fraumeni syndrome, characterized by very high cancer susceptibility [1, 2]. p53 knockout mice develop tumors with short latency and 100% penetrance [3]. In approximately 50% of human cancers p53 is mutated; in many of the remaining 50%, the function of the retained wild type (wt) p53 protein is compromised by deregulation of upstream or downstream components of the p53 pathway [4]. En masse, these observations demonstrate the critical role of p53 in tumor prevention.
In unstressed cells, p53 is constitutively restrained by Mdm2, an E3 ubiquitin ligase that promotes p53 degradation; the Mdm2 gene is positively regulated by p53, defining a negative feedback loop that controls p53 activity. Cellular stress relieves Mdm2's inhibitory effects, triggering p53 stabilization and activation. Once activated, p53 facilitates DNA repair and inhibits the proliferation of potentially tumorigenic cells, chiefly through instigating cell cycle arrest, senescence or apoptosis.
The p53 response is elicited by a wide variety of stress signals conducive to or associated with malignant transformation, such as DNA damage, oncogene activation, abnormal mitosis, loss of cell–cell contact and hypoxia [5]. Although seemingly dissimilar, many of these signals may actually converge on one another. Biochemically, p53 is a potent transcriptional regulator capable of controlling the expression of hundreds of genes [4, 5]. Within this context, it interacts with numerous cofactors and binding partners that modulate its transcriptional output. The p53 gene family includes two additional members, p63 and p73, also acting as transcriptional modulators.
The great interest in p53 has spawned numerous excellent reviews. Therefore, we will focus only on a limited set of recent studies, pertaining particularly to new functions of p53 and family.
Section snippets
p53 and metabolism
Recent years have seen a renaissance of interest in the links between cancer and metabolism; p53 research is no exception.
p53 engages in an intricate interplay with reactive oxygen species (ROS). Under conditions of mild, physiological oxidative stress, p53 preferentially induces expression of antioxidant genes; when ROS production is aberrantly high, p53 instead activates pro-oxidant genes that may facilitate apoptosis, along with overt proapoptotic genes such as PUMA, Bax and Pig3 [6•].
p53 and non-coding RNAs
MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate protein levels by binding to specific mRNAs, inhibiting their translation and often also accelerating their degradation. As is the case for protein-coding mRNAs, miRNA expression patterns are also grossly altered in cancer. p53 modulates the expression of numerous miRNA species, including miR-34a,b and c [17, 18]. It may not be coincidental that some of the mRNA species targeted by p53-responsive miRNAs are also directly
The p53 family and tumor cell invasion
Increased invasiveness of cancer cells is a major driver of metastasis and malignancy. This has not escaped the attention of p53 and its family member p63 (Figure 3). Loss of p53 augments cancer cell invasion [27]; conversely, p53 activation suppresses migration and invasion [28]. This inhibitory effect of p53 is partly mediated by Mdm2, which promotes the ubiquitination and degradation of Slug and Snail, pivotal transcription factors that drive tumor cell invasiveness [29, 30]. The
p53 in stem cells (SCs) and aging — two sides of the same coin?
Recently, there has been a flourish of publications demonstrating that p53 deficiency facilitates reprogramming of differentiated cells into induced pluripotent stem (iPS) cells, closely resembling embryonic stem (ES) cells [42•, 43•, 44•, 45•, 46•]. The exact nature of the antagonism between p53 and reprogramming pathways is still debated. One possibility is that the iPS procedure indirectly causes DNA damage, driving p53 to activate a barrier of anti-proliferative senescence [47, 48].
Conclusion
Since its discovery more than 30 years ago, a massive amount of data has accumulated that attests to the tumor suppressing role of p53. However, as we keep exploring the intricacies of p53 activity, more and more of its diverse functions are cropping up. The field of tumor suppression is experiencing a growing interest in «esoteric» subjects such as metabolism and SCs. Perhaps, with knowledge from this broader picture, we will also better understand the workings of cancer cells.
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
Work in the authors’ laboratories is supported by grants from the National Cancer Institute (R37 CA40099), the Flight Attendant Medical Research Institute, the European Commission (OncomiRs, FP7 Contract 201102 and INFLACARE, FP7 Contract 223151), the Robert Bosch Foundation, and the M.D. Moross Cancer Institute. M.O. is the incumbent of the Andre Lwoff Professorial Chair in Molecular Biology at the Weizmann Institute.
