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Biomolecules
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Deciphering alternative functions of the INK4a/ARF locus
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Deciphering alternative functions of the INK4a/ARF locus

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (1 September 2020) | Viewed by 28314

Special Issue Editor

Dr. Maria Vivo

E-Mail Website
Guest Editor
Department of Chemistry and Biology, University of Salerno, 84084 Fisciano, Italy
Interests: autophagy; cellular mechanics; cell biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The CDKN2a/ARF locus encodes two completely unrelated proteins, p16INK4a and ARF, thanks to alternative first exons and a shared second exon that is endowed with two overlapped ORFs. The two proteins, although not displaying amino acid sequence identity, share the function of both being potent tumor suppressors. While p16INK4a (inhibitor of the cyclin-dependent kinases 4 and 6) blocks cells in the G1 phase by functioning in the pRb pathway, ARF (alternative reading frame) halts cell growth by both p53-dependent and independent routes through multiple mechanisms. In recent years, a pro-oncogenic function has been observed for ARF, thus highlighting a multifaceted role for this protein. Indeed, ARF appears to play a role in cellular stress response, autophagy, mitochondrial homeostasis, differentiation, anoikis resistance and tumor evolution. Besides, the locus itself is epigenetically re-shaped during development, and both its protein products appear to counteract stemness and to play a role in aging. This Special Issue aims to collect experimental observations about the functions of both ARF and INK4a, as well as the mechanisms that control their expression, in either physiological or pathological contexts. The presence of overlapped ORFs within exon 2, highly conserved during evolution, raises the question of how this unique genomic arrangement might have come about, leading to the intriguing speculation that the organization of INK4A-ARF genes could reflect the need for a finely coordinated control of the two proteins’ expression.

Dr. Maria Vivo
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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

  • tumor suppression
  • autophagy
  • anoikis
  • sumoylation
  • CDKN2a locus
  • cytoskeleton
  • senescence
  • oxidative stress
  • ribosomal biogenesis
  • B23

Published Papers (8 papers)

