Genomes and Genes
tumor suppressor protein p14arf
Summary: A gene product of the p16 tumor suppressor gene (GENES, P16). It antagonizes the function of MDM2 PROTEIN (which regulates P53 TUMOR SUPPRESSOR PROTEIN by targeting it for degradation). p14ARF is produced from the beta mRNA transcript of the p16 gene. The other gene product, produced from the alternatively spliced alpha transcript, is CYCLIN-DEPENDENT KINASE INHIBITOR P16. Both p16 gene products have tumor suppressor functions.
- Amente S, Gargano B, Diolaiti D, Della Valle G, Lania L, Majello B. p14ARF interacts with N-Myc and inhibits its transcriptional activity. FEBS Lett. 2007;581:821-5 pubmed..Finally, we determine that the N-terminal region of the p14(ARF) protein is involved in binding to c-Myc and N-Myc proteins. ..
- Badal V, Menendez S, Coomber D, Lane D. Regulation of the p14ARF promoter by DNA methylation. Cell Cycle. 2008;7:112-9 pubmed..Additionally, we could show a dependency between the demethylation of the p14(ARF) promoter, the induction of p14(ARF) mRNA and protein and the effect of 5-aza-CdR on cell cycle. ..
- McGowan E, Alling N, Jackson E, Yagoub D, Haass N, Allen J, et al. Evaluation of cell cycle arrest in estrogen responsive MCF-7 breast cancer cells: pitfalls of the MTS assay. PLoS ONE. 2011;6:e20623 pubmed publisher..These experiments demonstrate how the combined measurement of metabolic activity and DNA labeling provides a more reliable interpretation of cancer cell response to treatment regimens. ..
- Lee M, Sup Han W, Kyoung Kim O, Hee Sung S, Sun Cho M, Lee S, et al. Prognostic value of p16INK4a and p14ARF gene hypermethylation in human colon cancer. Pathol Res Pract. 2006;202:415-24 pubmed..This study suggests that simultaneous hypermethylation of both p16INK4a and p14ARF genes is greater prognostic value in sporadic human colorectal cancer. ..
- Sherr C. Divorcing ARF and p53: an unsettled case. Nat Rev Cancer. 2006;6:663-73 pubmed..However, ARF has been reported to physically associate with proteins other than MDM2 and to have p53-independent activities, most of which remain controversial and poorly understood. ..
- Oh J, Kim H, Kim H, Kim W, Lee S. Aberrant methylation of p14ARF gene correlates with poor survival in osteosarcoma. Clin Orthop Relat Res. 2006;442:216-22 pubmed..Prognostic study, Level II (retrospective study). See the Guidelines for Authors for a complete description of levels of evidence. ..
- Freedberg D, Rigas S, Russak J, Gai W, Kaplow M, Osman I, et al. Frequent p16-independent inactivation of p14ARF in human melanoma. J Natl Cancer Inst. 2008;100:784-95 pubmed publisher..Genetic and epigenetic analyses of the human 9p21 locus indicate that modifications of ARF occur independently of p16 inactivation in human melanoma and suggest that ARF is more frequently inactivated than p16. ..
- Efeyan A, Garcia Cao I, Herranz D, Velasco Miguel S, Serrano M. Tumour biology: Policing of oncogene activity by p53. Nature. 2006;443:159 pubmed
- Lessard F, Morin F, Ivanchuk S, Langlois F, Stefanovsky V, Rutka J, et al. The ARF tumor suppressor controls ribosome biogenesis by regulating the RNA polymerase I transcription factor TTF-I. Mol Cell. 2010;38:539-50 pubmed publisher..Thus, our data delineate the pathway by which ARF regulates ribosomal RNA synthesis and provide a compelling explanation for the role of NPM. ..
- Vivo M, Di Costanzo A, Fortugno P, Pollice A, Calabrò V, La Mantia G. Downregulation of DeltaNp63alpha in keratinocytes by p14ARF-mediated SUMO-conjugation and degradation. Cell Cycle. 2009;8:3545-51 pubmed..Remarkably, we found that DeltaNp63alpha is preferentially sumoylated by SUMO2, instead of SUMO1, and p14(ARF) increases the efficiency of this process. ..
- Shen J, Zhang S, Li Y, Zhang W, Chen J, Zhang M, et al. p14(ARF) inhibits the functions of adenovirus E1A oncoprotein. Biochem J. 2011;434:275-85 pubmed publisher..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. ..
