p73 isoforms meet evolution of metastasis

Logotheti, Stella; Pavlopoulou, Athanasia; Marquardt, Stephan; Takan, Işıl; Georgakilas, Alexandros G.; Stiewe, Thorsten

doi:10.1007/s10555-022-10057-z

Cited by 11 publications

(8 citation statements)

References 123 publications

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“…For example, while wild-type TP53 induces radiosensitivity, expression of its missense mutants correlates with radioresistance [ 124 ]. Similarly, TP73, a sibling of TP53, synthesizes not only full-length TAp73 isoforms, which sensitize cells to irradiation, but also N-terminal truncated isoforms that are generated via aberrant splicing or alternative promoter usage at the 5’end and act as dominant negative inhibitors of their TAp73 counterparts, favoring resistance to radiation [ 125 , 126 ]. In cases of such genes, where their various protein products exert divergent effects on DDR and radiosensitivity, our database detects general associations with irradiation, without deciphering among the functionally divergent isoforms.…”

Section: Discussionmentioning

confidence: 99%

Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues

et al. 2022

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Ionizing radiation (IR) is a genuine genotoxic agent and a major modality in cancer treatment. IR disrupts DNA sequences and exerts mutagenic and/or cytotoxic properties that not only alter critical cellular functions but also impact tissues proximal and distal to the irradiated site. Unveiling the molecular events governing the diverse effects of IR at the cellular and organismal levels is relevant for both radiotherapy and radiation protection. Herein, we address changes in the expression of mammalian genes induced after the exposure of a wide range of tissues to various radiation types with distinct biophysical characteristics. First, we constructed a publicly available database, termed RadBioBase, which will be updated at regular intervals. RadBioBase includes comprehensive transcriptomes of mammalian cells across healthy and diseased tissues that respond to a range of radiation types and doses. Pertinent information was derived from a hybrid analysis based on stringent literature mining and transcriptomic studies. An integrative bioinformatics methodology, including functional enrichment analysis and machine learning techniques, was employed to unveil the characteristic biological pathways related to specific radiation types and their association with various diseases. We found that the effects of high linear energy transfer (LET) radiation on cell transcriptomes significantly differ from those caused by low LET and are consistent with immunomodulation, inflammation, oxidative stress responses and cell death. The transcriptome changes also depend on the dose since low doses up to 0.5 Gy are related with cytokine cascades, while higher doses with ROS metabolism. We additionally identified distinct gene signatures for different types of radiation. Overall, our data suggest that different radiation types and doses can trigger distinct trajectories of cell-intrinsic and cell-extrinsic pathways that hold promise to be manipulated toward improving radiotherapy efficiency and reducing systemic radiotoxicities.

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Section: Discussionmentioning

confidence: 99%

Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues

et al. 2022

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“…The emerging field of evolutionary medicine or “Darwinian medicine” allows the investigation of human diseases from an evolutionary perspective ( Nesse, 2001 ; Kranke, 2022 ; Logotheti et al, 2022 ). Thus, deciphering the genetic and molecular factors/mechanisms that contribute to shaping disease evolution, by examining their conservation across diverse species, would probably increase our knowledge regarding the etiology, development, progression and treatment of chronic diseases like cancer ( Lineweaver, Davies & Vincent, 2014 ; Marquardt et al, 2021 ; Trigos et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“In the light of evolution:” keratins as exceptional tumor biomarkers

Takan

Karakülah

Louka

et al. 2023

PeerJ

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Keratins (KRTs) are the intermediate filament-forming proteins of epithelial cells, classified, according to their physicochemical properties, into “soft” and “hard” keratins. They have a key role in several aspects of cancer pathophysiology, including cancer cell invasion and metastasis, and several members of the KRT family serve as diagnostic or prognostic markers. The human genome contains both, functional KRT genes and non-functional KRT pseudogenes, arranged in two uninterrupted clusters on chromosomes 12 and 17. This characteristic renders KRTs ideal for evolutionary studies. Herein, comprehensive phylogenetic analyses of KRT homologous proteins in the genomes of major taxonomic divisions were performed, so as to fill a gap in knowledge regarding the functional implications of keratins in cancer biology among tumor-bearing species. The differential expression profiles of KRTs in diverse types of cancers were investigated by analyzing high-throughput data, as well. Several KRT genes, including the phylogenetically conserved ones, were found to be deregulated across several cancer types and to participate in a common protein-protein interaction network. This indicates that, at least in cancer-bearing species, these genes might have been under similar evolutionary pressure, perhaps to support the same important function(s). In addition, semantic relations between KRTs and cancer were detected through extensive text mining. Therefore, by applying an integrative in silico pipeline, the evolutionary history of KRTs was reconstructed in the context of cancer, and the potential of using non-mammalian species as model organisms in functional studies on human cancer-associated KRT genes was uncovered.

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“…These core mutations are also referred to as temperature sensitive mutations because DNA binding is retained at low temperatures, which do not induce global unfolding. In contrast to p53 and p63, to date neither cancer nor other human diseases have been linked to mutations in the p73 gene [ 3 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree

et al. 2023

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The transcription factor p63 shares a high sequence identity with the tumour suppressor p53 which manifests itself in high structural similarity and preference for DNA sequences. Mutations in the DNA binding domain (DBD) of p53 have been studied in great detail, enabling a general mechanism-based classification. In this study we provide a detailed investigation of all currently known mutations in the p63 DBD, which are associated with developmental syndromes, by measuring their impact on transcriptional activity, DNA binding affinity, zinc binding capacity and thermodynamic stability. Some of the mutations we have further characterized with respect to their ability to convert human dermal fibroblasts into induced keratinocytes. Here we propose a classification of the p63 DBD mutations based on the four different mechanisms of DNA binding impairment which we identified: direct DNA contact, zinc finger region, H2 region, and dimer interface mutations. The data also demonstrate that, in contrast to p53 cancer mutations, no p63 mutation induces global unfolding and subsequent aggregation of the domain. The dimer interface mutations that affect the DNA binding affinity by disturbing the interaction between the individual DBDs retain partial DNA binding capacity which correlates with a milder patient phenotype.

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p73 isoforms meet evolution of metastasis

Cited by 11 publications

References 123 publications

Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues

Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues

“In the light of evolution:” keratins as exceptional tumor biomarkers

Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree

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