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Research

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11 pages, 1850 KiB  
Article
Pancreatic Progenitor Commitment Is Marked by an Increase in Ink4a/Arf Expression
by Elena Montano, Alessandra Pollice, Valeria Lucci, Geppino Falco, Ornella Affinito, Girolama La Mantia, Maria Vivo and Tiziana Angrisano
Biomolecules 2021, 11(8), 1124; https://doi.org/10.3390/biom11081124 - 30 Jul 2021
Cited by 2 | Viewed by 1896
Abstract
The identification of the molecular mechanisms controlling early cell fate decisions in mammals is of paramount importance as the ability to determine specific lineage differentiation represents a significant opportunity for new therapies. Pancreatic Progenitor Cells (PPCs) constitute a regenerative reserve essential for the [...] Read more.
The identification of the molecular mechanisms controlling early cell fate decisions in mammals is of paramount importance as the ability to determine specific lineage differentiation represents a significant opportunity for new therapies. Pancreatic Progenitor Cells (PPCs) constitute a regenerative reserve essential for the maintenance and regeneration of the pancreas. Besides, PPCs represent an excellent model for understanding pathological pancreatic cellular remodeling. Given the lack of valid markers of early endoderm, the identification of new ones is of fundamental importance. Both products of the Ink4a/Arf locus, in addition to being critical cell-cycle regulators, appear to be involved in several disease pathologies. Moreover, the locus’ expression is epigenetically regulated in ES reprogramming processes, thus constituting the ideal candidates to modulate PPCs homeostasis. In this study, starting from mouse embryonic stem cells (mESCs), we analyzed the early stages of pancreatic commitment. By inducing mESCs commitment to the pancreatic lineage, we observed that both products of the Cdkn2a locus, Ink4a and Arf, mark a naïve pancreatic cellular state that resembled PPC-like specification. Treatment with epi-drugs suggests a role for chromatin remodeling in the CDKN2a (Cycline Dependent Kinase Inhibitor 2A) locus regulation in line with previous observations in other cellular systems. Our data considerably improve the comprehension of pancreatic cellular ontogeny, which could be critical for implementing pluripotent stem cells programming and reprogramming toward pancreatic lineage commitment. Full article
(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)
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20 pages, 51922 KiB  
Article
Role of Cdkn2a in the Emery–Dreifuss Muscular Dystrophy Cardiac Phenotype
by Gloria Pegoli, Marika Milan, Pierluigi Giuseppe Manti, Andrea Bianchi, Federica Lucini, Philina Santarelli, Claudia Bearzi, Roberto Rizzi and Chiara Lanzuolo
Biomolecules 2021, 11(4), 538; https://doi.org/10.3390/biom11040538 - 6 Apr 2021
Cited by 2 | Viewed by 4409
Abstract
The Cdkn2a locus is one of the most studied tumor suppressor loci in the context of several cancer types. However, in the last years, its expression has also been linked to terminal differentiation and the activation of the senescence program in different cellular [...] Read more.
The Cdkn2a locus is one of the most studied tumor suppressor loci in the context of several cancer types. However, in the last years, its expression has also been linked to terminal differentiation and the activation of the senescence program in different cellular subtypes. Knock-out (KO) of the entire locus enhances the capability of stem cells to proliferate in some tissues and respond to severe physiological and non-physiological damages in different organs, including the heart. Emery–Dreifuss muscular dystrophy (EDMD) is characterized by severe contractures and muscle loss at the level of skeletal muscles of the elbows, ankles and neck, and by dilated cardiomyopathy. We have recently demonstrated, using the LMNA Δ8–11 murine model of Emery–Dreifuss muscular dystrophy (EDMD), that dystrophic muscle stem cells prematurely express non-lineage-specific genes early on during postnatal growth, leading to rapid exhaustion of the muscle stem cell pool. Knock-out of the Cdkn2a locus in EDMD dystrophic mice partially restores muscle stem cell properties. In the present study, we describe the cardiac phenotype of the LMNA Δ8–11 mouse model and functionally characterize the effects of KO of the Cdkn2a locus on heart functions and life expectancy. Full article
(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)
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14 pages, 2217 KiB  
Article
p19Arf Exacerbates Cigarette Smoke-Induced Pulmonary Dysfunction
by Ryuta Mikawa, Tadashi Sato, Yohei Suzuki, Hario Baskoro, Koichiro Kawaguchi and Masataka Sugimoto
Biomolecules 2020, 10(3), 462; https://doi.org/10.3390/biom10030462 - 17 Mar 2020
Cited by 9 | Viewed by 2867
Abstract
Senescent cells accumulate in tissues during aging or pathological settings. The semi-genetic or pharmacological targeting of senescent cells revealed that cellular senescence underlies many aspects of the aging-associated phenotype and diseases. We previously reported that cellular senescence contributes to aging- and disease-associated pulmonary [...] Read more.
Senescent cells accumulate in tissues during aging or pathological settings. The semi-genetic or pharmacological targeting of senescent cells revealed that cellular senescence underlies many aspects of the aging-associated phenotype and diseases. We previously reported that cellular senescence contributes to aging- and disease-associated pulmonary dysfunction. We herein report that the elimination of Arf-expressing cells ameliorates cigarette smoke-induced lung pathologies in mice. Cigarette smoke induced the expression of Ink4a and Arf in lung tissue with concomitant increases in lung tissue compliance and alveolar airspace. The elimination of Arf-expressing cells prior to cigarette smoke exposure protected against these changes. Furthermore, the administration of cigarette smoke extract lead to pulmonary dysfunction, which was ameliorated by subsequent senescent cell elimination. Collectively, these results suggest that senescent cells are a potential therapeutic target for cigarette smoking-associated lung disease. Full article
(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)
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Review