- Löf Öhlin Z, Nilsson T. Pyrosequencing assays to study promoter CpG site methylation of the O6-MGMT, hMLH1, p14ARF, p16INK4a, RASSF1A, and APC1A genes. Oncol Rep. 2009;21:721-9 pubmed..This approach provides a more comprehensive picture of the distribution of DNA methylation throughout the promoter regions of the studied set of six genes, which will be of benefit in oncological research. ..
- Brady S, Maggi L, Winkeler C, Toso E, Gwinn A, Pelletier C, et al. Nucleophosmin protein expression level, but not threonine 198 phosphorylation, is essential in growth and proliferation. Oncogene. 2009;28:3209-20 pubmed publisher..Thus, we demonstrate that the reduction in NPM protein expression blocks cellular growth and proliferation, whereas phosphorylation of NPM-Thr198 is not essential for NPM's capacity to drive cell cycle progression and proliferation. ..
- Chen Z, Carracedo A, Lin H, Koutcher J, Behrendt N, Egia A, et al. Differential p53-independent outcomes of p19(Arf) loss in oncogenesis. Sci Signal. 2009;2:ra44 pubmed publisher..Collectively, these data reveal differential consequences of p19(Arf) inactivation in prostate cancer and MEFs upon Pten loss that are independent of the p53 pathway. ..
- Ayrault O, Andrique L, Fauvin D, Eymin B, Gazzeri S, Seite P. Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation. Oncogene. 2006;25:7577-86 pubmed..Taken together, these data define a new p53-independent pathway that could regulate cell cycle through the negative control of rRNA transcription. ..
- Zhang C, Guo X, Zhang L, Lu Z, Ma N, Cheng Y, et al. Methylation-related silencing of p14ARF gene correlates with telomerase activity and mRNA expression of human telomerase reverse transcriptase in hepatocellular carcinoma. J Surg Oncol. 2008;98:462-8 pubmed publisher..p14(ARF) hypermethylation may contribute to silencing of p14(ARF) mRNA expression in HCC. Telomerase activity is association with inactivation of the p14(ARF)-p53 pathway induced by methylation in HCC. ..
- Müer A, Overkamp T, Gillissen B, Richter A, Pretzsch T, Milojkovic A, et al. p14(ARF)-induced apoptosis in p53 protein-deficient cells is mediated by BH3-only protein-independent derepression of Bak protein through down-regulation of Mcl-1 and Bcl-xL proteins. J Biol Chem. 2012;287:17343-52 pubmed publisher..Moreover, our data suggest that the simultaneous inhibition of two central endogenous Bak inhibitors, i.e. Mcl-1 and Bcl-x(L), may be sufficient to activate mitochondrial apoptosis in the absence of BH3-only protein regulation. ..
- Campbell K, Witty J, Rocha S, Perkins N. Cisplatin mimics ARF tumor suppressor regulation of RelA (p65) nuclear factor-kappaB transactivation. Cancer Res. 2006;66:929-35 pubmed..Moreover, our data indicate that at least with respect to RelA, cisplatin functions as an ARF mimic. Other drugs capable of mimicking this aspect of ARF function might therefore have therapeutic potential. ..
- Khoronenkova S, Dianov G. The emerging role of Mule and ARF in the regulation of base excision repair. FEBS Lett. 2011;585:2831-5 pubmed publisher..In this review, we will summarise the major properties of Mule and ARF and their roles in the coordination of DNA repair and DNA replication. ..
- Herkert B, Dwertmann A, Herold S, Abed M, Naud J, Finkernagel F, et al. The Arf tumor suppressor protein inhibits Miz1 to suppress cell adhesion and induce apoptosis. J Cell Biol. 2010;188:905-18 pubmed publisher..Our data point to a tumor-suppressive pathway that weakens cell-cell and cell-matrix interactions in response to expression of Arf and that may thereby facilitate the elimination of cells harboring an oncogenic mutation. ..
- Eymin B, Claverie P, Salon C, Leduc C, Col E, Brambilla E, et al. p14ARF activates a Tip60-dependent and p53-independent ATM/ATR/CHK pathway in response to genotoxic stress. Mol Cell Biol. 2006;26:4339-50 pubmed..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. ..
- He L, Fan C, Ning X, Feng X, Liu Y, Chen B, et al. Interaction of p14ARF with Brca1 in cancer cell lines and primary breast cancer. Cell Biol Int. 2008;32:1302-9 pubmed publisher..This co-localization is enhanced in primary breast cancer. Taken together, the results show that p14ARF associates with Brca1, which may play a major role in tumor suppression. ..
