Artykuły w czasopismach: „P14ARF”

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Cilluffo, Danilo, Viviana Barra i Aldo Di Leonardo. "P14ARF: The Absence that Makes the Difference". Genes 11, nr 7 (20.07.2020): 824. http://dx.doi.org/10.3390/genes11070824.

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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.

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Eymin, Béatrice, Paule Claverie, Caroline Salon, Camille Leduc, Edwige Col, Elisabeth Brambilla, Saadi Khochbin i Sylvie Gazzeri. "p14ARF Activates a Tip60-Dependent and p53-Independent ATM/ATR/CHK Pathway in Response to Genotoxic Stress". Molecular and Cellular Biology 26, nr 11 (1.06.2006): 4339–50. http://dx.doi.org/10.1128/mcb.02240-05.

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ABSTRACT p14ARF is a tumor suppressor that controls a well-described p53/Mdm2-dependent checkpoint in response to oncogenic signals. Here, new insights into the tumor-suppressive function of p14ARF are provided. We previously showed that p14ARF can induce a p53-independent G2 cell cycle arrest. In this study, we demonstrate that the activation of ATM/ATR/CHK signaling pathways contributes to this G2 checkpoint and highlight the interrelated roles of p14ARF and the Tip60 protein in the initiation of this DNA damage-signaling cascade. We show that Tip60 is a new direct p14ARF binding partner and that its expression is upregulated and required for ATM/CHK2 activation in response to p14ARF. Strikingly, both p14ARF and Tip60 products accumulate following a cell treatment with alkylating agents and are absolutely required for ATM/CHK2 activation in this setting. Moreover, and consistent with p14ARF being a determinant of CHK2 phosphorylation in lung carcinogenesis, a strong correlation between p14ARF and phospho-CHK2 (Thr68) protein expression is observed in human lung tumors (P < 0.00006). Overall, these data point to a novel regulatory pathway that mediates the p53-independent negative-cell-growth control of p14ARF. Inactivation of this pathway is likely to contribute to lung carcinogenesis.

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He, Mingwei, Jinlei Pang, Haiyan Sun, Guanrong Zheng, Yan Lin i Weipeng Ge. "P14ARF inhibits regional inflammation and vascularization in intervertebral disc degeneration by upregulating TIMP3". American Journal of Physiology-Cell Physiology 318, nr 4 (1.04.2020): C751—C761. http://dx.doi.org/10.1152/ajpcell.00271.2019.

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In this study, we identified P14 alternate reading frame (P14ARF) as a novel regulator of inflammation and vascularization in intervertebral disk degeneration (IVDD). We collected IVD tissues from IVDD patients and normal individuals for analysis of P14ARF expression. We also induced experimental IVDD by needle puncture injuries in the caudal intervertebral disks of Sprague-Dawley (SD) rats and achieved recombinant adenovirus-mediated P14ARF overexpression in experimental IVDD rats. Regulation relationships between P14ARF and tissue inhibitors of metalloproteinases-3 (TIMP3) were confirmed in P14ARF-overexpressed and TIMP3-depleted nucleus pulposus (NP) cells. Tube formation in vitro was evaluated in coculture systems of human umbilical vein endothelial cells (HUVECs) and rat degenerated NP cells (DNPCs). Inflammatory response was assessed from levels of TNF-α, IL-1β, and IL-6 and neovascularization from expression of endothelial growth factor (VEGF). The P14ARF and TIMP3 were downregulated in degenerated IVD tissue derived from patients and experimental IVDD rats. Overexpressed P14ARF suppressed inflammatory cytokine levels and vascularization. There was decreased in vitro tube formation in response to P14ARF overexpression and TIMP3 elevation. Finally, attenuated inflammatory responses and suppression of VEGF were achieved by P14ARF-mediated promotion of TIMP3 in rat DNPCs. Taken together, the present study reveals that P14ARF/TIMP3 modulation of inflammatory response and vascularization in the context of IVDD highlights a potential target for future therapeutic strategies.

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Shamanin, Vladimir A., i Elliot J. Androphy. "Immortalization of Human Mammary Epithelial Cells Is Associated with Inactivation of the p14ARF-p53 Pathway". Molecular and Cellular Biology 24, nr 5 (1.03.2004): 2144–52. http://dx.doi.org/10.1128/mcb.24.5.2144-2152.2004.

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ABSTRACT Inactivation of the ARF-p53 tumor suppressor pathway leads to immortalization of murine fibroblasts. The role of this pathway in immortalization of human epithelial cells is not clear. We analyzed the functionality of the p14ARF-p53 pathway in human mammary epithelial cells (MEC) immortalized by human papillomavirus 16 (HPV16) E6, the p53 degradation-defective E6 mutant Y54D, or hTERT. E6-MEC or E6Y54D-MEC maintains high-level expression of p14ARF. Late-passage hTERT-immortalized MEC express p53 but down-regulate p14ARF. Enforced expression of p14ARF induces p53-dependent senescence in hTERT-MEC, while both E6-MEC and E6Y54D-MEC are resistant. We show that E6Y54D inhibits p14ARF-induced activation of p53 without inactivation of the p53-dependent DNA damage response. Hence, p53 degradation and inhibition of p14ARF signaling to p53 are independent functions of HPV16 E6. Our observations imply that long-term proliferation of MEC requires inactivation of the p14ARF-p53 pathway.

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Cho, E. Y., Y. L. Choi, S. W. Chae, J. H. Sohn i G. H. Ahn. "Relationship between p53-associated proteins and estrogen receptor status in ovarian serous neoplasms". International Journal of Gynecologic Cancer 16, nr 3 (2006): 1000–1006. http://dx.doi.org/10.1136/ijgc-00009577-200605000-00008.

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We studied the immunoexpression of p14ARF, MDM2, and p53, in addition to relationships between those protein expressions and estrogen receptor (ER)α in ovarian serous tumors including benign (n = 23), borderline (n = 41), and malignant (n = 94). The aberrant expressions of p14ARF, MDM2, and p53 were observed in 19.6% (31/158), 47.5% (75/158), and 39.9% (63/158) of cases, respectively. The expression of MDM2 was significantly higher in borderline tumors compared to benign (P = 0.04) and malignant (P < 0.01) tumors. p53 expression in borderline tumors was uncommon, and p14ARF expression loss was mainly observed in carcinomas. Altered expression of p14ARF, MDM2, and p53 shows significant relationship with stage. Overexpression of MDM2 (P = 0.01) and loss of p14ARF expression (P = 0.04) were significantly associated with ER expression. Our results suggest that alteration of p14ARF–MDM2–p53 pathway proteins may contribute significantly to the tumorigenesis of ovarian serous neoplasms, and ER is involved in cellular regulation of p14ARF–MDM2–p53 pathway in ovarian serous neoplasms.

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Sánchez-Aguilera, Abel, Margarita Sánchez-Beato, Juan F. Garcı́a, Ignacio Prieto, Marina Pollan i Miguel A. Piris. "p14ARF nuclear overexpression in aggressive B-cell lymphomas is a sensor of malfunction of the common tumor suppressor pathways". Blood 99, nr 4 (15.02.2002): 1411–18. http://dx.doi.org/10.1182/blood.v99.4.1411.

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p14ARF, the alternative product from the humanINK4a/ARF locus, antagonizes Hdm2 and mediates p53 activation in response to oncogenic stimuli. An immunohistochemical study of p14ARF expression in 74 samples of aggressive B-cell lymphomas was performed, demonstrating an array of different abnormalities. A distinct nucleolar expression pattern was detected in nontumoral tissue and a subset of lymphomas (50/74). In contrast, a group of cases (8/74) showed absence of p14ARF expression, dependent either on promoter hypermethylation or gene loss. Additionally, 16 out of 74 cases displayed an abnormal nuclear p14ARF overexpression not confined to the nucleoli, as confirmed by confocal microscopy, and that was associated with high levels of p53 and Hdm2. A genetic study of these cases failed to show any alteration in the p14ARF gene, but revealed the presence of p53 mutations in over 50% of these cases. An increased growth fraction and a more aggressive clinical course, with a shortened survival time, also characterized the group of tumors with p14ARF nuclear overexpression. Moreover, this p14ARF expression pattern was more frequent in tumors displaying accumulated alterations in the p53, p16INK4a, and p27KIP1 tumor supressors. These observations, together with the consideration of the central role of p14ARF in cell cycle control, suggest that p14ARF abnormal nuclear overexpression is a sensor of malfunction of the major cell cycle regulatory pathways, and consequently a marker of a high tumor aggressivity.