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14 pages, 5450 KiB  
Review
Non-Canonical Functions of the ARF Tumor Suppressor in Development and Tumorigenesis
by Nefeli Lagopati, Konstantinos Belogiannis, Andriani Angelopoulou, Angelos Papaspyropoulos and Vassilis Gorgoulis
Biomolecules 2021, 11(1), 86; https://doi.org/10.3390/biom11010086 - 12 Jan 2021
Cited by 18 | Viewed by 3240
Abstract
P14ARF (ARF; Alternative Reading Frame) is an extensively characterized tumor suppressor which, in response to oncogenic stimuli, mediates cell cycle arrest and apoptosis via p53-dependent and independent routes. ARF has been shown to be frequently lost through CpG island promoter methylation in a [...] Read more.
P14ARF (ARF; Alternative Reading Frame) is an extensively characterized tumor suppressor which, in response to oncogenic stimuli, mediates cell cycle arrest and apoptosis via p53-dependent and independent routes. ARF has been shown to be frequently lost through CpG island promoter methylation in a wide spectrum of human malignancies, such as colorectal, prostate, breast, and gastric cancers, while point mutations and deletions in the p14ARF locus have been linked with various forms of melanomas and glioblastomas. Although ARF has been mostly studied in the context of tumorigenesis, it has been also implicated in purely developmental processes, such as spermatogenesis, and mammary gland and ocular development, while it has been additionally involved in the regulation of angiogenesis. Moreover, ARF has been found to hold important roles in stem cell self-renewal and differentiation. As is often the case with tumor suppressors, ARF functions as a pleiotropic protein regulating a number of different mechanisms at the crossroad of development and tumorigenesis. Here, we provide an overview of the non-canonical functions of ARF in cancer and developmental biology, by dissecting the crosstalk of ARF signaling with key oncogenic and developmental pathways. Full article
(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)
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18 pages, 4222 KiB  
Review
Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression
by Zizhen Ming, Su Yin Lim and Helen Rizos
Biomolecules 2020, 10(10), 1447; https://doi.org/10.3390/biom10101447 - 15 Oct 2020
Cited by 19 | Viewed by 3968
Abstract
Genetic alterations in the INK4a/ARF (or CDKN2A) locus have been reported in many cancer types, including melanoma; head and neck squamous cell carcinomas; lung, breast, and pancreatic cancers. In melanoma, loss of function CDKN2A alterations have been identified in approximately 50% of [...] Read more.
Genetic alterations in the INK4a/ARF (or CDKN2A) locus have been reported in many cancer types, including melanoma; head and neck squamous cell carcinomas; lung, breast, and pancreatic cancers. In melanoma, loss of function CDKN2A alterations have been identified in approximately 50% of primary melanomas, in over 75% of metastatic melanomas, and in the germline of 40% of families with a predisposition to cutaneous melanoma. The CDKN2A locus encodes two critical tumor suppressor proteins, the cyclin-dependent kinase inhibitor p16INK4a and the p53 regulator p14ARF. The majority of CDKN2A alterations in melanoma selectively target p16INK4a or affect the coding sequence of both p16INK4a and p14ARF. There is also a subset of less common somatic and germline INK4a/ARF alterations that affect p14ARF, while not altering the syntenic p16INK4a coding regions. In this review, we describe the frequency and types of somatic alterations affecting the CDKN2A locus in melanoma and germline CDKN2A alterations in familial melanoma, and their functional consequences in melanoma development. We discuss the clinical implications of CDKN2A inactivating alterations and their influence on treatment response and resistance. Full article
(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)
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16 pages, 3034 KiB  
Review
Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes
by Yasmina Kahoul, Frédérik Oger, Jessica Montaigne, Philippe Froguel, Christophe Breton and Jean-Sébastien Annicotte
Biomolecules 2020, 10(9), 1350; https://doi.org/10.3390/biom10091350 - 22 Sep 2020
Cited by 12 | Viewed by 3488
Abstract
Besides its role as a cell cycle and proliferation regulator, the INK4a/ARF (CDKN2A) locus and its associated pathways are thought to play additional functions in the control of energy homeostasis. Genome-wide association studies in humans and rodents have revealed that single [...] Read more.
Besides its role as a cell cycle and proliferation regulator, the INK4a/ARF (CDKN2A) locus and its associated pathways are thought to play additional functions in the control of energy homeostasis. Genome-wide association studies in humans and rodents have revealed that single nucleotide polymorphisms in this locus are risk factors for obesity and related metabolic diseases including cardiovascular complications and type-2 diabetes (T2D). Recent studies showed that both p16INK4a-CDK4-E2F1/pRB and p19ARF-P53 (p14ARF in humans) related pathways regulate adipose tissue (AT) physiology and adipocyte functions such as lipid storage, inflammation, oxidative activity, and cellular plasticity (browning). Targeting these metabolic pathways in AT emerged as a new putative therapy to alleviate the effects of obesity and prevent T2D. This review aims to provide an overview of the literature linking the INK4a/ARF locus with AT functions, focusing on its mechanisms of action in the regulation of energy homeostasis. Full article
(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)
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21 pages, 1664 KiB  
Review
Post-Translational Regulation of ARF: Perspective in Cancer
by Jinho Seo, Daehyeon Seong, Seung Ri Lee, Doo-Byoung Oh and Jaewhan Song
Biomolecules 2020, 10(8), 1143; https://doi.org/10.3390/biom10081143 - 4 Aug 2020
Cited by 11 | Viewed by 4581
Abstract
Tumorigenesis can be induced by various stresses that cause aberrant DNA mutations and unhindered cell proliferation. Under such conditions, normal cells autonomously induce defense mechanisms, thereby stimulating tumor suppressor activation. ARF, encoded by the CDKN2a locus, is one of the most frequently mutated [...] Read more.
Tumorigenesis can be induced by various stresses that cause aberrant DNA mutations and unhindered cell proliferation. Under such conditions, normal cells autonomously induce defense mechanisms, thereby stimulating tumor suppressor activation. ARF, encoded by the CDKN2a locus, is one of the most frequently mutated or deleted tumor suppressors in human cancer. The safeguard roles of ARF in tumorigenesis are mainly mediated via the MDM2-p53 axis, which plays a prominent role in tumor suppression. Under normal conditions, low p53 expression is stringently regulated by its target gene, MDM2 E3 ligase, which induces p53 degradation in a ubiquitin-proteasome-dependent manner. Oncogenic signals induced by MYC, RAS, and E2Fs trap MDM2 in the inhibited state by inducing ARF expression as a safeguard measure, thereby activating the tumor-suppressive function of p53. In addition to the MDM2-p53 axis, ARF can also interact with diverse proteins and regulate various cellular functions, such as cellular senescence, apoptosis, and anoikis, in a p53-independent manner. As the evidence indicating ARF as a key tumor suppressor has been accumulated, there is growing evidence that ARF is sophisticatedly fine-tuned by the diverse factors through transcriptional and post-translational regulatory mechanisms. In this review, we mainly focused on how cancer cells employ transcriptional and post-translational regulatory mechanisms to manipulate ARF activities to circumvent the tumor-suppressive function of ARF. We further discussed the clinical implications of ARF in human cancer. Full article
(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)
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Other

