Structural insight into the molecular mechanism of p53-mediated mitochondrial apoptosis

Wei, Hudie; Qu, Lingzhi; Dai, Shuyan; Li, Yun; Wang, Haolan; Feng, Yuhua; Chen, Xiaojuan; Jiang, Longying; Guo, Ming; Li, Jun; Chen, Zhuchu; Chen, Lin; Zhang, Ye; Chen, Yongheng

doi:10.1038/s41467-021-22655-6

Cited by 57 publications

(39 citation statements)

References 47 publications

(76 reference statements)

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“…Mechanistically, p53's cytosolic proapoptotic function upon genotoxic stress has been suggested to be regulated through the transcription of its target gene PUMA, which in turn disrupts cytosolic BCLX/p53 complexes by competitive binding [93,95]. p53 binding of BCLX is meanwhile supported by crystal structure data [96] and has been successfully targeted in glioblastoma xenograft models to induce apoptosis [97]. Its interaction with the apoptosis effectors BAX and BAK, however, have been mainly addressed with recombinant protein studies or in overexpression settings.…”

Section: P53-induced Apoptosismentioning

confidence: 99%

At a Crossroads to Cancer: How p53-induced Cell Fate Decisions Secure Genome Integrity

Rizzotto

Englmaier

Villunger

2021

Preprint

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P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular details on how this transcription factor prevents oncogenesis or how to leverage current knowledge about its function to improve cancer treatment. Multiple cues, including DNA-damage or mitotic errors, can lead to the stabilization and nuclear translocation of p53, initiating the expression of multiple target genes. These transcriptional programs may well be cell type and stimulus-specific, as is their outcome that ultimately imposes a barrier to cellular transformation. Cell cycle arrest and cell death are two well-studied consequences of p53 activation, but, while being considered as critical, they do not fully explain the consequences of p53 loss-of-function phenotypes in cancer. Here, we discuss how mitotic errors alert the p53 network and give an overview on multiple ways how p53 can trigger cell death. We argue that a comparative analysis of different types of p53 responses, elicited by different triggers in a time-resolved manner in well-defined model systems is critical to understand cell type specific cell fate induced by p53 upon its activation, in order to resolve the remaining mystery of its tumor suppressive function.

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Section: P53-induced Apoptosismentioning

confidence: 99%

At a Crossroads to Cancer: How p53-induced Cell Fate Decisions Secure Genome Integrity

Rizzotto

Englmaier

Villunger

2021

Preprint

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“…Nuclear p53 is usually in a tetrameric state [ 20 ]. According to some studies, dimerization may occur under stress conditions when p53 interacts with Bcl-2 proteins on the outer mitochondrial membrane [ 21 , 22 ], although the non-nuclear p53 is supposed to be mostly monomeric.…”

Section: Structural Determinants Of Homo- and Heterologous Protein Co...mentioning

confidence: 99%

“…Under stress conditions, the dimers of p53 are accumulated at the outer membrane of mitochondria [ 21 ], which is essential for p53 interaction with Bcl-2 proteins [ 22 ]. In the mitochondrial matrix, p53 oligomerization into fibrillar structures may occur as a result of its interaction with prolyl peptidyl isomerase D (PPIF, cyclophilin D), known to catalyze p53 aggregation in vitro [ 50 ].…”

Section: Distribution Of Cellular P53 Between Different Compartmentsmentioning

confidence: 99%

“…Under stress, the cytosolic p53 substitutes, BAX and BID, in their complex with BCL-xl on the outer mitochondrial membrane, thus releasing these proapoptotic proteins for initiating apoptosis [ 22 ]. In addition, p53 interaction with BAX changes the BAX conformation, resulting in BAX homo-oligomerization promoting mitochondrial outer membrane permeabilization (MOMP) [ 74 ].…”

Section: Other Interaction Partners Of P53 Outside the Nucleusmentioning

confidence: 99%

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Regulation of p53 Function by Formation of Non-Nuclear Heterologous Protein Complexes

