Dietary downregulation of mutant p53 levels via glucose restriction

Rodriguez, Olga; Choudhury, Sujatra; Kolukula, Vamsi Krishna; Vietsch, Eveline E.; Catania, Jason; Preet, Anju; Reynoso, Katherine; Bargonetti, Jill; Wellstein, Anton; Albanese, Chris; Avantaggiati, Maria Laura

doi:10.4161/cc.22778

Cited by 106 publications

(126 citation statements)

References 37 publications

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“…It has been reported that prolonged glucose deprivation can lead to the degradation of mutant p53 through macroautophagy (Rodriguez et al 2012). However, prolonged glucose starvation has been shown to lead to reduction of autophagy (Fuertes et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Chaperone-mediated autophagy degrades mutant p53

Vakifahmetoglu-Norberg

et al. 2013

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Missense mutations in the gene TP53, which encodes p53, one of the most important tumor suppressors, are common in human cancers. Accumulated mutant p53 proteins are known to actively contribute to tumor development and metastasis. Thus, promoting the removal of mutant p53 proteins in cancer cells may have therapeutic significance. Here we investigated the mechanisms that govern the turnover of mutant p53 in nonproliferating tumor cells using a combination of pharmacological and genetic approaches. We show that suppression of macroautophagy by multiple means promotes the degradation of mutant p53 through chaperone-mediated autophagy in a lysosome-dependent fashion. In addition, depletion of mutant p53 expression due to macroautophagy inhibition sensitizes the death of dormant cancer cells under nonproliferating conditions. Taken together, our results delineate a novel strategy for killing tumor cells that depend on mutant p53 expression by the activation of chaperone-mediated autophagy and potential pharmacological means to reduce the levels of accumulated mutant p53 without the restriction of mutant p53 conformation in quiescent tumor cells.

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Section: Discussionmentioning

confidence: 99%

Chaperone-mediated autophagy degrades mutant p53

Vakifahmetoglu-Norberg

et al. 2013

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“…16 As a consequence of the transactivation of so many different promoters so far described, p53 is able to activate different biochemical pathways affecting the regulation of life and death of the cell. A recently discovered, relevant set of novel p53 targets include the metabolism of the cell, 17,18 for example the pathways of mevalonate, 19,20 serine, 21 malate, 22 and glutaminolysis. 23 This results in the regulation of cell death 24 or cell cycle.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics of the full-length p53 monomer

Chillemi¹,

Davidovich

D’Abramo³

et al. 2013

Cell Cycle

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The p53 protein is frequently mutated in a very large proportion of human tumors, where it seems to acquire gain-of-function activity that facilitates tumor onset and progression. A possible mechanism is the ability of mutant p53 proteins to physically interact with other proteins, including members of the same family, namely p63 and p73, inactivating their function. Assuming that this interaction might occurs at the level of the monomer, to investigate the molecular basis for this interaction, here, we sample the structural flexibility of the wild-type p53 monomeric protein. The results show a strong stability up to 850 ns in the DNA binding domain, with major flexibility in the N-terminal transactivations domains (TAD1 and TAD2) as well as in the C-terminal region (tetramerization domain). Several stable hydrogen bonds have been detected between N-terminal or C-terminal and DNA binding domain, and also between N-terminal and C-terminal. Essential dynamics analysis highlights strongly correlated movements involving TAD1 and the proline-rich region in the N-terminal domain, the tetramerization region in the C-terminal domain; Lys120 in the DNA binding region. The herein presented model is a starting point for further investigation of the whole protein tetramer as well as of its mutants

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“…Wild-type p53 is typically expressed at low levels because of its degradation via the proteasome, which is controlled mainly by the E3-ubiquitin ligase MDM2. However, mutant p53 forms, which are widely expressed in tumors, are thought to be able to evade proteolysis by blocking MDM2 transcription and causing subsequent aberrant interactions (Prives and White, 2008;Brosh and Rotter, 2009;Rodriguez et al, 2012). A recent study done by Cooks et al (Cooks et al, 2013) reported the prolongation of TNF-α-induced NF-κB activation by mutant p53 in vivo in intestinal cells.…”

Section: Micrornamentioning

confidence: 98%

“…The restriction of caloric intake displays effects at the cellular and organismal levels, altering various epigenetic mechanisms and signaling pathways Mercken et al, 2013). Rodriguez et al (Rodriguez et al, 2012) were able to show a correlation between CR, in the form of glucose restriction, and a downregulation of mutant p53, which is widely expressed in a majority of tumors. It is known that cancer cells metabolize glucose at an elevated rate compared with normal cells, and it is this phenomenon that makes glucose restriction a novel therapeutic approach in the impairment of cancer growth and progression.…”

Section: Caloric Restriction Aging and Cancermentioning

confidence: 99%

“…This epigenetic alteration results in increased gene expression via hyper-acetylated histones or a decrease in gene expression due to the deacetylation of histones H3 and H4 (Murphy et al, 1999;Barlev et al, 2001;Vrba et al, 2008). However, it has been reported and widely accepted that mutant forms of p53 acquire novel oncogenic functions compared with the wild-type form (FreedPastor and Prives, 2012;Rodriguez et al, 2012). Wild-type p53 is typically expressed at low levels because of its degradation via the proteasome, which is controlled mainly by the E3-ubiquitin ligase MDM2.…”

Section: Micrornamentioning

confidence: 99%

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Epigenetic linkage of aging, cancer and nutrition

Daniel

Tollefsbol

2015

Journal of Experimental Biology

139

104

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Epigenetic mechanisms play a pivotal role in the expression of genes and can be influenced by both the quality and quantity of diet. Dietary compounds such as sulforaphane (SFN) found in cruciferous vegetables and epigallocatechin-3-gallate (EGCG) in green tea exhibit the ability to affect various epigenetic mechanisms such as DNA methyltransferase (DNMT) inhibition, histone modifications via histone deacetylase (HDAC), histone acetyltransferase (HAT) inhibition, or noncoding RNA expression. Regulation of these epigenetic mechanisms has been shown to have notable influences on the formation and progression of various neoplasms. We have shown that an epigenetic diet can influence both cellular longevity and carcinogenesis through the modulation of certain key genes that encode telomerase and p16. Caloric restriction (CR) can also play a crucial role in aging and cancer. Reductions in caloric intake have been shown to increase both the life-and health-span in a variety of animal models. Moreover, restriction of glucose has been demonstrated to decrease the incidence of age-related diseases such as cancer and diabetes. A diet rich in compounds such as genistein, SFN and EGCG can positively modulate the epigenome and lead to many health benefits. Also, reducing the quantity of calories and glucose in the diet can confer an increased health-span, including reduced cancer incidence.

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Dietary downregulation of mutant p53 levels via glucose restriction

Cited by 106 publications

References 37 publications

Chaperone-mediated autophagy degrades mutant p53

Chaperone-mediated autophagy degrades mutant p53

Molecular dynamics of the full-length p53 monomer

Epigenetic linkage of aging, cancer and nutrition

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