- Kawagishi H, Nakamura H, Maruyama M, Mizutani S, Sugimoto K, Takagi M, et al. ARF suppresses tumor angiogenesis through translational control of VEGFA mRNA. Cancer Res. 2010;70:4749-58 pubmed publisher..Taken together, our results define a mechanism by which the ARF tumor suppressor targets the translational repression of specific oncogenes during neoplastic transformation...
- Itahana K, Zhang Y. Mitochondrial p32 is a critical mediator of ARF-induced apoptosis. Cancer Cell. 2008;13:542-53 pubmed publisher..These findings provide a potential explanation for the frequent human cancer mutations targeting the ARF C terminus. ..
- Muniz V, Barnes J, Paliwal S, Zhang X, Tang X, Chen S, et al. The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis. Mol Cancer Res. 2011;9:867-77 pubmed publisher..These findings establish a new bioluminescent mouse tumor model for rapidly assessing the biological significance of suspected PDAC metastasis genes. This system may also provide a valuable platform for testing innovative therapies. ..
- Ito S, Ohga T, Saeki H, Watanabe M, Kakeji Y, Morita M, et al. Promoter hypermethylation and quantitative expression analysis of CDKN2A (p14ARF and p16INK4a) gene in esophageal squamous cell carcinoma. Anticancer Res. 2007;27:3345-53 pubmed..The decrease in p14ARF gene expression associated with invasive and metastatic phenotypes may be significant as an indicator of the malignant potential of human ESCC. ..
- Zhang Y, Sturgis E, Zafereo M, Wei Q, Li G. p14ARF genetic polymorphisms and susceptibility to second primary malignancy in patients with index squamous cell carcinoma of the head and neck. Cancer. 2011;117:1227-35 pubmed publisher..Therefore, p14(ARF) polymorphisms may be susceptible markers of the risk of developing an SPM in patients with SCCHN. ..
- Christophorou M, Ringshausen I, Finch A, Swigart L, Evan G. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature. 2006;443:214-7 pubmed..Such protection is absolutely dependent on p19(ARF)--a tumour suppressor induced not by DNA damage, but by oncogenic disruption of the cell cycle. ..
- Agrawal A, Yang J, Murphy R, Agrawal D. Regulation of the p14ARF-Mdm2-p53 pathway: an overview in breast cancer. Exp Mol Pathol. 2006;81:115-22 pubmed..The complexity of interaction of components of the pathway and the underlying development of cancer is emphasized. Opportunities for future therapeutic innovations are indicated. ..
- Pardal R, Molofsky A, He S, Morrison S. Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors. Cold Spring Harb Symp Quant Biol. 2005;70:177-85 pubmed..Imbalances within such networks cause cancer or premature declines in stem cell activity that resemble accelerated aging. ..
- Sivakolundu S, Nourse A, Moshiach S, Bothner B, Ashley C, Satumba J, et al. Intrinsically unstructured domains of Arf and Hdm2 form bimolecular oligomeric structures in vitro and in vivo. J Mol Biol. 2008;384:240-54 pubmed publisher..Our studies provide the first insights into the molecular basis through which Arf nullifies the p53-inhibiting activity of Hdm2, indirectly activating the tumor-suppressor function of p53 in mammalian cells. ..
- Knappskog S, Geisler J, Arnesen T, Lillehaug J, Lønning P. A novel type of deletion in the CDKN2A gene identified in a melanoma-prone family. Genes Chromosomes Cancer. 2006;45:1155-63 pubmed
- Ha L, Ichikawa T, Anver M, Dickins R, Lowe S, Sharpless N, et al. ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence. Proc Natl Acad Sci U S A. 2007;104:10968-73 pubmed..Thus, therapeutics designed to restore wild-type p53 function may be insufficient to counter melanoma and other malignancies in which ARF holds p53-independent tumor suppressor activity. ..
- Carr J, Bell E, Pearson A, Kees U, Beris H, Lunec J, et al. Increased frequency of aberrations in the p53/MDM2/p14(ARF) pathway in neuroblastoma cell lines established at relapse. Cancer Res. 2006;66:2138-45 pubmed..If these data are confirmed in neuroblastoma tumors, this suggests that p53-independent therapy and reactivation of inactive p53 approaches would be useful in the management of relapsed neuroblastoma. ..
- Kominami K, Nagasaka T, Cullings H, Hoshizima N, Sasamoto H, Young J, et al. Methylation in p14(ARF) is frequently observed in colorectal cancer with low-level microsatellite instability. J Int Med Res. 2009;37:1038-45 pubmed..Thus, promoter methylation of p14(ARF) could be a significant alteration leading to CRC with MSI-L. ..
