Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development

Aubrey, Brandon J.; Janic, Ana; Chen, Yunshun; Chang, Catherine; Lieschke, Elizabeth; Diepstraten, Sarah T; Kueh, Andrew J.; Bernardini, Jonathan P.; Dewson, Grant; O’Reilly, Lorraine A.; Whitehead, Lachlan; Voss, Anne K.; Smyth, Gordon K.; Strasser, Andreas; Kelly, Gemma L.

doi:10.1101/gad.314286.118

Cited by 30 publications

(26 citation statements)

References 46 publications

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“…Mutations beyond six codons called the hotspot codons account for approximately 30% of all p53 mutations and influence the protein‐DNA interactions and also the conformation of the protein (Hermeking, 2012). Many p53 mutants are reported to disrupt p53 function and drive tumorigenesis by dominant‐negative effects over normal TP53 allele; that is, when a mutant allele not only lose its tumor‐suppressive activities but also interfere with the function of wild‐type p53 in a manner advantageous for neoplastic transformation (Aubrey et al, 2018; Merkle et al, 2017). Because the p53 protein functions as a tetrameric transcription factor, mono‐allelic mutation of the p53 gene is thought to inhibit the function of wild‐type p53 protein within a heterotetrameric complex (Kamada et al, 2016).…”

Section: P53 and Cancersmentioning

confidence: 99%

P53 long noncoding RNA regulatory network in cancer development

Aravindhan

Younus

Lafta

et al. 2021

Cell Biology International

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The protein p53 as a transcription factor with strong tumor-suppressive activities is known to trigger apoptosis via multiple pathways and is directly involved in the recognition of DNA damage and DNA repair processes. P53 alteration is now recognized as a common event in the pathogenesis of many types of human malignancies. Deregulation of tumor suppressor p53 pathways plays an important role in the activation of cell proliferation or inactivation of apoptotic cell death during carcinogenesis and tumor progression. Mounting evidence indicates that the p53 status of tumors and also the regulatory functions of p53 may be relevant to the long noncoding RNAs (lncRNA)-dependent gene regulation programs. Besides

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Section: P53 and Cancersmentioning

confidence: 99%

P53 long noncoding RNA regulatory network in cancer development

Aravindhan

Younus

Lafta

et al. 2021

Cell Biology International

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“…The major functional divergences in mitochondrial apoptotic pathways observed among animals 8,80–82 mainly originated in the recruitment of paralogous actors from the same multigenic families reflecting the adaptive processes specific to each taxon, which lead ultimately to convergent evolutionary histories. Interestingly, this richness of the apoptotic genetic repertoire was suggested to be links to the persistence of stem cells in adults from different phyla 83,84 .…”

Section: Discussionmentioning

confidence: 99%

Intrinsic apoptosis is evolutionarily divergent among metazoans

Krasovec

Qeinnec

Chambon

2021

Preprint

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Apoptosis is characterised by an analogous set of morphological features1 that depend on a proteolytic multigenic family, the caspases. Each apoptotic signalling pathway involves a specific initiator caspase, upstream of the pathway regulation, which finally converges to common executioner caspases. Intrinsic apoptosis, previously known as the mitochondrial apoptotic pathway, is often considered as ancestral and evolutionary conserved among animals. First identified in the nematode Caenorhabditis elegans, intrinsic apoptosis was next characterised in fruit fly Drosophila melanogaster and mammals. Intrinsic apoptosis depends on the key initiator caspase-9 (named Ced-3 and Dronc in Caenorhabditis and Drosophila, respectively), the activator Apaf-1 and the Bcl-2 multigenic family. Many functional studies have led to a deep characterisation of intrinsic apoptosis based on those classical models. Nevertheless, the biochemical role of mitochondria, the pivotal function of cytochrome c and the modality of caspases activation remain highly heterogeneous and hide profound molecular divergences among apoptotic pathways in animals. Independent of functional approaches, the phylogenetic history of the signal transduction actors, mostly the caspase family, is the Rosetta Stone to shed light on intrinsic apoptosis evolution. Here, after exhaustive research on CARD-caspases, we demonstrate by phylogenetic analysis that the caspase-9, the fundamental key of intrinsic apoptosis, is deuterostomes-specific, while it is the caspase-2 which is ancestral and common to bilaterians. Our analysis of Bcl-2 family and Apaf-1 confirm the high heterogeneity in apoptotic pathways elaboration in animals. Taken together, our results support convergent emergence of distinct intrinsic apoptotic pathways during metazoan evolution.

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“…TP53 is one of the most important genes in human cancer. It appears that p53 protein is critical for tumor suppression not during the acute responses to cellular stress, which is characterized by extensive apoptosis, but for the killing or silencing of the cancer initiating cells that have acquired oncogenic lesions driving the neoplastic transformation [ 23 ]. Moreover, p53 provides a major barrier to tumor progression and metastasis.…”

Section: Discussionmentioning

confidence: 99%

(+)-Usnic acid modulates the Nrf2-ARE pathway in FaDu hypopharyngeal carcinoma cells

et al. 2021

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Naturally occurring phytochemicals of different origin and structure, arctigenin, bergenin, usnic acid and xanthohumol, were shown to affect Nrf2 pathway in the context of various diseases, but their effect on this pathway in cancer cells was not extensively investigated. This study aimed to evaluate the effect of these compounds on Nrf2 expression and activation in hypopharyngeal FaDu squamous cell carcinoma cells. FaDu cells were treated with 2 or 10 μM arctigenin, bergenin, (+)-usnic acid or xanthohumol for 24 h. While arctigenin, bergenin, and xanthohumol did not affect either Nrf2 expression or activation, (+)-usnic acid treatment increased its transcript level and increased the nuclear/cytosol Nrf2 protein ratio—the measure of Nrf2 pathway activation. Consequently, (+)-usnic acid enhanced the transcription and translation of Nrf2 target genes: NQO1, SOD, and to a lesser extent, GSTP. The treatment of FaDu cells with (+)-usnic acid decreased both GSK-3β transcript and protein level, indicating its possible involvement in Nrf2 activation. All the tested compounds decreased Bax mRNA but did not change the level of Bax protein. (+)-Usnic acid tended to increase the percentage of early apoptotic cells and LC3 protein, autophagy marker. Significant induction of p53 also was observed after treatment with (+)-usnic acid. In summary, the results of this study indicate that low concentrations of (+)-usnic acid activate Nrf2 transcription factor, most probably as a result of ROS accumulation, but do not lead to FaDu hypopharyngeal carcinoma cells death.

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Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development

Cited by 30 publications

References 46 publications

P53 long noncoding RNA regulatory network in cancer development

P53 long noncoding RNA regulatory network in cancer development

Intrinsic apoptosis is evolutionarily divergent among metazoans

(+)-Usnic acid modulates the Nrf2-ARE pathway in FaDu hypopharyngeal carcinoma cells

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