References (62)
p53 and the Li-Fraumeni syndrome
Cancer Genet Cytogenet
(1993)- et al.
Blinded by the light: the growing complexity of p53
Cell
(2009) - et al.
p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation
Nat Cell Biol
(2008) - et al.
A pivotal role for p53: balancing aerobic respiration and glycolysis
J Bioenerg Biomembr
(2007) - et al.
AMP-activated protein kinase induces a p53-dependent metabolic checkpoint
Mol Cell
(2005) - et al.
The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways
Cancer Res
(2007) - et al.
Transcriptional activation of miR-34a contributes to p53-mediated apoptosis
Mol Cell
(2007) - et al.
p53-Responsive micrornas 192 and 215 are capable of inducing cell cycle arrest
Cancer Res
(2008) - et al.
Regulation of VDR by deltaNp63alpha is associated with inhibition of cell invasion
J Cell Sci
(2009) - et al.
Mutant p53 drives invasion by promoting integrin recycling
Cell
(2009)
The Ink4/Arf locus is a barrier for iPS cell reprogramming
Nature
Mutant p53 facilitates somatic cell reprogramming and augments the malignant potential of reprogrammed cells
J Exp Med
Induced pluripotent stem cells and senescence: learning the biology to improve the technology
EMBO Rep
p53 regulates hematopoietic stem cell quiescence
Cell Stem Cell
Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older populations
Proc Natl Acad Sci USA
Tumourigenesis associated with the p53 tumour suppressor gene
Br J Cancer
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
Nature
The first 30 years of p53: growing ever more complex
Nat Rev Cancer
The antioxidant function of the p53 tumor suppressor
Nat Med
Brick by brick: metabolism and tumor cell growth
Curr Opin Genet Dev
TIGAR, a p53-inducible regulator of glycolysis and apoptosis
Cell
The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein
Trends Cell Biol
The coordinate regulation of the p53 and mTOR pathways in cells
Proc Natl Acad Sci USA
DRAM, a p53-induced modulator of autophagy, is critical for apoptosis
Cell
Regulation of autophagy by cytoplasmic p53
Nat Cell Biol
A microRNA component of the p53 tumour suppressor network
Nature
p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC
Cell Death Differ
miR-34a repression of SIRT1 regulates apoptosis
Proc Natl Acad Sci USA
p53 represses c-Myc through induction of the tumor suppressor miR-145
Proc Natl Acad Sci USA
p53-Repressed miRNAs are involved with E2F in a feed-forward loop promoting proliferation
Mol Syst Biol
Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals
Nature
Cited by (89)
Concurrent TP53 Mutation and Deletion in Refractory Low-grade Follicular Lymphoma
2021, Clinical Lymphoma, Myeloma and LeukemiaCitation Excerpt :In addition to chromosomal abnormalities, molecular mutations in KMT2D (MLL2) (approximately 85%), TNFRSF14 (45%-65%), EZH2 (approximately 60%), EPHA7 (approximately 70%), BCL6 (approximately 45%) and CREBPP (approximately 33%) are some of the genes mutated commonly in FL.13 TP53 is a tumor suppressor gene with the ability to induce cell cycle arrest, DNA repair, senescence and apoptosis.14 Mutations and deletions of TP53 are the most frequent (>50%) genetic alterations detected in human tumors.15
Role of the GH-IGF1 system in progression of cancer
2020, Molecular and Cellular EndocrinologyP-MAPA activates TLR2 and TLR4 signaling while its combination with IL-12 stimulates CD4+ and CD8+ effector T cells in ovarian cancer
2020, Life SciencesCitation Excerpt :In non-cancer cells, IL-1β cytokine can stimulate the NF-kB and IRF7 through a MyD88-dependent pathway with TRAF6 promoting the upregulation of IL-6, TNF-α, IFN-α, IFN-β and IFN-γ expression [49]. The activity of IL-1β in OC samples has been associated with poor prognosis [46,50]; furthermore IL-1β was secreted by OC cells suppressing the p53 expression and the genomic integrity [51]. In our study, the P-MAPA+IL-12 treatment increased the IL-1β levels in the serum of animals possibly indicating a stimulation of this process against the OC progression.
A comprehensive study of p53 protein
2022, Journal of Cellular Biochemistry