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Olcha, Piotr, Marek Cybulski, Danuta Skomra, Bogdan Obrzut, Atanas Ignatov, Maciej Jóźwik, Regine Schneider-Stock i Andrzej Semczuk. "The Pattern of p14ARF Expression in Primary and Metastatic Human Endometrial Carcinomas". International Journal of Gynecologic Cancer 20, nr 6 (lipiec 2010): 993–99. http://dx.doi.org/10.1111/igc.0b013e3181e76a4d.

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Objectives:Alterations of p53 pathway (p14ARF/MDM2/p53) play a crucial role in the development and progression of various human neoplasms, including endometrial carcinoma (EC). The aim of the current research was to examine the p14ARF expression pattern in primary ECs and corresponding metastatic lesions.Materials and Methods:We studied 47 primary ECs and corresponding metastatic lesions applying immunohistochemistry and investigated the relationship between p14ARF overexpression and clinicopathological variables of carcinoma as well as TP53 alterations.Results:Protein expression was predominantly nuclear, present in 32 (68%) of 47 primary cases and in 28 (60%) of 47 metastatic lesions. There were seven p14ARF-positive primary tumors showing negative reactivity in the metastatic lesions. On the other hand, 3 cases lacked protein immunoreactivity in the primary ECs but revealed weak nuclear staining in the corresponding metastases. A case of primary cervical adenocarcinoma metastasizing to the lymph nodes showed p14ARF expression both in the primary tumor and the corresponding metastases. A trend was found between the p14ARF expression in primary tumors and the presence of the neoplasms in the fallopian tube (P = 0.063), but none of the other clinicopathological variables of carcinoma was related to protein immunoreactivity in advanced-stage uterine neoplasms. The p14ARF expression in EC metastases was related to the presence of the primary tumor in the fallopian tube (P = 0.036). The p14ARF expression was not associated with unfavorable outcome both in the primary tumors (P = 0.302) and in the corresponding metastases (P = 0.217). There was also no relationship between the p14ARF expression pattern and TP53 pathway alterations.Conclusions:Altogether, the p14ARF protein is expressed in more than half of the primary ECs and metastatic lesions analyzed and is associated with the transtubal dissemination of the primary tumor. The pattern of the p14ARF expression is not associated with the alterations of other TP53 pathway members in advanced-stage human ECs.

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Song, Joon Seon, Joo Mi Yi, Hanbyoul Cho, Chel Hun Choi, Yoonho Park, Eun Joo Chung, Jaewhan Song, Joon-Yong Chung i Seung-Mo Hong. "Dual loss of USP10 and p14ARF protein expression is associated with poor prognosis in patients with small intestinal adenocarcinoma". Tumor Biology 40, nr 10 (30.10.2018): 101042831880867. http://dx.doi.org/10.1177/1010428318808678.

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Oncogene-induced senescence occurs following oncogene activation in normal cells and is considered as a critical tumor-suppressing mechanism. Ubiquitin-specific protease 10 (USP10) has been reported to play a vital role in oncogene-induced senescence via the deubiquitination-dependent stabilization of p14ARF. However, knowledge of the clinical significance of USP10 and p14ARF expression in patients with small intestinal adenocarcinoma is limited. To study the clinical significance of USP10 and p14ARF expression, we performed immunohistochemistry for USP10 and p14ARF on 195 surgically resected small intestinal adenocarcinoma specimens. Furthermore, we performed methylation analysis on five small intestinal adenocarcinoma samples and matched adjacent normal intestinal tissue samples. UPS10 ( p = 0.023) and p14ARF ( p = 0.007) expression were significantly decreased in adenocarcinoma in comparison with normal tissue. The loss of USP10 was observed in 124/194 (63.9%) of small intestinal adenocarcinoma samples and was correlated with a higher pT stage ( p = 0.044), lymphatic invasion ( p = 0.033), and the absence of sporadic adenoma ( p = 0.024) and peritumoral dysplasia ( p = 0.019). p14ARF expression was downregulated in 75/195 (38.5%) of small intestinal adenocarcinoma samples and was associated with vascular ( p = 0.011) and lymphatic ( p = 0.013) invasions. The loss of USP10 expression was associated with the loss of p14ARF expression ( r = 0.342, p < 0.001). Multivariate survival analysis revealed that the combined loss of USP10 and p14ARF expression could be an independent prognostic factor for overall survival in small intestinal adenocarcinoma. Furthermore, the aberrant hypermethylation of the USP10 and p14ARF promoter could be a key mechanism for the downregulation of USP10 and p14ARF proteins in small intestinal adenocarcinoma. These findings suggest that the dual loss of USP10 and p14ARF could be used as a prognostic indicator of small intestinal adenocarcinoma.

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Martinez, Juan Carlos, Santiago Ropero, Concepcion Mateos, Maria DEL VAL Toledo, Rafael Samaniego, Silvia Sacristan i Manel Esteller. "Alteration of the p53 and Rb tumor suppressor pathways by p16/INK4a and p14/ARF promoter methylation and loss of protein expression in recurrent and nonrecurrent meningiomas." Journal of Clinical Oncology 31, nr 15_suppl (20.05.2013): 2064. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2064.

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2064 Background: Promoter methylation inactivates tumor suppressor genes (TSG). The INK4a/ARF locus encodes p16INKa and p14ARF cell cycle regulatory proteins, which control Rb and p53 TSG pathways. Most meningiomas are slow growing tumors, but in spite of complete surgical removal, the recurrence rate at 5 years is 5%, rising to 19% in long-term follow-up. However, there are no markers predictive of this evolution. Epigenetic changes in low-grade meningiomas have not been previously addressed. To get insights into the possible role of p16INK4a and p14ARF TSG alterations in grade 1 meningiomas, we study the methylation status and protein expression of these genes in 140 specimens of meningiomas: 29 nonrecurrent and 57 recurrent in one, two or three times. Methods: Methylation specific PCR and bisulfate modification followed by bisulfate genomic sequencing of CpG islands and staining with p16INKa and p14ARF antibodies (Ab’s). Results: Our data show p16INK4a and p14ARF methylation in 43.4% and14.2% meningiomas respectively. Methylation of p16INK4a is found in a similar proportion in non-recurrent meningiomas (37.9%) and the first biopsy of recurrent cases (38.8%) and increases to a 52.3% in successive biopsies of recurrent cases. Methylation of p14ARF occurs in 13.8% of nonrecurrent vs. 9.6% recurrent meningiomas (first biopsy) and 19.6% of successive recurrent meningiomas. Loss of p16INK4a and p14ARF protein expression was shown in 52.7% and 18.6% of meningiomas respectively. p16INK4a and p14ARF methylation was associated with loss of protein expression in 54.7% and 18.8% of meningiomas. Loss of p16INK4a and p14ARF expression was associated with unmethylated promoters in 52.9% and 17.6% of cases respectively. Conclusions: Epigenetic changes of p16INK4a and p14ARF genes and loss of protein expression leading to Rb and p53 TSG pathways alterations, may have a pathogenic role in human meningiomas. Loss of p16INK4a and p14ARF protein expression associated with unmethylated promoters, could be due to loss of heterozigosity or gen mutation. Increase of p16INK4a and p14ARF methylation along the following biopsies of recurrent cases suggests a possible role of methylation in tumor progression.

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Bai, Ming, Nan-Ze Yu, Fei Long, Cheng Feng i Xiao-Jun Wang. "Effects of CDKN2A (p16INK4A/p14ARF) Over-Expression on Proliferation and Migration of Human Melanoma A375 Cells". Cellular Physiology and Biochemistry 40, nr 6 (2016): 1367–76. http://dx.doi.org/10.1159/000453189.

