p63-related signaling at a glance

Fisher, Mike; Balinth, Seamus; Mills, Alea A.

doi:10.1242/jcs.228015

Cited by 67 publications

(61 citation statements)

References 124 publications

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“…Although originally thought of in terms of modifying p53 activities, it is now clear that p63 is p53‐independent, acting as a master regulator of epidermal development and with roles in mesenchymal‐derived cells and germ cell maintenance. Whilst many transcriptional targets of p63 have been identified [5–7], much less is known about how p63 is itself regulated, which is important for understanding function and for rational design and application of p63‐targeting therapeutics.…”

Section: The P53/p63/p73 Familymentioning

confidence: 99%

The foggy world(s) of p63 isoform regulation in normal cells and cancer

Pokorná

Vysloužil

Hrabal

et al. 2021

The Journal of Pathology

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The p53 family member p63 exists as two major protein variants (TAp63 and ΔNp63) with distinct expression patterns and functional properties. Whilst downstream target genes of p63 have been studied intensively, how p63 variants are themselves controlled has been relatively neglected. Here, we review advances in understanding ΔNp63 and TAp63 regulation, highlighting their distinct pathways. TAp63 has roles in senescence and metabolism, and in germ cell genome maintenance, where it is activated post‐transcriptionally by phosphorylation cascades after DNA damage. The function and regulation of TAp63 in mesenchymal and haematopoietic cells is less clear but may involve epigenetic control through DNA methylation. ΔNp63 functions to maintain stem/progenitor cells in various epithelia and is overexpressed in squamous and certain other cancers. ΔNp63 is transcriptionally regulated through multiple enhancers in concert with chromatin modifying proteins. Many signalling pathways including growth factors, morphogens, inflammation, and the extracellular matrix influence ΔNp63 levels, with inconsistent results reported. There is also evidence for reciprocal regulation, including ΔNp63 activating its own transcription. ΔNp63 is downregulated during cell differentiation through transcriptional regulation, while post‐transcriptional events cause proteasomal degradation. Throughout the review, we identify knowledge gaps and highlight discordances, providing potential explanations including cell‐context and cell–matrix interactions. Identifying individual p63 variants has roles in differential diagnosis and prognosis, and understanding their regulation suggests clinically approved agents for targeting p63 that may be useful combination therapies for selected cancer patients. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: The P53/p63/p73 Familymentioning

confidence: 99%

The foggy world(s) of p63 isoform regulation in normal cells and cancer

Pokorná

Vysloužil

Hrabal

et al. 2021

The Journal of Pathology

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“…Interestingly, we found that all mouse VDAC promoters bear specific motifs in their sequences recognized by the family of the p53 tumor suppressor transcription factors, including p63 in addition to p53. Their role in cell death, cell-cycle arrest, senescence, and metabolic regulation in response to cellular stress is well-known to affect cancer development (Chillemi et al, 2017 ; Fisher et al, 2020 ). Conservation of these TF families in mouse VDAC promoters allows us to hypothesize that the VDAC proteins are crucial in mitochondrial metabolism and in the balance of cell life and death.…”

Section: Vdac Gene Promoter and Transcription Factor Binding Sites Distributionmentioning

confidence: 99%

VDAC Genes Expression and Regulation in Mammals

et al. 2021

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VDACs are pore-forming proteins, coating the mitochondrial outer membrane, and playing the role of main regulators for metabolites exchange between cytosol and mitochondria. In mammals, three isoforms have evolutionary originated, VDAC1, VDAC2, and VDAC3. Despite similarity in sequence and structure, evidence suggests different biological roles in normal and pathological conditions for each isoform. We compared Homo sapiens and Mus musculus VDAC genes and their regulatory elements. RNA-seq transcriptome analysis shows that VDAC isoforms are expressed in human and mouse tissues at different levels with a predominance of VDAC1 and VDAC2 over VDAC3, with the exception of reproductive system. Numerous transcript variants for each isoform suggest specific context-dependent regulatory mechanisms. Analysis of VDAC core promoters has highlighted that, both in a human and a mouse, VDAC genes show features of TATA-less ones. The level of CG methylation of the human VDAC genes revealed that VDAC1 promoter is less methylated than other two isoforms. We found that expression of VDAC genes is mainly regulated by transcription factors involved in controlling cell growth, proliferation and differentiation, apoptosis, and bioenergetic metabolism. A non-canonical initiation site termed “the TCT/TOP motif,” the target for translation regulation by the mTOR pathway, was identified in human VDAC2 and VDAC3 and in every murine VDACs promoter. In addition, specific TFBSs have been identified in each VDAC promoter, supporting the hypothesis that there is a partial functional divergence. These data corroborate our experimental results and reinforce the idea that gene regulation could be the key to understanding the evolutionary specialization of VDAC isoforms.

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“…These isoforms are created by the use of two different N-terminal promotors that create either proteins containing the full-length transactivation domain (TA-isoforms) or with a truncated transactivation domain (∆N-isoforms). The different N-termini are combined with several different C-termini created by splicing events [22][23][24]. The expression of TAp63α, the longest and only expressed isoform in oocytes, increases around the time of birth, with approximately 20% of oocytes showing expression at E18.5 [25].…”

Section: Double-strand Break Checkpointmentioning

confidence: 99%

DNA Damaged Induced Cell Death in Oocytes

et al. 2020

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The production of haploid gametes through meiosis is central to the principle of sexual reproduction. The genetic diversity is further enhanced by exchange of genetic material between homologous chromosomes by the crossover mechanism. This mechanism not only requires correct pairing of homologous chromosomes but also efficient repair of the induced DNA double-strand breaks. Oocytes have evolved a unique quality control system that eliminates cells if chromosomes do not correctly align or if DNA repair is not possible. Central to this monitoring system that is conserved from nematodes and fruit fly to humans is the p53 protein family, and in vertebrates in particular p63. In mammals, oocytes are stored for a long time in the prophase of meiosis I which, in humans, can last more than 50 years. During the entire time of this arrest phase, the DNA damage checkpoint remains active. The treatment of female cancer patients with DNA damaging irradiation or chemotherapeutics activates this checkpoint and results in elimination of the oocyte pool causing premature menopause and infertility. Here, we review the molecular mechanisms of this quality control system and discuss potential therapeutic intervention for the preservation of the oocyte pool during chemotherapy.

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p63-related signaling at a glance

Cited by 67 publications

References 124 publications

The foggy world(s) of p63 isoform regulation in normal cells and cancer

The foggy world(s) of p63 isoform regulation in normal cells and cancer

VDAC Genes Expression and Regulation in Mammals

DNA Damaged Induced Cell Death in Oocytes

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