Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy ...represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours' aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future.
Regulation of Adult Neurogenesis in Mammalian Brain Niklison-Chirou, Maria Victoria; Agostini, Massimiliano; Amelio, Ivano ...
International journal of molecular sciences,
07/2020, Letnik:
21, Številka:
14
Journal Article
Recenzirano
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Adult neurogenesis is a multistage process by which neurons are generated and integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized ...niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Neurogenesis plays a fundamental role in postnatal brain, where it is required for neuronal plasticity. Moreover, perturbation of adult neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative diseases. The interplay between extrinsic and intrinsic factors is fundamental in regulating neurogenesis. Over the past decades, several studies on intrinsic pathways, including transcription factors, have highlighted their fundamental role in regulating every stage of neurogenesis. However, it is likely that transcriptional regulation is part of a more sophisticated regulatory network, which includes epigenetic modifications, non-coding RNAs and metabolic pathways. Here, we review recent findings that advance our knowledge in epigenetic, transcriptional and metabolic regulation of adult neurogenesis in the SGZ of the hippocampus, with a special attention to the p53-family of transcription factors.
p73 (encoded by TP73 gene) is a p53 related protein that functions as a transcriptional factor. Similarly to p53, following DNA damage, p73 is stabilized and activated and controls expression of ...target genes that are involved in the regulation of cycle arrest and apoptosis. However, great complexity to the function of this gene is given by the wide range of its non-tumor-related roles, which include neurological development, ciliogenesis and fertility. From the structural point of view, p73 displays an intricate range of regulations because it can be expressed both as an N-terminally deleted dominant-negative isoforms and as multiple alternatively spliced C-terminal isoforms, which can include or not a sterile alpha motif domain. More is known about the functions of the N-terminal isoforms of p73 (TAp73 and ΔNp73) and their opposing pro- and anti-apoptotic roles, whereas the functional differences of the distinct C-terminal splice forms of p73 are very far away from been defined. Here we summarize the current available literature regarding p73 C-terminal isoforms and the contribution of the sterile alpha motif domain to p73 function, trying to provide an unified view in this complex and sometime controversial field. Current data indicate that the full-length, TAp73α, is the major, if not the exclusive, isoform detected in physiological systems, indicating that detailed spatio-temporal expression analysis and functional studies are highly demanded to support a physiological role for the p73 alternative splicing. With this article, we also aim to emphasize the need to further investigation on the topic, refocusing the attention on what we believe are the most relevant unanswered questions.
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•p73 is a p53 family member involved in tumor suppression and development.•Alternative splicing and dual promoter usage generate a wide range of p73 isoforms.•Alternative splicing at the C-terminal region of p73 generates at least seven different splice forms.•The current data indicate that the full-length p73 isoform, p73α, is the major expressed form and is required for p73 function.
The mutation of TP53 gene affects half of all human cancers, resulting in impairment of the regulation of several cellular functions, including cell cycle progression and cell death in response to ...genotoxic stress. In the recent years additional p53-mediated tumour suppression mechanisms have been described, questioning the contribution of its canonical pathway for tumour suppression. These include regulation of alternative cell death modalities (i.e. ferroptosis), cell metabolism and the emerging role in RNA stability. Here we briefly summarize our knowledge on p53 "canonical DNA damage response" and discuss the most relevant recent findings describing potential mechanistic explanation of p53-mediated tumour suppression.
The
genomic locus is a target of mutational events in at least half of cancers. Despite several decades of study, a full consensus on the relevance of the acquisition of p53 gain-of-function missense ...mutants has not been reached. Depending on cancer type, type of mutations and other unidentified factors, the relevance for tumour development and progression of the oncogenic signalling directed by p53 mutants might significantly vary, leading to inconsistent observations that have fuelled a long and fierce debate in the field. Here, we discuss how interaction with the microenvironment and stressors might dictate the gain-of-function effects exerted by individual mutants. We report evidence from the most recent literature in support of the context dependency of p53 mutant biology. This perspective article aims to raise a discussion in the field on the relevance that context might have on p53 gain-of-function mutants, assessing whether this should generally be considered a cell non-autonomous process.