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11 pages, 1711 KiB  
Brief Report
Methylation of the Suppressor Gene p16INK4a: Mechanism and Consequences
by Alfonso Tramontano, Francesca Ludovica Boffo, Giusi Russo, Mariarosaria De Rosa, Ilaria Iodice and Antonio Pezone
Biomolecules 2020, 10(3), 446; https://doi.org/10.3390/biom10030446 - 13 Mar 2020
Cited by 14 | Viewed by 2941
Abstract
Tumor suppressor genes in the CDKN2A/B locus (p15INK4b, p16INK4a, and p14ARF) function as biological barriers to transformation and are the most frequently silenced or deleted genes in human cancers. This gene silencing frequently occurs due to DNA methylation of [...] Read more.
Tumor suppressor genes in the CDKN2A/B locus (p15INK4b, p16INK4a, and p14ARF) function as biological barriers to transformation and are the most frequently silenced or deleted genes in human cancers. This gene silencing frequently occurs due to DNA methylation of the promoter regions, although the underlying mechanism is currently unknown. We present evidence that methylation of p16INK4a promoter is associated with DNA damage caused by interference between transcription and replication processes. Inhibition of replication or transcription significantly reduces the DNA damage and CpGs methylation of the p16INK4a promoter. We conclude that de novo methylation of the promoter regions is dependent on local DNA damage. DNA methylation reduces the expression of p16INK4a and ultimately removes this barrier to oncogene-induced senescence. Full article
(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)
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