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Objective: This study aims to investigate the effects of CDKN2A (p16INK4A/p14ARF) over-expression on the proliferation and migration of human melanoma A375 cells. Methods: Melanoma tissues and pigmented nevi tissues were collected. Human melanoma A375 cells were transfected by CDKN2A (p16INK4A) and CDKN2A (p14ARF) over-expressing vectors and then assigned into blank, negative control (NC), p16INK4A and p14ARF groups. The expression of CDKN2A (p16INK4A) and CDKN2A (p14ARF) mRNA and protein was detected by qRT-PCR and Western blotting. CCK-8, flow cytometry and Transwell assays were applied to observe cell proliferation, the cell cycle and apoptosis, and migration and invasion, respectively. The model of subcutaneous xenografts in nude mice was established to measure cell growth in vivo. Results: Compared with pigmented nevi tissues, CDKN2A (p16INK4A) and CDKN2A (p14ARF) mRNA and protein expression were significantly decreased in melanoma tissues. CDKN2A (p16INK4A) and CDKN2A (p14ARF) over-expression inhibited proliferation, migration, invasion and progression from G0/G1 to S phase of A375 cells and xenograft tumor growth, but promoted apoptosis. Conclusion: Our study demonstrated that over-expression of CDKN2A (p16INK4A) and CDKN2A (p14ARF) suppressed proliferation and migration of human melanoma A375 cells.

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Kordi-Tamandani, Dor Mohammad, Abdolkarim Moazeni-Roodi, Mohammad Ayoub Rigi Ladez, Mohammad Hashemi, Elnaz Birjandian i Adam Torkamanzehi. "Analysis of Methylation Patterns and Expression Profiles of P14Arf Gene in Patients with Oral Squamous Cell Carcinoma". International Journal of Biological Markers 25, nr 2 (kwiecień 2010): 99–103. http://dx.doi.org/10.1177/172460081002500207.

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Aims To analyze the promoter methylation profile and mRNA expression of the p14ARF gene in oral squamous cell carcinoma (OSCC). Methods Promoter methylation of the p14ARF gene was investigated by methylation-specific polymerase chain reaction in paraffin-embedded tissues from 76 patients with OSCC and 57 oral tissues used as healthy controls. Expression of p14ARF mRNA was also determined using real-time quantitative reverse-transcription PCR. The methylation status and mRNA level profile of the gene and their relationship with clinical data were analyzed. Results Methylation of the p14ARF gene in OSCC was significantly increased compared to normal control tissues (χ2 = 16.73, p<0.0001). The relative expression of p14ARF mRNA in OSCC was not significantly different from that in healthy control samples. Conclusion Promoter methylation of p14ARF may be an important mechanism in OSCC, and its determination may be considered an important tool in the early diagnosis and treatment of OSCC.

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Shen, Jia, Shengping Zhang, Yang Li, Wen Zhang, Jiandong Chen, Mary Zhang, Ting Wang i in. "p14ARF inhibits the functions of adenovirus E1A oncoprotein". Biochemical Journal 434, nr 2 (11.02.2011): 275–85. http://dx.doi.org/10.1042/bj20101163.

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The tumour suppressor ARF (alternative reading frame) is one of the most important oncogenic stress sensors. ARF provides an ‘oncogenic checkpoint’ function through both p53-dependent and p53-independent mechanisms. In the present study, we demonstrate a novel p53-independent interaction between p14ARF and the adenovirus oncoprotein E1A. p14ARF inhibits E1A transcriptional function and promotes ubiquitination-dependent degradation of E1A. p14ARF overexpression relocalizes E1A into the nucleolus and inhibits E1A-induced cellular DNA replication independent of p53. Knockdown of endogenous p14ARF increases E1A transactivation. In addition, E1A can competitively inhibit ARF–Mdm2 (murine double minute 2) complex formation. These results identify a novel binding partner of p14ARF and reveal a mutually inhibitory interaction between p14ARF and E1A. We speculate that the ARF–E1A interaction may represent an additional host defence mechanism to limit viral replication. Alternatively, the interaction may allow adenovirus to sense the functional state of p53 in host cells, and fine-tune its own replication activity to prevent the triggering of a detrimental host response.

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Huang, Hsuan-Ying, Peter B. Illei, Zhiquan Zhao, Madhu Mazumdar, Andrew G. Huvos, John H. Healey, Leonard H. Wexler, Richard Gorlick, Paul Meyers i Marc Ladanyi. "Ewing Sarcomas Withp53Mutation orp16/p14ARFHomozygous Deletion: A Highly Lethal Subset Associated With Poor Chemoresponse". Journal of Clinical Oncology 23, nr 3 (20.01.2005): 548–58. http://dx.doi.org/10.1200/jco.2005.02.081.

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PurposeEWS-FLI1 fusion type, p53 mutation, and homozygous deletion of p16/p14ARF have each been shown to be prognostically significant in Ewing sarcoma (ES). We provide the first combined prognostic analysis of these three molecular parameters in ES.Patients and MethodsWe studied 60 patients with ES (stage: localized in 54, metastatic in six). All cases were confirmed to contain the EWS-FLI1 (29 type 1, 12 type 2, 14 other types) or EWS-ERG fusions (five cases). Homozygous deletion of p16/p14ARF, and p53 mutations were determined by fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) p53 GeneChip microarray hybridization, respectively.ResultsEight cases (13.3%) contained point mutations of p53, and eight cases (13.3%) showed p16/p14ARF deletion, including one case with both alterations. Among 32 cases with data on histologic chemoresponse, all 10 with alterations in p53 or p16/p14ARF showed a poor chemoresponse (P = .03). Variables predicting poorer overall survival included p53 mutation alone (P < .001), either p53 or p16/p14ARF alteration (P < .001), and stage (P < .01). In multivariate analysis, alterations of p53 and/or p16/p14ARF as a single variable, was the most adverse prognostic factor (P < .001), followed by stage (P = .04). In a multivariate analysis with alterations of p53 and p16/p14ARF as separate variables, both were significant (P < .001 and P = .03, respectively). Six cases with p16/p14ARF deletion were also studied for co-deletion of the contiguous methylthioadenosine phosphorylase gene, and this was detected in four cases.ConclusionAlterations in p53 or p16/p14ARF are found in a fourth of ES cases and define a subset with highly aggressive behavior and poor chemoresponse.

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Cisneros, José, James Hagood, Marco Checa, Blanca Ortiz-Quintero, Miguel Negreros, Iliana Herrera, Carlos Ramos, Annie Pardo i Moisés Selman. "Hypermethylation-mediated silencing of p14ARF in fibroblasts from idiopathic pulmonary fibrosis". American Journal of Physiology-Lung Cellular and Molecular Physiology 303, nr 4 (15.08.2012): L295—L303. http://dx.doi.org/10.1152/ajplung.00332.2011.

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Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. A conspicuous feature is the formation and persistence of fibroblastic/myofibroblastic foci throughout the lung parenchyma. Mechanisms remain unknown, but data indicate that fibroblasts acquire an antiapoptotic phenotype. We hypothesized that transcriptional silencing of proapoptotic genes may be implicated, and accordingly we evaluated the epigenetic regulation of p14ARF. The expression of p14ARF was analyzed by RT-PCR in IPF ( n = 8) and normal derived fibroblasts ( n = 4) before and after treatment with 5-aza-2′-deoxycytidine (5-aza) and trichostatin A (TSA). p14ARF gene promoter methylation was determined by methylation-specific PCR (MS-PCR) and by DNA digestion with endonuclease McrBc, which cleaves 50% of methylated CpG. Apoptosis was evaluated by Annexin-V and nuclear staining. p14ARF expression was significantly decreased in four of the eight IPF fibroblasts lines, which was restored after 5-aza treatment. No changes were found with TSA. MS-PCR of bisulfite-treated genomic DNA showed a correlation between the reduced expression of p14ARF and the presence of hypermethylated promoter. No amplification was observed in the DNA treated with the McrBc enzyme, corroborating promoter hypermethylation. p14ARF-hypermethylated IPF fibroblasts were significantly more resistant to staurosporine-and S-nitrosoglutathione-induced apoptosis compared with normal and nonmethylated IPF fibroblasts ( P < 0.01) and showed reduced levels of p53. Resistance to apoptosis was provoked in fibroblasts when p14ARF expression was inhibited by siRNA ( P < 0.05). These findings demonstrate that many IPF fibroblasts have reduced expression of the proapoptotic p14ARF attributable to promoter hypermethylation and indicate that epigenetic mechanisms may underlie their resistance to apoptosis.

