Cyclin-dependent kinase inhibitor-2A (CDKN2A) goes by the colloquial designation p16, which is sometimes referred to as p16(INK4). The alpha transcript of CDKN2A has been shown to encode p16(INK4a), a recognized tumor suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of the RB protein by the cyclin-dependent kinases CDK4 and CDK6. The beta transcript of CDKN2A encodes p14(ARF). The predicted 132-amino acid p14(ARF) is shorter than the corresponding mouse protein, p19(ARF), and the 2 proteins share only 50% identity. However, both proteins have the ability to elicit a p53 response, manifest in the increased expression of both CDKN1A and MDM2, and resulting in a distinctive cell cycle arrest in both the G1 and G2/M phases. Two unrelated proteins encoded by the INK4A-ARF locus function in tumor suppression. ARF binds to MDM2 and promotes the rapid degradation of MDM2. This interaction is mediated by the E1-beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53 stabilization and accumulation. The p19(Arf) tumor suppressor inhibits production of ribosomal RNA, retarding processing of 47/45S and 32S precursors. These effects correlate with but do not strictly depend upon inhibition of rRNA biosynthesis or cell cycle arrest, are not mimicked by p53, and require neither p53 nor Mdm2. Arf mutants lacking conserved amino acid residues 2-14 do not block rRNA synthesis and processing or inhibit cell proliferation. Evolution may have linked a primordial nucleolar Arf function to Mdm2 and p53, creating a more efficient checkpoint-signaling pathway for coordinating ribosomal biogenesis and cell cycle progression.
Contributor: Kosi Gramatikoff, PhD
REFERENCES: de Stanchina E, McCurrach ME, Zindy F, Shieh SY, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CJ, Lowe SW. E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev. 1998 Aug 1;12(15):2434-42. Eymin B, Karayan L, Seite P, Brambilla C, Brambilla E, Larsen CJ, Gazzeri S. Human ARF binds E2F1 and inhibits its transcriptional activity. Oncogene. 2001 Mar 1;20(9):1033-41. Guo F, Gao Y, Wang L, Zheng Y. p19Arf-p53 Tumor Suppressor Pathway Regulates Cell Motility by Suppression of Phosphoinositide 3-Kinase and Rac1 GTPase Activities. J Biol Chem. 2003 Apr 18;278(16):14414-9. Lingbeek ME, Jacobs JJ, van Lohuizen M. The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. J Biol Chem. 2002 Jul 19;277(29):26120-7. Llanos S, Clark PA, Rowe J, Peters G. Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus. Nat Cell Biol. 2001 May;3(5):445-52. Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH, Hannon GJ. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999 Sep 1;13(17):2207-17. Menendez S, Khan Z, Coomber DG, Lane DP, Higgins M, Koufali MM, Lain S. Oligomerisation of the human ARF tumor suppressor and its response to oxidative stress. J Biol Chem. 2003 Feb 11 Radfar A, Unnikrishnan I, Lee HW, DePinho RA, Rosenberg N. p19(Arf) induces p53-dependent apoptosis during abelson virus-mediated pre-B cell transformation. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13194-9. Schmitt CA, McCurrach ME, de Stanchina E, Wallace-Brodeur RR, Lowe SW. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev. 1999 Oct 15;13(20):2670-7. Serrano, M.; Lee, H.-W.; Chin, L.; Cordon-Cardo, C.; Beach, D.; DePinho, R. A. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85: 27-37, 1996. Sugimoto M, Kuo ML, Roussel MF, Sherr CJ. Nucleolar arf tumor suppressor inhibits ribosomal RNA processing. Mol Cell 2003 Feb;11(2):415-24 Sugimoto M, Kuo ML, Roussel MF, Sherr CJ. Nucleolar Arf tumor suppressor inhibits ribosomal RNA processing. Mol Cell. 2003 Feb;11(2):415-24. Tsai KY, MacPherson D, Rubinson DA, Nikitin AY, Bronson R, Mercer KL, Crowley D, Jacks T. ARF mutation accelerates pituitary tumor development in Rb+/- mice. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16865-70. Zhang, Y.; Xiong, Y.; Yarbrough, W. G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92: 725-734, 1998. Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 1998 Aug 1;12(15):2424-33.