- He J, Qiao J, Zhu H. p14ARF promoter region methylation as a marker for gliomas diagnosis. Med Oncol. 2011;28:1218-24 pubmed publisher..Therefore, our data suggest that methylation in the promoter region of the p14ARF gene may be used as a biomarker for the diagnosis of gliomas. ..
- Lee C, Smith B, Bandyopadhyay K, Gjerset R. DNA damage disrupts the p14ARF-B23(nucleophosmin) interaction and triggers a transient subnuclear redistribution of p14ARF. Cancer Res. 2005;65:9834-42 pubmed..The results implicate the nucleolus and nucleolar interactions of the ARF, including potentially novel interactions involving its COOH terminus as sites for early DNA damage and stress-mediated cellular events. ..
- Di Tommaso A, Hagen J, Tompkins V, Muniz V, Dudakovic A, Kitzis A, et al. Residues in the alternative reading frame tumor suppressor that influence its stability and p53-independent activities. Exp Cell Res. 2009;315:1326-35 pubmed publisher..Most intriguingly, this work reveals a novel and direct role for p14ARF in the p53-independent maintenance of genomic stability. ..
- Pasmant E, Laurendeau I, Heron D, Vidaud M, Vidaud D, Bieche I. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res. 2007;67:3963-9 pubmed
- Sharma G, Mirza S, Prasad C, Srivastava A, Gupta S, Ralhan R. Promoter hypermethylation of p16INK4A, p14ARF, CyclinD2 and Slit2 in serum and tumor DNA from breast cancer patients. Life Sci. 2007;80:1873-81 pubmed..Further, expression profile of p16(INK4A) could be linked to epigenetic events, thus suggesting this pathway as a potential target for therapeutic strategies based on reversal of epigenetic silencing. ..
- Chang D, Qiu W, Ying H, Zhang Y, Chen C, Xiao Z. ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2. Oncogene. 2007;26:4627-34 pubmed..Thus, this study demonstrates that ARF plays a direct role in regulation of Rb and suggests that inactivation of ARF may lead to defects in both p53 and Rb pathways in human cancer development. ..
- Leduc C, Claverie P, Eymin B, Col E, Khochbin S, Brambilla E, et al. p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation. Oncogene. 2006;25:4147-54 pubmed..Overall, our results identify a novel mechanism by which p14ARF controls the RB pathway to trigger its antiproliferative function. ..
- Wang P, Greiner T, Lushnikova T, Eischen C. Decreased Mdm2 expression inhibits tumor development induced by loss of ARF. Oncogene. 2006;25:3708-18 pubmed..Our findings also indicate that Mdm2 can function independently from ARF and imply that targeting Mdm2 in tumors that lack ARF expression should be an effective therapeutic approach. ..
- Bandyopadhyay K, Lee C, Haghighi A, Baneres J, Parello J, Gjerset R. Serine phosphorylation-dependent coregulation of topoisomerase I by the p14ARF tumor suppressor. Biochemistry. 2007;46:14325-34 pubmed..Certain cancer associated defects affecting ARF/topoisomerase I complex formation could contribute to cellular resistance to camptothecin. ..
- Ozenne P, Eymin B, Brambilla E, Gazzeri S. The ARF tumor suppressor: structure, functions and status in cancer. Int J Cancer. 2010;127:2239-47 pubmed publisher..In this review, we present the current knowledge on ARF regulation and major functions. The ARF status in human tumors is also briefly summarized. ..
- Mounawar M, Mukeria A, Le Calvez F, Hung R, Renard H, Cortot A, et al. Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history. Cancer Res. 2007;67:5667-72 pubmed
- Garcia M, Collado M, Munoz Fontela C, Matheu A, Marcos Villar L, Arroyo J, et al. Antiviral action of the tumor suppressor ARF. EMBO J. 2006;25:4284-92 pubmed..Finally, Arf-null mice were hypersensitive to viral infection compared to wild-type mice. Together, our results reveal a novel and unexpected role for the tumor suppressor ARF in viral infection surveillance. ..
- Tago K, Chiocca S, Sherr C. Sumoylation induced by the Arf tumor suppressor: a p53-independent function. Proc Natl Acad Sci U S A. 2005;102:7689-94 pubmed..Reduction of Ubc9 levels with short hairpin RNAs rendered similar results. We suggest that Arf's p53-independent effects on gene expression and tumor suppression might depend on Arf-induced sumoylation. ..
- Qi Y, Gregory M, Li Z, Brousal J, West K, Hann S. p19ARF directly and differentially controls the functions of c-Myc independently of p53. Nature. 2004;431:712-7 pubmed..This direct feedback mechanism represents a p53-independent checkpoint to prevent c-Myc-mediated tumorigenesis. ..