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Palrasu, Manikandan, Elena Zaika, El-Rifai Wael, Richard Peek i Alexander Zaika. "Regulation of p14ARF by Siva1 in H. pylori-infected gastric epithelial cells." Journal of Clinical Oncology 39, nr 3_suppl (20.01.2021): 243. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.243.

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243 Background: Helicobacter pylori ( H. pylori) is the strongest known risk factor for gastric cancer. Bacterial degradation of tumor suppressor proteins affect the host microbe’s interactions and host cellular response, which contribute to tumorigenesis. p14ARF, a crucial tumor suppressor protein that activates p53 protein under oncogenic stress plays a major role in oncogenic stress response (OSR) regulation. However, little is known about the mechanism of ARF and OSR regulation in H. pylori-infected gastric epithelial cells. Methods: The expression of p14ARF and cytotoxin-associated gene A (CagA) were analyzed in gastric cells co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas by immunoblotting. To investigate the potential role of CagA in regulation of p14ARF, we employed isogenic cagA− and cagE− H. pylori mutants in gastric epithelial cells, and C57BL/6 mice (n = 10). We also analyzed the expression of Siva1 in human individual infected with cagA-positive (n = 13) and cagA-negative (n = 13) bacteria as well as uninfected human subjects (n = 6). siRNA was used to inhibit activity of Siva1 protein. Results: In this study, H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p14ARF compared with low-risk strains in vivo and in vitro. We found that degradation of p14ARF induced by CagA is mediated by E3 ubiquitin ligase Siva1, which works in concert with another E3 ubiquitin ligase TRIP12. Decreased expression of Siva1 protein and consequent up-regulation of p14ARF was also found in gastric mucosa of H. pylori-infected mice and human individuals. Tumorigenic strain 7.13 was more potent in upregulation of Siva1 and downregulation of p14ARF than non-tumorigenic strain B128. Inhibition of p14ARF protein by H. pylori causes inhibition of autophagy in infected cells. Conclusions: Our results provide first evidence that carcinogenic H. pylori strains significantly alter the host tumor suppressor protein p14ARF, leading to suppression of host OSR and autophagy, which may affect host-bacteria interactions and tumorigenic alteration in the stomach.

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Kozik, Bojana, Milena Krajnovic, Nikola Kokanov, Snezana Jovanovic-Cupic, Ana Bozovic, Lidija Todorovic i Vesna Mandusic. "Combined analysis of KARS mutation and p16INK4a and p14ARF methylation status in locally advanced rectal carcinoma treated with preoperative chemoradiotherapy". Archives of Biological Sciences, nr 00 (2022): 11. http://dx.doi.org/10.2298/abs220222011k.

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Current management of locally advanced rectal carcinoma (LARC) involves preoperative chemoradiotherapy (preCRT) before surgery. Despite improved local control rate, the response to preCRT of individual patients is variable and may reflect heterogeneous biological properties among tumors of the same clinical stage. Identifying novel molecular parameters with predictive and/or prognostic value is of great clinical importance for a personalized therapeutic approach. In this study, KRAS mutation status was analyzed by direct sequencing, while methylation-specific polymerase chain reaction (MSP) was used to examine p16INK4a and p14ARF gene methylation status in pretreatment tumor biopsies of 60 patients with LARC. The examined molecular changes of KRAS, p16INK4a and p14ARF genes were mutually independent (p16INK4a/KRAS, P=0.272; p14ARF/KRAS, P=0.923; p16INK4a/p14ARF, P=0.715). However, the simultaneous presence of p14ARF methylation and KRAS mutation was associated with a more frequent appearance of local recurrences and distant metastasis (P=0.027). Moreover, patients with the simultaneous presence of p16INK4a and p14ARF methylation and KRAS mutation had significantly shorter overall survival (P=0.011). The obtained results strongly suggest that combined analyses of examined genetic and epigenetic molecular alterations could contribute to the identification of LARC patient subgroups with more aggressive tumor behavior and worse disease outcome.

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de Almeida Simão, Tatiana, Gabriela Loureiro De Bonis Almeida Simões, Fabiana Siqueira Ribeiro, Daniela Anhel de Paula Cidade, Nelson Adami Andreollo, Luiz Roberto Lopes, Jacyara Maria Brito Macedo i in. "Lower expression of p14ARF and p16INK4a correlates with higher DNMT3B expression in human oesophageal squamous cell carcinomas". Human & Experimental Toxicology 25, nr 9 (wrzesień 2006): 515–22. http://dx.doi.org/10.1191/0960327106het649oa.

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Oesophageal squamous cell carcinoma (ESCC) is one of the most common malignancies and is the sixth cause of cancer-related death in the world. Inactivation of cell-cycle regulating genes, such as p14ARF and p16INK4a, and cell adhesion genes, such as E-cadherin, is common in cancer, and results from genetic and/or epigenetic alterations. Therefore, we have analysed the mRNA expression of p14ARF, p16INK4a and E-cadherin in 17 matched ESCC and normal mucosal samples obtained from Brazilian patients by semi-quantitative RT-PCR. The expression of p14ARF and p16INK4a was absent or reduced in several ESCC samples. Hypermethylation of CpG islands, caused by the action of DNA methyltransferases (DNMTs), is a major form of epigenetic inactivation of the p14ARF and p16INK4a genes in tumours. Hence, we also investigated the mRNA expression of the human DNA methyltransferases in normal oesophageal mucosa and in the tumour matched samples. All DNMTs were constitutively expressed in the normal oesophageal mucosa but a significantly higher expression of DNMT3B was observed in the tumours. Data analysis by the Spearman rank test showed that the expression of DNMT3B was inversely correlated with that of p14ARF and p16INK4a. Our results suggest that DNMT3B over-expression may be involved in the suppression or lower expression of p14ARF and p16INK4a observed in ESCC.

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Paul, Esbjörn, Bertil Uggla, Kals G. Wiman, Christer Paul, Soren Lehmann i Hareth Nahi. "Low Expression of p14ARF in De Novo AML with Normal Karyotype Is Associated with Short Survival but Increased in Vitro Sensitivity to p53 Modulating Drugs". Blood 112, nr 11 (16.11.2008): 2937. http://dx.doi.org/10.1182/blood.v112.11.2937.2937.

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Abstract Background: The p53 protein is strongly regulated by the E3 ligase HDM-2, which specifically binds to p53 and causes proteosomal degradation. The p14ARF protein activates p53 by binding to and inhibiting HDM-2. Design and methods: To further study the prognostic impact of p14ARF in AML, leukemic cells from 57 adult patients with normal karyotype de novo AML were analysed for p14ARF mRNA expression level using real-time PCR. We also measured the cytotoxicity against conventional cytostatics and PRIMA-1, a novel small molecule shown to activate mutated p53 (Nature Medicine2002; 8: 282–288) using an ATP-assay. Intracellular p53 protein was measured by FACS after incubation with PRIMA-1 in combination with the HDM-2 blocking agent RITA (Nature Medicine2004; 10: 1321–1328) Results: Patients whose cells expressed more p14ARF mRNA than the 75th percentile (0.26) showed significantly better survival compared with those with lower levels, 61% vs. 30% 3-year survival (p=0.033). The difference remained significant also when NPM1/FLT3 status was considered. The mean effects of all tested conventional antileukemic drugs were greater in leukemic cell samples expressing p14ARF mRNA ≥0.26, but the differences did not reach statistical significance. In contrast, PRIMA-1 had a significantly greater effect on leukemic cell samples with low levels of p14ARF mRNA and PRIMA-1 and RITA significantly increased intracellular p53 levels. Conclusions: Low level of p14ARF mRNA in leukemic cells from patients with normal karyotype AML is a strong marker for poor prognosis and decreased sensitivity to conventional cytostatics. Treatment with drugs targeting p53 can be a future possibility to improve the outcome for these patients.