The transcription factor p63 mediates distinct cellular responses, primarily regulating epithelial and oocyte biology. In addition to the two amino terminal isoforms, TAp63 and ΔNp63, the 3'-end of ...p63 mRNA undergoes tissue-specific alternative splicing that leads to several isoforms, including p63α, p63β and p63γ. To investigate in vivo how the different isoforms fulfil distinct functions at the cellular and developmental levels, we developed a mouse model replacing the p63α with p63β by deletion of exon 13 in the Trp63 gene. Here, we report that whereas in two organs physiologically expressing p63α, such as thymus and skin, no abnormalities are detected, total infertility is evident in heterozygous female mice. A sharp reduction in the number of primary oocytes during the first week after birth occurs as a consequence of the enhanced expression of the pro-apoptotic transcriptional targets Puma and Noxa by the tetrameric, constitutively active, TAp63β isoform. Hence, these mice show a condition of ovary dysfunction, resembling human primary ovary insufficiency. Our results show that the p63 C-terminus is essential in TAp63α-expressing primary oocytes to control cell death in vivo, expanding the current understanding of human primary ovarian insufficiency.
Aetiogenesis of cancer has not been fully determined. Recent advances have clearly defined a role for microenvironmental factors in cancer progression and initiation; in this context, microbiome has ...recently emerged with a number of reported correlative and causative links implicating alterations of commensal microbes in tumorigenesis. Bacteria appear to have the potential to directly alter physiological pathways of host cells and in specific circumstances, such as the mutation of the tumour suppressive factor p53, they can also directly switch the function of a gene from oncosuppressive to oncogenic. In this minireview, we report a number of examples on how commensal microbes alter the host cell biology, affecting the oncogenic process. We then discuss more in detail how interaction with the gut microbiome can affect the function of p53 mutant in the intestinal tumorigenesis.
The tumor suppressor p53 regulates different cellular pathways involved in cell survival, DNA repair, apoptosis, and senescence. However, according to an increasing number of studies, the ...p53-mediated canonical DNA damage response is dispensable for tumor suppression. p53 is involved in mechanisms regulating many other cellular processes, including metabolism, autophagy, and cell migration and invasion, and these pathways might crucially contribute to its tumor suppressor function. In this review we summarize the canonical and non-canonical functions of p53 in an attempt to provide an overview of the potentially crucial aspects related to its tumor suppressor activity.
Nuclear organisation and architecture are essential for the maintenance of genomic integrity as well as for the epigenetic regulations and gene expression. Disruption of lamin B1, major structural ...and functional member of the nuclear lamina, is observed in human laminopathies and in sporadic cancers, and leads to chromosomal rearrangements and alterations of gene expression. The tumour suppressor p53 has been shown to direct specific transcriptional programmes by regulating lamin A/C, however its relationship with lamin B1 has remained elusive. Here, we show that loss of p53 correlates with increased expression of members belonging to the nuclear pore complex and nuclear lamina and directly regulates transcription of lamin B1. We show that the genomic loci of a fraction of p53-dependent genes physically interact with lamin B1 and Nup210. This observation provides a possible mechanistic explanation for the p53-depedent changes of chromatin accessibility, with the consequent influence of expression and rearrangement of these genomic sites in pancreatic cancer. Overall, these data suggest a potential functional and biochemical regulatory network connecting p53 and nuclear architecture.
Most inactivating mutations in TP53 gene generates neomorphic forms of p53 proteins that experimental evidence and clinical observations suggest to exert gain-of-function effects. While massive ...effort has been deployed in the dissection of wild type p53 transcriptional programme, p53 mutant pro-tumorigenic gene network is still largely elusive. To help dissecting the molecular basis of p53 mutant GOF, we performed an analysis of a fully annotated genomic and transcriptomic human pancreatic adenocarcinoma to select candidate players of p53 mutant network on the basis their differential expression between p53 mutant and p53 wild-type cohorts and their prognostic value. We identified NUAK2 and RCan2 whose p53 mutant GOF-dependent regulation was further validated in pancreatic cancer cellular model. Our data demonstrated that p53
can physically bind RCan2 gene locus in regulatory regions corresponding to the chromatin permissive areas where known binding partners of p53 mutant, such as p63 and Srebp, bind. Overall, starting from clinically relevant data and progressing into experimental validation, our work suggests NUAK2 and RCan2 as novel candidate players of the p53 mutant pro-tumorigenic network whose prognostic and therapeutic interest might attract future studies.
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