Tumor suppression in the absence of p53-mediated cell cycle arrest, apoptosis, and senescence

By Tongyuan Li, N. Kon, Le Jiang, M. Tan, T. Ludwig, Yingming Zhao, R. Baer, W. Gu. Cell, 2012

909 citations recorded by the source corpus.

Summary Cell-cycle arrest, apoptosis, and senescence are widely accepted as major mechanisms by which p53 inhibits tumor formation. Nevertheless, it remains unclear whether they are rate-limiting steps in tumor suppression. Here, we have generated mice bearing lysine to arginine mutations at one (p53K117R) or three (p533KR; K117R+K161R+K162R) of the critical p53 acetylation sites. While p53K117R/K117R cells are competent for p53-mediated cell-cycle arrest and senescence, but not apoptosis, all three of these processes are ablated in p533KR/3KR cells. Surprisingly, unlike p53-null mice, which rapidly succumb to spontaneous thymic lymphomas, early-onset tumor formation does not occur in either p53K117R/K117R or p533KR/3KR animals. Notably, p533KR retains the ability to modulate energy metabolism and reactive oxygen species (ROS) production by regulating metabolic p53 target genes. These findings underscore the crucial role of acetylation in differentially modulating p53 responses and suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for suppression of early-onset spontaneous tumorigenesis.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/0e2d5c7f3fdac6053b71906aa57e9d59113ded67

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Citations in the corpus

Mitochondrial reactive oxygen species and cancer (2014, background): “However, recent evidence has shown that endogenous expression of p53 with mutations that prevent its ability to cause cell cycle arrest, apoptosis, or senescence still maintains its tumor suppressive function [74].”
Targeting p53 pathways: mechanisms, structures and advances in therapy (2023, background): “…ferroptosis by increasing the biosynthesis of GSH. 127 p53 also regulates SLC7A11 expression in a non-transcriptional manner. p53(3KR ) is an acetylation-de ﬁ cient mutant that fails to induce cell cycle arrest, apoptosis and senescence, 128 but retains the ability to regulate SLC7A11 expression.”
Fundamentals of cancer metabolism (2016, background): “However, recent studies indicate that p53 tumor-suppressive actionsmight be independent of these canonical p53 activities but rather dependent on the regulation ofmetabolism and oxidative stress (20, 21).”
How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? (2017, background): “, PumaNoxap21 mice) do not spontaneously develop any tumours (Figure 4).(107,109,110) Notably, the cells from all of these mutant mice are unable to undergo apoptosis, cell cycle arrest or senescence upon p53 activation.”
Ferroptosis: mechanisms and links with diseases (2021, background): “P53(3KR), an acetylation-defective mutant that fails to induce the above process, retains the ability to suppression of early-onset spontaneous tumorigenesis.(101) The function of p53 (3KR) tumorigenesis suppression is realized by inhibiting SLC7A11 expression and inducing ferroptosis in xenograft m”
Ferroptosis: process and function (2016, background): “p53 mice lacking cell-cycle arrest, apoptosis, or senescence still exhibit tumor suppression function.(31) This tumor suppressor function of p53 is dependent on the induction of ferroptosis.”
Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses (2016, background): “Moreover, mice that harbor these mutations still retain intact tumor suppression (9).”
ROS Function in Redox Signaling and Oxidative Stress (2014, background): “Furthermore, a recent study suggested that the major tumor-suppressive function of p53 might be the regulation of antioxidant and metabolism genes rather than apoptosis and cell-cycle arrest [55].”
Mechanisms of ferroptosis (2016, background): “…model into question and it now appears that alterations in intracellular metabolism may account for the ability of p53 to suppress tumor formation [68–70]. p53-dependent effects on SLC7A11 -mediated Cys 2 uptake ﬁt within this emerging picture of p53-dependent metabolic modulation, although it…”
Senescence and apoptosis: dueling or complementary cell fates? (2014, neutral): “For instance, separation-of-function mutants show that individual acetylation sites on p53 can control the choice to senesce or apoptose [64].”