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Dimri, Goberdhan P., Koji Itahana, Meileen Acosta i Judith Campisi. "Regulation of a Senescence Checkpoint Response by the E2F1 Transcription Factor and p14ARF Tumor Suppressor". Molecular and Cellular Biology 20, nr 1 (1.01.2000): 273–85. http://dx.doi.org/10.1128/mcb.20.1.273-285.2000.

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ABSTRACT Normal cells do not divide indefinitely due to a process known as replicative senescence. Human cells arrest growth with a senescent phenotype when they acquire one or more critically short telomeres as a consequence of cell division. Recent evidence suggests that certain types of DNA damage, chromatin remodeling, and oncogenic forms of Ras or Raf can also elicit a senescence response. We show here that E2F1, a multifunctional transcription factor that binds the retinoblastoma (pRb) tumor suppressor and that can either promote or suppress tumorigenesis, induces a senescent phenotype when overexpressed in normal human fibroblasts. Normal human cells stably arrested proliferation and expressed several markers of replicative senescence in response to E2F1. This activity of E2F1 was independent of its pRb binding activity but dependent on its ability to stimulate gene expression. The E2F1 target gene critical for the senescence response appeared to be the p14ARF tumor suppressor. Replicatively senescent human fibroblasts overexpressed p14ARF, and ectopic expression of p14ARF in presenescent cells induced a phenotype similar to that induced by E2F1. Consistent with a critical role for p14ARF, cells with compromised p53 function were immune to senescence induction by E2F1, as were cells deficient in p14ARF. Our findings support the idea that the senescence response is a critical tumor-suppressive mechanism, provide an explanation for the apparently paradoxical roles of E2F1 in oncogenesis, and identify p14ARF as a potentially important mediator of the senescent phenotype.

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Tomicic, Maja T., Franziska Krämer, Alexandra Nguyen, Christian Schwarzenbach i Markus Christmann. "Oxaliplatin-Induced Senescence in Colorectal Cancer Cells Depends on p14ARF-Mediated Sustained p53 Activation". Cancers 13, nr 9 (22.04.2021): 2019. http://dx.doi.org/10.3390/cancers13092019.

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Senescence is an important consequence of cytostatic drug-based tumor therapy. Here we analyzed to which degree the anticancer drug oxaliplatin induces cell death, cell cycle arrest, and senescence in colorectal cancer (CRC) cells and elucidated the role of p53. Oxaliplatin treatment resulted in the G2-phase arrest in all CRC lines tested (HCT116p53+/+, HCT116p53−/−, LoVo, SW48 and SW480). Immunoblot analysis showed that within the p53-competent lines p53 and p21CIP1 are activated at early times upon oxaliplatin treatment. However, at later times, only LoVo cells showed sustained activation of the p53/p21CIP1 pathway, accompanied by a strong induction of senescence as measured by senescence-associated β-Gal staining and induction of senescence-associated secretory phenotype (SASP) factors. Opposite to LoVo, the p53/p21CIP1 response and senescence induction was much weaker in the p53-proficient SW48 and SW480 cells, which was due to deficiency for p14ARF. Thus, among lines studied only LoVo express p14ARF protein and siRNA-mediated knockdown of p14ARF significantly reduced sustained p53/p21CIP1 activation and senescence. Vice versa, ectopic p14ARF expression enhanced oxaliplatin-induced senescence in SW48 and SW480 cells. Our data show that oxaliplatin-induced senescence in CRC cells is dependent on p53 proficiency; however, a significant induction can only be observed upon p14ARF-mediated p53 stabilization.

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Paul, Esbjorn O., Stefan Deneberg, Soren Lehmann, Sofia Bengtzén i Hareth Nahi. "Expression of p14ARF in De Novo AML with Normal Karyotype. Implication on Drug Resistance and Survival." Blood 110, nr 11 (16.11.2007): 4261. http://dx.doi.org/10.1182/blood.v110.11.4261.4261.

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Abstract The p53 protein exerts a significant role in growth control of cells and impaired function of p53 by mutation or otherwise is regarded to be important for development of many human cancers. The p53 protein is strongly regulated by the E3-ligase HDM-2 that specifically binds to p53 and causes proteosomal degradation. P14ARF encoded from the INK 4a/ARF gene locus of chromosome 9p, activates the p53 pathway by binding to and inhibiting HDM-2. The objective was to study if the level of mRNA for p14ARF in leukemic cells from patients with AML was related to in vitro drug resistance and clinical outcome. Leukemic cells (>90% pure) isolated from 46 adult patients with normal karyotype de novo AML were incubated with antileukemic drugs (daunorubicin, mitoxantrone, etoposide and Ara-C) cultured for 4 days. The effect was determined by bioluminiscence measuring of intracellular ATP compared to an untreated control. We also tested the activity against PRIMA (p53-dependent reactivation and induction of massive apoptosis), a novel, small molecule shown to activate down regulated p53. mRNA for p14ARF was determined by real time PCR. Results: Patients whose leukemic cells expressed high level of p14ARF mRNA in the leukemic cells (≥0.2 compared to the housekeeping gene) had a significantly better survival compared to those with low level (<0.02). Median survival not obtained compared to 9 months. The mean activity of all tested conventional antileukemic drugs was higher on leukemic cell samples expressing p14ARF mRNA ≥0.2 compared to those with low levels. In contrast, PRIMA exerted significantly higher in vitro effect on leukemic cell samples with low levels of p14ARF mRNA. We conclude that low levels of p14ARF in leukemic cells from patients with normal karyotype AML is a marker for poor prognosis, which may depend on impaired p53 activity causing resistance against conventional antileukemic drugs. Treatment with p53 targeting drugs as PRIMA may be a future possibility to improve the outcome for these patients.

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Mason, Sarah L., Öonagh Loughran i Nicholas B. La Thangue. "p14ARF regulates E2F activity". Oncogene 21, nr 27 (czerwiec 2002): 4220–30. http://dx.doi.org/10.1038/sj.onc.1205524.

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Edwards, Sara J., Brett R. Dix, Colleen J. Myers, Deirdre Dobson-Le, Lily Huschtscha, Merilyn Hibma, Janice Royds i Antony W. Braithwaite. "Evidence that Replication of the Antitumor Adenovirus ONYX-015 Is Not Controlled by the p53 and p14ARF Tumor Suppressor Genes". Journal of Virology 76, nr 24 (15.12.2002): 12483–90. http://dx.doi.org/10.1128/jvi.76.24.12483-12490.2002.

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ABSTRACT The adenovirus mutant ONYX-015 is in phase III clinical trials as a novel antitumor therapy. Its apparent efficacy is thought to be due to its ability to replicate selectively in tumor cells defective in the signaling pathway for p53. Recent data have shown that p14ARF, a positive regulator of p53, inhibits ONYX-015 replication in cells with a wild-type p53, a phenotype that characterizes normal cells. We, however, found that ONYX-015 activates p53 in tumor cells and in normal cells and that this can occur without p14ARF induction. We also show that ONYX-015 is not attenuated in cells with functional p53, whether or not p14ARF is expressed, and that where attenuation does occur, it is cell type specific.

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Ivanchuk, S., S. Mondal i J. Rutka. "Identifying novel p14ARF binding partners". European Journal of Cancer 37 (kwiecień 2001): S122. http://dx.doi.org/10.1016/s0959-8049(01)80938-2.

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Ming, Zizhen, Su Yin Lim i Helen Rizos. "Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression". Biomolecules 10, nr 10 (15.10.2020): 1447. http://dx.doi.org/10.3390/biom10101447.

