Evasion of Oncogene Induced Senescence Due to p14ARF Defects

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R-HSA-9646303
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Homo sapiens
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In cell culture, p14ARF (CDKN2A transcript 4, CDKN2A-4, ARF), one of the two main protein products of the CDKN2A gene, contributes to oncogene induced senescence by stabilizing TP53 (p53). The function of p14ARF in p53 stabilization through sequestration of MDM2, a p53 ubiquitin ligase, depends on the nuclear localization of p14ARF and its ability to interact with MDM2. The nuclear localization signal and the MDM2 interaction domain map to the first 15 amino acids of the N-terminus of p14ARF. This region is encoded by the p14ARF-specific exon 1beta of CDKN2A. An independent MDM2-binding domain localized to the C-terminus of p14ARF (Lohrum et al. 2000). Insertion of 16 nucleotides in exon 1beta results in a frameshift truncation of p14ARF, responsible for a familial melanoma syndrome in which the p16INK4A product of the CDKN2A gene is unaffected. This mutation is rare and has so far been reported in one family only. The mutant protein, p14ARF R21RfsTER47 has the nucleotide localization signal and the N-terminal MDM2 interaction region preserved, but is unable to translocate from the cytosol to the nucleus, possibly due to aberrant conformation (Rizos, Puig et al. 2001), and also lacks the C-terminal MDM2 interaction region. Relocation of wild type p14ARF to the cytosol has been observed in melanoma (Rizos, Darmanian et al. 2001) and aggressive thyroid papillary carcinoma (Ferru et al. 2006). Genomic deletion of exon 1beta, with exons 1alpha, 2 and 3 intact, has been reported in about 30% of melanoma cases with genomic deletions involving the CDKN2A locus (Freedberg et al. 2008). Several different familial melanoma germline mutations map to the exon 1beta splice donor site (Harland et al. 2005).
The ability of p14ARF to localize to the nucleolus also plays a role in p14ARF-mediated stabilization of p53. Mutations in exon 2 of the CDKN2A gene can lead to missense mutations in p14ARF that affect its nucleolar localization and p53 stabilization, but the exact mechanism has not been fully elucidated (Zhang and Xiong 1999, reviewed by Fontana et al. 2019).

Literature References
PubMed ID Title Journal Year
18505964 Frequent p16-independent inactivation of p14ARF in human melanoma

Freedberg, DE, Rigas, SH, Russak, J, Gai, W, Kaplow, M, Osman, I, Turner, F, Randerson-Moor, JA, Houghton, A, Busam, K, Timothy Bishop, D, Bastian, BC, Newton-Bishop, JA, Polsky, D

J. Natl. Cancer Inst. 2008
10801444 Contribution of two independent MDM2-binding domains in p14(ARF) to p53 stabilization

Lohrum, MA, Ashcroft, M, Kubbutat, MH, Vousden, KH

Curr. Biol. 2000
11518711 Mutations in the INK4a/ARF melanoma susceptibility locus functionally impair p14ARF

Rizos, H, Darmanian, AP, Holland, EA, Mann, GJ, Kefford, RF

J. Biol. Chem. 2001
30836703 Dual Role of the Alternative Reading Frame ARF Protein in Cancer

Fontana, R, Ranieri, M, La Mantia, G, Vivo, M

Biomolecules 2019
15856016 A mutation hotspot at the p14ARF splice site

Harland, M, Taylor, CF, Chambers, PA, Kukalizch, K, Randerson-Moor, JA, Gruis, NA, de Snoo, FA, ter Huurne, JA, Goldstein, AM, Tucker, MA, Bishop, DT, Bishop, JA

Oncogene 2005
11571653 A melanoma-associated germline mutation in exon 1beta inactivates p14ARF

Rizos, H, Puig, S, Badenas, C, Malvehy, J, Darmanian, AP, Jiménez, L, Milà, M, Kefford, RF

Oncogene 2001
17117177 The status of CDKN2A alpha (p16INK4A) and beta (p14ARF) transcripts in thyroid tumour progression

Ferru, A, Fromont, G, Gibelin, H, Guilhot, J, Savagner, F, Tourani, JM, Kraimps, JL, Larsen, CJ, Karayan-Tapon, L

Br. J. Cancer 2006
10360174 Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53

Zhang, Y, Xiong, Y

Mol. Cell 1999
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Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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