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Pleiotropic Roles of Tumor Suppressors
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Pleiotropic Roles of Tumor Suppressors

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 14004

Special Issue Editor

Prof. Dr. Alessandra Pollice

E-Mail Website
Guest Editor
Department of Biology, Federico II University, 80131 Naples, Italy
Interests: biology of cancer; biological effects of natural compounds; stress response

Special Issue Information

Dear Colleagues,

Proper control of cell cycle progression is among the most crucial homeostatic mechanisms that protect the health of cells. Organisms have evolved sophisticated mechanisms to allow correct duplication and segregation of the genetic material through an orchestrated web of checkpoint effectors, including tumor suppressors. Loss of the proper control of the cell cycle, due to perturbation or lack of checkpoints, is crucial for cancer development. Intriguingly, tumor suppressors, apart from (or linked to) a role in cancer, can play pivotal and sometimes opposite roles in the cell, depending on the genetic or environmental context. For example, despite the role played by p21 and p53 in halting cellular proliferation, these tumor suppressors have been shown to promote senescence. Under certain conditions, p21 can even promote oncogenicity, and p53 can play a role in non-cancer-associated activities such as metabolic homeostasis. Particularly intriguing is p14ARF (p19 in mouse), which acts as a sensor of critical surveillance but is also involved in several biological processes such as differentiation, apoptosis, senescence, autophagy, mitochondrial homeostasis, oxidative stress, and ribosome biogenesis. Unexpectedly, it has also recently been reported that ARF is expressed at high levels in several human cancers in which it plays a pro-oncogenic function, challenging its traditional oncosuppressive role.

Knowledge and modulation of tumor suppressors’ dependent pathways have enormous potential in the treatment and eventually the early diagnosis of tumors. Therefore, this Special Issue aims to collect reviews and original articles that advance our understanding of the multicellular functions played by tumor suppressors, both in cancer and in (un)related cellular processes. We especially welcome manuscripts considering the mechanisms governing the regulation of intracellular levels of tumor suppressors and their involvement in cellular pathways such as those of development, regeneration, inflammation, and diseases.

Prof. Alessandra Pollice
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • p14ARF
  • p19ARF
  • Tumor suppressors
  • Development
  • Oncogenic stress
  • Oxidative stress
  • Cell cycle
  • Signaling pathways
  • Inflammation
  • Regeneration

Published Papers (4 papers)

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Research

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14 pages, 2634 KiB  
Article
Human ARF Specifically Inhibits Epimorphic Regeneration in the Zebrafish Heart
by Solomon Lee, Robert Hesse, Stanley Tamaki, Catharine Garland and Jason H. Pomerantz
Genes 2020, 11(6), 666; https://doi.org/10.3390/genes11060666 - 18 Jun 2020
Cited by 1 | Viewed by 2473
Abstract
The Alternative Reading Frame (ARF) protein is a tumor suppressor encoded by the Cyclin Dependent Kinase Inhibitor 2A gene in mammals but not lower regenerative vertebrates, and has been previously implicated as a context-sensitive suppressor of regeneration in murine skeletal muscle and humanized [...] Read more.
The Alternative Reading Frame (ARF) protein is a tumor suppressor encoded by the Cyclin Dependent Kinase Inhibitor 2A gene in mammals but not lower regenerative vertebrates, and has been previously implicated as a context-sensitive suppressor of regeneration in murine skeletal muscle and humanized ARF-expressing zebrafish fins. This study extends our investigation of the role of ARF in the regeneration of other solid tissues, including the zebrafish heart and the mammalian digit. Heart regeneration after cryoinjury was used to mimic massive myocardial infarction. ARF gene expression was upregulated during the cardiac regenerative process and slowed the rate of morphological recovery. ARF specifically impacts cardiomyocytes, neovascularization, and the endothelial-mesenchymal transition, while not affecting epicardial proliferation. This suggests that in the context of regeneration, ARF is specifically expressed in cells undergoing dedifferentiation. To investigate ARF as a suppressor of epimorphic regeneration in mammalian systems, we also tested whether the absence of ARF was permissive for murine digit regeneration, but found that ARF absence alone was insufficient to significantly alter digit restoration. These findings provide additional evidence that ARF suppresses epimorphic regeneration, but suggests that modulation of ARF alone is insufficient to permit regeneration. Full article
(This article belongs to the Special Issue Pleiotropic Roles of Tumor Suppressors)
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Review