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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.

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Calabrò, Viola, Gelsomina Mansueto, Raffaela Santoro, Antonio Gentilella, Alessandra Pollice, Pamela Ghioni, Luisa Guerrini i Girolama La Mantia. "Inhibition of p63 Transcriptional Activity by p14ARF: Functional and Physical Link between Human ARF Tumor Suppressor and a Member of the p53 Family". Molecular and Cellular Biology 24, nr 19 (1.10.2004): 8529–40. http://dx.doi.org/10.1128/mcb.24.19.8529-8540.2004.

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ABSTRACT The ARF/MDM2/p53 pathway is a principal defense mechanism to protect the organism from uncontrolled effects of deregulated oncogenes. Oncogenes activate ARF, which interacts with and inhibits the ubiquitin ligase MDM2, resulting in p53 stabilization and activation. Once stabilized and activated, p53 can either induce or repress a wide array of different gene targets, which in turn can regulate cell cycle, DNA repair, and a number of apoptosis-related genes. Here we show that, unlike p53, p63, a member of the p53 family, directly interacts with p14ARF. Through this interaction ARF inhibits p63-mediated transactivation and transrepression. In p63-transfected cells, ARF, which normally localizes into nucleoli, accumulates in the nucleoplasm. Based on these observations, we suggest that stimuli inducing p14ARF expression can, at the same time, activate p53 and impair p63 transcriptional activity, altering the pattern of p53 target gene expression. Here we show, for the first time, a physical and functional link between the p14ARF tumor suppressor protein and p63, a member of the p53 family.

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Gjerset, Ruth A., i Keya Bandyopadhyay. "Regulation of p14ARF Through Subnuclear Compartmentalization". Cell Cycle 5, nr 7 (28.03.2006): 686–90. http://dx.doi.org/10.4161/cc.5.7.2623.

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Dobrowolski, Rafael, Rüdiger Hein, Reinhard Buettner i Anja Bosserhoff. "Loss of p14ARF expression in melanoma". Archives of Dermatological Research 293, nr 11 (27.11.2001): 545–51. http://dx.doi.org/10.1007/s00403-001-0274-y.

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Lee, Casey, Brian A. Smith, Keya Bandyopadhyay i Ruth A. Gjerset. "DNA Damage Disrupts the p14ARF-B23(Nucleophosmin) Interaction and Triggers a Transient Subnuclear Redistribution of p14ARF". Cancer Research 65, nr 21 (1.11.2005): 9834–42. http://dx.doi.org/10.1158/0008-5472.can-05-1759.

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Wang, Yu-Chien, Ruo-Kai Lin, Yi-Hung Tan, Jung-Ta Chen, Chih-Yi Chen i Yi-Ching Wang. "Wild-Type p53 Overexpression and Its Correlation With MDM2 and p14ARF Alterations: An Alternative Pathway to Non–Small-Cell Lung Cancer". Journal of Clinical Oncology 23, nr 1 (1.01.2005): 154–64. http://dx.doi.org/10.1200/jco.2005.03.139.

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Purpose We found a relatively reduced frequency of p53 mutation with a much greater frequency of p53 protein overexpression, which reflected stabilization of p53 protein in the absence of p53 gene mutation. Therefore, we investigated the possibility of alternative mechanisms leading to p53 protein stabilization. Patients and Methods We performed gene and protein alteration studies on p53 and its upstream effectors, MDM2 and p14ARF, in tumors from 94 non–small-cell lung cancer (NSCLC) patients. Results Immunohistochemical and sequencing analyses indicated that 37 tumors showed overexpression of wild-type p53. An absence of nuclear staining of MDM2 protein was found in 95% of these tumors (35 of 37; P < .001). The tumors with negative MDM2 staining showed a significantly high concordance of loss of Akt activity and low MDM2 mRNA expression (P < .001). Sequencing analysis revealed five distinct MDM2 splicing variants disrupting the conserved p53 binding domain. Corresponding variant proteins were detected in three lung cancer cell lines using the Western blot analysis. Our results also indicated that among the tumors with overexpression of the wild-type p53, 92% (34 of 37) showed immunoreactivity to p14ARF (P = .001). In addition, the deregulation of p53 and MDM2 genes was significantly associated with squamous lung cancer (P < .05) and was correlated with advanced stages (P < .05) and poor prognosis (P < .05). Conclusion Our data suggest that immunopositivity of p14ARF together with a low expression of MDM2 contributes to accumulation of the wild-type p53, and that deregulation of the p53-MDM2-p14ARF pathway is important in the pathogenesis and outcome of a subset of NSCLC.

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Sok, Vanessa, Alec Z. Jacinto, Natalie Peng, Mohamed Eldemerdash, Lysa Le, Philip D. Tran, Li Feng Feng i in. "G protein coupled receptor kinase 5 modifies the nucleolar stress response activated by actinomycin D". Biochemistry and Cell Biology 99, nr 4 (sierpień 2021): 508–18. http://dx.doi.org/10.1139/bcb-2020-0480.

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G protein coupled receptor kinase 5 (GRK5) is localized within the nucleus and moderates functions such as DNA transcription, in addition to its localization at the plasma membrane. In this report, we show that GRK5 modifies the nucleolar stress response activated by the DNA polymerase inhibitor, actinomycin D (ActD). We show an increased sensitivity to the apoptotic effects of ActD on cervical HeLa cells and the breast cancer cell line MDA MB 231 with reduced protein expression of GRK5. We also tested two types of breast cancer cells (MDA MB 231 and MCF7 cells) and found that the rate of response to ActD varied between them because they have innate differences in the protein expression of GRK5. We also found that GRK5 phosphorylates nucleophosmin (NPM1) at T199 before and during the early stages of ActD treatment. Phosphorylation at T199 increases the ability of NPM1 to interact with p14ARF in vitro, which may affect the protein expression levels of p14ARF. We found that the expression levels of p14ARF were lower in the cells transfected with the control shRNA, but higher in cells transfected with GRK5 shRNA. Collectively, this suggests that GRK5 modifies the nucleolar stress response associated with ActD.

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Kowalczyk, Dominika, Mark A. Nakasone, Brian O. Smith i Danny T. Huang. "Bivalent binding of p14ARF to MDM2 RING and acidic domains inhibits E3 ligase function". Life Science Alliance 5, nr 12 (9.08.2022): e202201472. http://dx.doi.org/10.26508/lsa.202201472.

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ARF tumor suppressor protein is a key regulator of the MDM2-p53 signaling axis. ARF interferes with MDM2-mediated ubiquitination and degradation of p53 by sequestering MDM2 in the nucleolus and preventing MDM2-p53 interaction and nuclear export of p53. Moreover, ARF also directly inhibits MDM2 ubiquitin ligase (E3) activity, but the mechanism remains elusive. Here, we apply nuclear magnetic resonance and biochemical analyses to uncover the mechanism of ARF-mediated inhibition of MDM2 E3 activity. We show that MDM2 acidic and zinc finger domains (AD-ZnF) form a weak intramolecular interaction with the RING domain, where the binding site overlaps with the E2∼ubiquitin binding surface and thereby partially reduces MDM2 E3 activity. Binding of human N-terminal 32 residues of p14ARF to the acidic domain of MDM2 strengthens the AD-ZnF-RING domain interaction. Furthermore, the N-terminal RxFxV motifs of p14ARF participate directly in the MDM2 RING domain interaction. This bivalent binding mode of p14ARF to MDM2 acidic and RING domains restricts E2∼ubiquitin recruitment and massively hinders MDM2 E3 activity. These findings elucidate the mechanism by which ARF inhibits MDM2 E3 activity.

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Muñoz, Jorge, María del Mar Inda, Paula Lázcoz, Idoya Zazpe, Xing Fan, Jorge Alfaro, Teresa Tuñón, Juan A. Rey i Javier S. Castresana. "Promoter Methylation of RASSF1A Associates to Adult Secondary Glioblastomas and Pediatric Glioblastomas". ISRN Neurology 2012 (9.01.2012): 1–10. http://dx.doi.org/10.5402/2012/576578.

