Taking up the reins of power: metabolic functions of p53

Humpton, Timothy J.; Vousden, Karen H.

doi:10.1093/jmcb/mjz065

Cited by 20 publications

(25 citation statements)

References 58 publications

(62 reference statements)

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“…p53 is activated in response to various oncogenic stresses and behaves as a tumor suppressor via canonical tumor suppressive functions, including regulating the cell cycle, senescence and apoptosis, and non-canonical functions, such as metabolic stress modulation [32,33]. Recent studies have demonstrated that p53 is stabilized in PSMD14knockdown cells and that depletion of PSMD14 may induce cancer cell apoptosis mediated by p53 activation [19].…”

Section: Discussionmentioning

confidence: 99%

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PSMD7 downregulation suppresses lung cancer progression by regulating the p53 pathway

Xu¹,

Xuan²,

Zhang³

et al. 2021

J. Cancer

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Lung cancer is the second most common cancer in both men and women. The deubiquitinase PSMD7, as a core component of the 26S proteasome, is critical for the degradation of ubiquitinated proteins in the proteasome. Currently, PSMD7 expression and its roles in the progression of lung cancer remain largely unknown. In this study, we assessed PSMD7 expression and investigated the underlying molecular events by which PSMD7 regulates tumor progression in non-small cell lung cancer (NSCLC). The results showed that PSMD7 is more highly expressed in NSCLC tissues than in adjacent noncancerous tissues. PSMD7 expression was also closely associated with lymph node invasion and the laterality of the tumor in lung adenocarcinoma (LUAD). A high PSMD7 level predicted poor overall survival (OS) and disease-free survival (DFS) in LUAD patients, and PSMD7 knockdown significantly reduced cell proliferation and induced G0/G1-phase cell cycle arrest, cell senescence and apoptosis. PSMD7 knockdown inhibited expression of a set of proteins regulating cell cycle progression. Depletion of PSMD7 increased p53 levels and induced p21 and puma expression in a p53-dependent manner. Importantly, knockdown of PSMD7 markedly inhibited LUAD tumor growth in a xenograft mouse model. Taken together, these findings indicate that PSMD7 may serve as a valuable prognostic indicator and potential therapeutic target in LUAD.

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Section: Discussionmentioning

confidence: 99%

“…Bortezomib, a proteasome inhibitor, has been demonstrated to cause apoptosis in solid tumors [29]. Previous studies have shown that bortezomib induces apoptotic cell death in either a p53-dependent or p53-independent manner [32,33]. Notably, targeting PSMD7 may inhibit tumor growth in both p53 wild-type and mutant tumor types.…”

Section: Discussionmentioning

confidence: 99%

PSMD7 downregulation suppresses lung cancer progression by regulating the p53 pathway

Xu¹,

Xuan²,

Zhang³

et al. 2021

J. Cancer

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“…A cell line with WT p53, but not one with mutant p53, up-regulated p53 and its target p21 leading to growth suppression, which could be rescued by re-expressing ME2. The p53 response, rather than being specifically related to the ME2 pathway, may have reflected a more general association between AMPK and p53, both of which respond to ATP deficits by reducing energy-intensive functions such as protein translation, DNA replication and cell division [ 264 , 265 ].…”

Section: Malic Enzymes (Mes)mentioning

confidence: 99%

The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells

Prochownik

Wang

2021

Cells

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Pyruvate occupies a central metabolic node by virtue of its position at the crossroads of glycolysis and the tricarboxylic acid (TCA) cycle and its production and fate being governed by numerous cell-intrinsic and extrinsic factors. The former includes the cell’s type, redox state, ATP content, metabolic requirements and the activities of other metabolic pathways. The latter include the extracellular oxygen concentration, pH and nutrient levels, which are in turn governed by the vascular supply. Within this context, we discuss the six pathways that influence pyruvate content and utilization: 1. The lactate dehydrogenase pathway that either converts excess pyruvate to lactate or that regenerates pyruvate from lactate for use as a fuel or biosynthetic substrate; 2. The alanine pathway that generates alanine and other amino acids; 3. The pyruvate dehydrogenase complex pathway that provides acetyl-CoA, the TCA cycle’s initial substrate; 4. The pyruvate carboxylase reaction that anaplerotically supplies oxaloacetate; 5. The malic enzyme pathway that also links glycolysis and the TCA cycle and generates NADPH to support lipid bio-synthesis; and 6. The acetate bio-synthetic pathway that converts pyruvate directly to acetate. The review discusses the mechanisms controlling these pathways, how they cross-talk and how they cooperate and are regulated to maximize growth and achieve metabolic and energetic harmony.

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“…Beyond the AMPK-mTOR signaling, several of the metabolic effects of mutant p53 oppose the metabolic functions commonly acquired by the wild-type protein, including glycolysis, lipid metabolism, the mevalonate pathway, de novo serine synthesis, urea cycle and oxidative phosphorylation ( 107 , 108 ) ( Figure 1 ). Thus, it is well known that mutant p53 rewires cancer metabolism ( 109 ).…”

Section: Mutant P53 As a Regulator Of Autophagymentioning

confidence: 99%

Mutant p53 as a Regulator and Target of Autophagy

Shi

Norberg

Vakifahmetoglu-Norberg

2021

Front. Oncol.

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One of the most notoriously altered genes in human cancer is the tumor-suppressor TP53, which is mutated with high frequency in more cancers than any other tumor suppressor gene. Beyond the loss of wild-type p53 functions, mutations in the TP53 gene often lead to the expression of full-length proteins with new malignant properties. Among the defined oncogenic functions of mutant p53 is its effect on cell metabolism and autophagy. Due to the importance of autophagy as a stress adaptive response, it is frequently dysfunctional in human cancers. However, the role of p53 is enigmatic in autophagy regulation. While the complex action of the wild-type p53 on autophagy has extensively been described in literature, in this review, we focus on the conceivable role of distinct mutant p53 proteins in regulating different autophagic pathways and further discuss the available evidence suggesting a possible autophagy stimulatory role of mutant p53. Moreover, we describe the involvement of different autophagic pathways in targeting and degrading mutant p53 proteins, exploring the potential strategies of targeting mutant p53 in cancer by autophagy.

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Taking up the reins of power: metabolic functions of p53

Cited by 20 publications

References 58 publications

PSMD7 downregulation suppresses lung cancer progression by regulating the p53 pathway

PSMD7 downregulation suppresses lung cancer progression by regulating the p53 pathway

The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells

Mutant p53 as a Regulator and Target of Autophagy

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