Zavileyskiy

Bunik

2022

Biomolecules

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A transcription factor p53 is activated upon cellular exposure to endogenous and exogenous stresses, triggering either homeostatic correction or cell death. Depending on the stress level, often measurable as DNA damage, the dual outcome is supported by p53 binding to a number of regulatory and metabolic proteins. Apart from the nucleus, p53 localizes to mitochondria, endoplasmic reticulum and cytosol. We consider non-nuclear heterologous protein complexes of p53, their structural determinants, regulatory post-translational modifications and the role in intricate p53 functions. The p53 heterologous complexes regulate the folding, trafficking and/or action of interacting partners in cellular compartments. Some of them mainly sequester p53 (HSP proteins, G6PD, LONP1) or its partners (RRM2B, PRKN) in specific locations. Formation of other complexes (with ATP2A2, ATP5PO, BAX, BCL2L1, CHCHD4, PPIF, POLG, SOD2, SSBP1, TFAM) depends on p53 upregulation according to the stress level. The p53 complexes with SIRT2, MUL1, USP7, TXN, PIN1 and PPIF control regulation of p53 function through post-translational modifications, such as lysine acetylation or ubiquitination, cysteine/cystine redox transformation and peptidyl-prolyl cis-trans isomerization. Redox sensitivity of p53 functions is supported by (i) thioredoxin-dependent reduction of p53 disulfides, (ii) inhibition of the thioredoxin-dependent deoxyribonucleotide synthesis by p53 binding to RRM2B and (iii) changed intracellular distribution of p53 through its oxidation by CHCHD4 in the mitochondrial intermembrane space. Increasing knowledge on the structure, function and (patho)physiological significance of the p53 heterologous complexes will enable a fine tuning of the settings-dependent p53 programs, using small molecule regulators of specific protein–protein interactions of p53.

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“…Mechanistically, p53′s cytosolic pro-apoptotic function upon genotoxic stress has been suggested to be regulated through the transcription of its target gene PUMA , which in turn disrupts cytosolic BCLX/p53 complexes by competitive binding [ 111 , 113 ]. p53 binding of BCLX is meanwhile supported by crystal structure data [ 114 ] and has been successfully targeted in glioblastoma xenograft models to induce apoptosis [ 115 ]. Its interaction with the apoptosis effectors BAX and BAK, however, has been mainly addressed with recombinant protein studies or in overexpression settings.…”

Section: P53-induced Apoptosismentioning

confidence: 99%

At a Crossroads to Cancer: How p53-Induced Cell Fate Decisions Secure Genome Integrity

Rizzotto

Englmaier

Villunger

2021

IJMS

View full text Add to dashboard Cite

P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular details on how this transcription factor prevents oncogenesis or how to leverage current knowledge about its function to improve cancer treatment. Multiple cues, including DNA-damage or mitotic errors, can lead to the stabilization and nuclear translocation of p53, initiating the expression of multiple target genes. These transcriptional programs may be cell-type- and stimulus-specific, as is their outcome that ultimately imposes a barrier to cellular transformation. Cell cycle arrest and cell death are two well-studied consequences of p53 activation, but, while being considered critical, they do not fully explain the consequences of p53 loss-of-function phenotypes in cancer. Here, we discuss how mitotic errors alert the p53 network and give an overview of multiple ways that p53 can trigger cell death. We argue that a comparative analysis of different types of p53 responses, elicited by different triggers in a time-resolved manner in well-defined model systems, is critical to understand the cell-type-specific cell fate induced by p53 upon its activation in order to resolve the remaining mystery of its tumor-suppressive function.

show abstract

Structural insight into the molecular mechanism of p53-mediated mitochondrial apoptosis

Cited by 57 publications

References 47 publications

At a Crossroads to Cancer: How p53-induced Cell Fate Decisions Secure Genome Integrity

At a Crossroads to Cancer: How p53-induced Cell Fate Decisions Secure Genome Integrity

Regulation of p53 Function by Formation of Non-Nuclear Heterologous Protein Complexes

At a Crossroads to Cancer: How p53-Induced Cell Fate Decisions Secure Genome Integrity

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