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While allelic losses and mutations of tumor suppressor genes implicated in the etiology of astrocytoma have been widely assessed, the role of epigenetics is still a matter of study. We analyzed the frequency of promoter hypermethylation by methylation-specific PCR (MSP) in five tumor suppressor genes (PTEN, MGMT, RASSF1A, p14ARF, and p16INK4A), in astrocytoma samples and cell lines. RASSF1A was the most frequently hypermethylated gene in all grades of astrocytoma samples, in cell lines, and in adult secondary GBM. It was followed by MGMT. PTEN showed a slight methylation signal in only one GBM and one pilocytic astrocytoma, and in two cell lines; while p14ARF and p16INK4A did not show any evidence of methylation in primary tumors or cell lines. In pediatric GBM, RASSF1A was again the most frequently altered gene, followed by MGMT; PTEN, p14 and p16 showed no alterations. Lack or reduced expression of RASSF1A in cell lines was correlated with the presence of methylation. RASSF1A promoter hypermethylation might be used as a diagnostic marker for secondary GBM and pediatric GBM. Promoter hypermethylation might not be an important inactivation mechanism in other genes like PTEN, p14ARF and p16INK4A, in which other alterations (mutations, homozygous deletions) are prevalent.

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Shamanin, Vladimir A., Pedja Sekaric i Elliot J. Androphy. "hAda3 Degradation by Papillomavirus Type 16 E6 Correlates with Abrogation of the p14ARF-p53 Pathway and Efficient Immortalization of Human Mammary Epithelial Cells". Journal of Virology 82, nr 8 (6.02.2008): 3912–20. http://dx.doi.org/10.1128/jvi.02466-07.

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ABSTRACT Two activities of human papillomavirus type 16 E6 (HPV16 E6) are proposed to contribute to the efficient immortalization of human epithelial cells: the degradation of p53 protein and the induction of telomerase. However, the requirement for p53 inactivation has been debated. Another E6 target is the hAda3 protein, a p53 coactivator and a component of histone acetyltransferase complexes. We have previously described the role of hAda3 and p53 acetylation in p14ARF-induced human mammary epithelial cell (MEC) senescence (P. Sekaric, V. A. Shamanin, J. Luo, and E. J. Androphy, Oncogene 26:6261-6268, 2007). In this study, we analyzed a set of HPV16 E6 mutants for the ability to induce hAda3 degradation. E6 mutants that degrade hAda3 but not p53 could abrogate p14ARF-induced growth arrest despite the presence of normal levels of p53 and efficiently immortalized MECs. However, two E6 mutants that previously were reported to immortalize MECs with low efficiency were found to be defective for both p53 and hAda3 degradation. We found that these immortal MECs select for reduced p53 protein levels through a proteasome-dependent mechanism. The findings strongly imply that the inactivation of the p14ARF-p53 pathway, either by the E6-mediated degradation of p53 or hAda3 or by cellular adaptation, is required for MEC immortalization.

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Tian, Kai-hua, Yi Shen, Yi-rne Luo, Ming-zhao Wang, Hong-xu Liu, Hui-ru Zhao i Lin Zhang. "Hypermethylation of p14ARF promoter region and expresion of p14ARF gene product in non-small cell lung cancer". Chinese Journal of Cancer Research 18, nr 4 (grudzień 2006): 276–81. http://dx.doi.org/10.1007/s11670-006-0276-6.

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Blanco-Luquin, Idoia, Paula Lázcoz, Jon Celay, Javier S. Castresana i Ignacio J. Encío. "In Vitro Assessment of the Role of p53 on Chemotherapy Treatments in Neuroblastoma Cell Lines". Pharmaceuticals 14, nr 11 (19.11.2021): 1184. http://dx.doi.org/10.3390/ph14111184.

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Neuroblastoma is the most frequent malignant extracranial solid tumor of infancy. The overall objective of this work consists of determining the presence of alterations in the p53/MDM2/p14ARF signaling pathway in neuroblastoma cell lines and deciphering their possible relationship with resistance to known antineoplastic drugs and to differentiation agents. Firstly, we characterized 10 neuroblastoma cell lines for alterations at the p53/MDM2/p14ARF signaling pathway by analysis of TP53 point mutations, MYCN and MDM2 amplification, and p14ARF methylation, homozygous deletions, and expression. Secondly, we chose SK-N-FI (mutated at TP53) and SK-N-Be(2) (wild-type TP53) cell lines, treated them with chemotherapeutic agents (doxorubicin, etoposide, cisplatin, and melphalan) and with two isomers of retinoic acid (RA): (9-cis and all-trans). Finally, we analyzed the distribution of the cell cycle, the induction of apoptosis, and the expression levels of p53, p21, and Bcl-2 in those two cell lines. P14ARF did not present promoter methylation, homozygous deletions, and protein expression in any of the 10 neuroblastoma cell lines. One TP53 point mutation was detected in the SK-N-FI cell line. MYCN amplification was frequent, while most cell lines did not present MDM2 amplification. Treatment of SK-N-FI and SK-N-Be(2) cells with doxorubicin, etoposide, cisplatin, and melphalan increased apoptosis and blocked the cycle in G2/M, while retinoic acid isomers induced apoptosis and decreased the percentage of cells in S phase in TP53 mutated SK-N-FI cells, but not in TP53 wild-type SK-N-Be(2) cells. Treatment with cisplatin, melphalan, or 9-cis RA decreased p53 expression levels in SK-N-FI cells but not in SK-N-Be (2). The expression of p21 was not modified in either of the two cell lines. Bcl-2 levels were reduced only in SK-N-FI cells after treatment with cisplatin. However, treatments with doxorubicin, etoposide, or 9-cis-RA did not modify the levels of this protein in either of the two cell lines. In conclusion, TP53 mutated SK-N-FI cells respond better to the retinoic isomers than TP53 wild-type SK-N-Be(2) cells. Although these are in vitro results, it seems that deciphering the molecular alterations of the p53/MDM2/p14ARF signaling pathway prior to treating patients of neuroblastoma might be useful for standardizing therapies with the aim of improving survival.

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Itahana, Koji, i Yanping Zhang. "Mitochondrial targeting signals: Another barcode in p14ARF?" Cell Cycle 9, nr 5 (marzec 2010): 861–69. http://dx.doi.org/10.4161/cc.9.5.11039.

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McCormick, Frank. "ONYX-015 selectivity and the p14ARF pathway". Oncogene 19, nr 56 (grudzień 2000): 6670–72. http://dx.doi.org/10.1038/sj.onc.1204096.

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Anzola, Monica, Nerea Cuevas, Monica L??pez-Mart??nez, Alberto Saiz, Juan Jos?? Burgos i Marian Mart??nez de Pancorbo. "p14ARF gene alterations in human hepatocellular carcinoma". European Journal of Gastroenterology & Hepatology 16, nr 1 (styczeń 2004): 19–26. http://dx.doi.org/10.1097/00042737-200401000-00004.

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Huang, Yinghui, Christopher J. Peters, Rebecca C. Fitzgerald i Ruth A. Gjerset. "Progressive silencing of p14ARF in oesophageal adenocarcinoma". Journal of Cellular and Molecular Medicine 13, nr 2 (10.04.2008): 398–409. http://dx.doi.org/10.1111/j.1582-4934.2008.00336.x.

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Kashuba, Elena, Karin Mattsson, Katja Pokrovskaja, Csaba Kiss, Marina Protopopova, Barbro Ehlin-Henriksson, George Klein i Laszlo Szekely. "EBV-encoded EBNA-5 associates with P14ARF in extranucleolar inclusions and prolongs the survival of P14ARF-expressing cells". International Journal of Cancer 105, nr 5 (5.05.2003): 644–53. http://dx.doi.org/10.1002/ijc.11124.