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27 pages, 659 KiB  
Review
The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia
by Celia González-Gil, Jordi Ribera, Josep Maria Ribera and Eulàlia Genescà
Genes 2021, 12(1), 79; https://doi.org/10.3390/genes12010079 - 9 Jan 2021
Cited by 15 | Viewed by 3958
Abstract
Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives [...] Read more.
Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives initiation, clonal expansion and metastasis. In this process, alterations in genes encoding proteins that govern processes such as cell proliferation, differentiation, and growth provide us with some of the clearest mechanistic insights into how and why cancer arises. In such a scenario, deletions in the 9p21.3 cluster involving CDKN2A/ARF/CDKN2B genes arise as one of the oncogenic hallmarks of ALL. Deletions in this region are the most frequent structural alteration in T-cell acute lymphoblastic leukemia (T-ALL) and account for roughly 30% of copy number alterations found in B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). Here, we review the literature concerning the involvement of the CDKN2A/B genes as a prognosis marker of good or bad response in the two ALL subtypes (BCP-ALL and T-ALL). We compare frequencies observed in studies performed on several ALL cohorts (adult and child), which mainly consider genetic data produced by genomic techniques. We also summarize what we have learned from mouse models designed to evaluate the functional involvement of the gene cluster in ALL development and in relapse/resistance to treatment. Finally, we examine the range of possibilities for targeting the abnormal function of the protein-coding genes of this cluster and their potential to act as anti-leukemic agents in patients. Full article
(This article belongs to the Special Issue Pleiotropic Roles of Tumor Suppressors)
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Other

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8 pages, 1860 KiB  
Brief Report
YB-1 Oncoprotein Controls PI3K/Akt Pathway by Reducing Pten Protein Level
by Antonella Delicato, Eleonora Montuori, Tiziana Angrisano, Alessandra Pollice and Viola Calabrò
Genes 2021, 12(10), 1551; https://doi.org/10.3390/genes12101551 - 29 Sep 2021
Cited by 6 | Viewed by 2791
Abstract
YB-1 is a multifunctional protein overexpressed in many types of cancer. It is a crucial oncoprotein that regulates cancer cell progression and proliferation. Ubiquitously expressed in human cells, YB-1 protein functions are strictly dependent on its subcellular localization. In the cytoplasm, where YB-1 [...] Read more.
YB-1 is a multifunctional protein overexpressed in many types of cancer. It is a crucial oncoprotein that regulates cancer cell progression and proliferation. Ubiquitously expressed in human cells, YB-1 protein functions are strictly dependent on its subcellular localization. In the cytoplasm, where YB-1 is primarily localized, it regulates mRNA translation and stability. However, in response to stress stimuli and activation of PI3K and RSK signaling, YB-1 moves to the nucleus acting as a prosurvival factor. YB-1 is reported to regulate many cellular signaling pathways in different types of malignancies. Furthermore, several observations also suggest that YB-1 is a sensor of oxidative stress and DNA damage. Here we show that YB-1 reduces PTEN intracellular levels thus leading to PI3K/Akt pathway activation. Remarkably, PTEN reduction mediated by YB-1 overexpression can be observed in human immortalized keratinocytes and HEK293T cells and cannot be reversed by proteasome inhibition. Real-time PCR data indicate that YB-1 silencing up-regulates the PTEN mRNA level. Collectively, these observations indicate that YB-1 negatively controls PTEN at the transcript level and its overexpression could confer survival and proliferative advantage to PTEN proficient cancer cells. Full article
(This article belongs to the Special Issue Pleiotropic Roles of Tumor Suppressors)
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8 pages, 1359 KiB  
Brief Report
P14ARF: The Absence that Makes the Difference
by Danilo Cilluffo, Viviana Barra and Aldo Di Leonardo
Genes 2020, 11(7), 824; https://doi.org/10.3390/genes11070824 - 20 Jul 2020
Cited by 14 | Viewed by 4243
Abstract
P14ARF is a tumor suppressor encoded by the CDKN2a locus that is frequently inactivated in human tumors. P14ARF protein quenches oncogene stimuli by inhibiting cell cycle progression and inducing apoptosis. P14ARF functions can be played through interactions with several proteins. [...] Read more.
P14ARF is a tumor suppressor encoded by the CDKN2a locus that is frequently inactivated in human tumors. P14ARF protein quenches oncogene stimuli by inhibiting cell cycle progression and inducing apoptosis. P14ARF functions can be played through interactions with several proteins. However, the majority of its activities are notoriously mediated by the p53 protein. Interestingly, recent studies suggest a new role of p14ARF in the maintenance of chromosome stability. Here, we deepened this new facet of p14ARF which we believe is relevant to its tumor suppressive role in the cell. To this aim, we generated a monoclonal HCT116 cell line expressing the p14ARF cDNA cloned in the piggyback vector and then induced aneuploidy by treating HCT116 cells with the CENP-E inhibitor GSK923295. P14ARF ectopic re-expression restored the near-diploid phenotype of HCT116 cells, confirming that p14ARF counteracts aneuploid cell generation/proliferation. Full article
(This article belongs to the Special Issue Pleiotropic Roles of Tumor Suppressors)
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