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Ma, Hanhui, i Thoru Pederson. "Depletion of the Nucleolar Protein Nucleostemin Causes G1 Cell Cycle Arrest via the p53 Pathway". Molecular Biology of the Cell 18, nr 7 (lipiec 2007): 2630–35. http://dx.doi.org/10.1091/mbc.e07-03-0244.

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Nucleostemin (NS) is a nucleolar protein expressed in adult and embryo-derived stem cells, transformed cell lines, and tumors. NS decreases when proliferating cells exit the cell cycle, but it is unknown how NS is controlled, and how it participates in cell growth regulation. Here, we show that NS is down-regulated by the tumor suppressor p14ARF and that NS knockdown elevates the level of tumor suppressor p53. NS knockdown led to G1 cell cycle arrest in p53-positive cells but not in cells in which p53 was genetically deficient or depleted by small interfering RNA knockdown. These results demonstrate that, in the cells investigated, the level of NS is regulated by p14ARF and the control of the G1/S transition by NS operates in a p53-dependent manner.

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Maitra, Anirban, Helen Roberts, Arthur G. Weinberg i Joseph Geradts. "Aberrant Expression of Tumor Suppressor Proteins in the Ewing Family of Tumors". Archives of Pathology & Laboratory Medicine 125, nr 9 (1.09.2001): 1207–12. http://dx.doi.org/10.5858/2001-125-1207-aeotsp.

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Abstract Background.—Deregulation of tumor suppressor gene function and abrogation of cell cycle control are common features of malignant neoplasms, but corresponding data on Ewing sarcomas and primitive neuroectodermal tumors are relatively scarce. We studied the expression of 4 tumor suppressor proteins in the Ewing family of tumors (EFTs). Design.—We examined a series of 20 pediatric EFTs for abnormal expression of p16INK4a, p14ARF, p21WAF1, and pRB by immunohistochemical analysis of pretreatment, nondecalcified archival specimens. Clinical follow up was available in all cases (median, 21 months; range, 5–103 months). Five patients presented with metastatic disease, 8 had no evidence of disease at last follow up, and 12 had an adverse outcome (death or progressive tumor posttherapy). Results.—Twelve cases (60%) demonstrated abnormal expression of at least one tumor suppressor protein. There were 11 cases (55%) with loss of p21WAF1 expression, 4 (20%) with down-regulation of p16INK4a, 2 (10%) with absence of pRB, and one case (5%) with loss of p14ARF expression. Loss of p16INK4a expression correlated with metastatic disease at presentation (P = .026), and showed a trend toward shortened survival (P = .20). The p21WAF1, p14ARF, and pRB status was not significantly correlated with either metastatic disease at presentation or outcome. Conclusion.—Abrogation of the G1 checkpoint was common in this series of EFTs, and down-regulation of p21WAF1 and p16INK4a were the most frequent findings. Loss of p16INK4a expression may identify a subset of cases with a more aggressive phenotype.

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Hemmati, Philipp G., Guillaume Normand, Berlinda Verdoodt, Clarissa von Haefen, Anne Hasenjäger, Dilek Güner, Jana Wendt, Bernd Dörken i Peter T. Daniel. "Loss of p21 disrupts p14ARF-induced G1 cell cycle arrest but augments p14ARF-induced apoptosis in human carcinoma cells". Oncogene 24, nr 25 (7.03.2005): 4114–28. http://dx.doi.org/10.1038/sj.onc.1208579.

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Zhuang, Wen-yue, i Zi-Xing Chen. "Epigenetic Silencing of Bcl-2, C/Ebpa and p14ARF by the AML1/ETO Oncoprotein Contributing to Growth Arrest and Differentiation Blockage". Blood 116, nr 21 (19.11.2010): 3617. http://dx.doi.org/10.1182/blood.v116.21.3617.3617.

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Abstract Abstract 3617 The t(8; 21) is one of the most frequent chromosomal translocations associated with acute leukemia. The AML1(RUNX1)-ETO(MTG8) fusion transcription factor generated by the t (8; 21) translocation is believed to deregulate the expression of genes that are crucial for normal differentiation and proliferation of hematopoietic progenitors, resulting in acute myelogenous leukemia by recruiting co-repressor complexes to DNA. To investigate the role of AML1-ETO in leukemogenesis, we transfected the cloned AML1-ETO cDNA with plasmid and expressed the AML1-ETO protein in U937 myelomonocytic leukemia cells. Interestingly, we found dichotomous phenomena in these transfected leukemic cells, i.e. growth arrest versus differentiation block (detailed data?). The AML1-ETO transfected U937cells were growing significantly slower than that of empty vector-transfected cells and nontransfected cells (P<0.01). As the surface markers for myeloid differentiation, the expression of CD11b and CD14 measured by flow cytometry demonstrated that the percentage of CD11b+ cell was 4.1%-7.0% in U937-A/E1-4 cells, which was significantly lower(P<0.01) than those in U937-Mock cells (11.4%) and U937-WT cells (11.0%). Moreover, the expression of CD14 antigen was decreased by 1.5–2-fold as compared with the control cells. By focusing on the anti-apoptotic gene (Bcl-2), a key transcription factor (C/EBPA) which regulates granulocytic differentiation and a tumor suppressor gene (p14ARF), we found that AML1-ETO- expressing cell subclones displayed low levels of these three genes in comparison with the non-transfected U937 (P<0.001). In primary bone marrow cells of acute myeloid leukemia containing t(8;21)/AML1-ETO, levels of Bcl-2, C/EBPA and p14ARF mRNA were markedly lower (P<0.001) when compared with other acute myeloid leukemias lacking this translocation (n=10). Chromatin immunoprecipitation assays (ChIP) demonstrated that Bcl-2, C/EBPA and p14ARF were among the direct transcriptional regulating targets of AML1-ETO. The universal binding of AML1-ETO to genomic DNA resulted in MeCP2 recruitment (P<0.01), reduction of histone H3 (P<0.0 1) or histone H4(P<0.01) acetylation and increased tri-methylation on histone H3 lysine 9 (P<0.01)as well as histone H3 lysine 27 (P<0.01), indicating that AML1-ETO induced heterochromatic silencing of Bcl-2, C/EBPA and p14ARF. These results suggested that the aberrant transcription factor AML1-ETO epigenetically silences the function of Bcl-2, C/EBPA and p14ARF gene by inducing repressed chromatin configurations at their promoters through histone modification. Considering that apoptosis-enhancing effect of AML1-ETO would not be favorable to the leukemogenesis, it must be compensated by some other effects to permit its leukemogenic potential. Disclosures: No relevant conflicts of interest to declare.

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Xiong, Chao-Liang, i Yuan Huang. "Methylation and expression of p14ARF in colorectal cancer". World Chinese Journal of Digestology 18, nr 8 (2010): 786. http://dx.doi.org/10.11569/wcjd.v18.i8.786.

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Badal, Vinay, Sergio Ménendez, David Coomber i David P. Lane. "Regulation of the p14ARF promoter by DNA methylation". Cell Cycle 7, nr 1 (styczeń 2008): 112–19. http://dx.doi.org/10.4161/cc.7.1.5137.

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Taniguchi, T., N. Chikatsu, S. Takahashi, A. Fujita, K. Uchimaru, S. Asano, T. Fujita i T. Motokura. "Expression of p16INK4A and p14ARF in hematological malignancies". Leukemia 13, nr 11 (listopad 1999): 1760–69. http://dx.doi.org/10.1038/sj.leu.2401557.

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Lee, Y. K., J.-Y. Park, H. J. Kang i H. C. Cho. "Overexpression of p16INK4A and p14ARF in haematological malignancies". Clinical & Laboratory Haematology 25, nr 4 (23.07.2003): 233–37. http://dx.doi.org/10.1046/j.1365-2257.2003.00520.x.

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Bates, Stewart, Andrew C. Phillips, Paula A. Clark, Francesca Stott, Gordon Peters, Robert L. Ludwig i Karen H. Vousden. "p14ARF links the tumour suppressors RB and p53". Nature 395, nr 6698 (wrzesień 1998): 124–25. http://dx.doi.org/10.1038/25867.

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