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Tumor suppressor ARF

Definition:

Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Plays a role in inhibiting ribosome biogenesis, perhaps by binding to the nucleolar localization sequence of transcription termination factor TTF1, and thereby preventing nucleolar localization of TTF1 (By similarity). Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development.; [Isoform smARF]: May be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP.

References:

[1]. B Eymin, et al. Human ARF binds E2F1 and inhibits its transcriptional activity. Oncogene. 2001 Mar 1;20(9):1033-41. [Content Brief]

[2]. Delin Chen, et al. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell. 2005 Jul 1;121(7):1071-83. [Content Brief]

[3]. L Karayan, et al. Human ARF protein interacts with topoisomerase I and stimulates its activity. Oncogene. 2001 Feb 15;20(7):836-48. [Content Brief]

[4]. Sharon Reef, et al. A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death. Mol Cell. 2006 May 19;22(4):463-75. [Content Brief]

[5]. Hiroaki Suzuki, et al. The ARF tumor suppressor inhibits BCL6-mediated transcriptional repression. Biochem Biophys Res Commun. 2005 Jan 7;326(1):242-8. [Content Brief]

[6]. Yafen Huang, et al. Tumor suppressor ARF promotes non-classic proteasome-independent polyubiquitination of COMMD1. J Biol Chem. 2008 Apr 25;283(17):11453-60. [Content Brief]

[7]. Helen Rizos, et al. p14ARF interacts with the SUMO-conjugating enzyme Ubc9 and promotes the sumoylation of its binding partners. Cell Cycle. 2005 Apr;4(4):597-603. [Content Brief]

[8]. Akihiro Watari, et al. A novel proapoptotic gene PANO encodes a post-translational modulator of the tumor suppressor p14ARF. Exp Cell Res. 2012 Feb 1;318(3):187-95. [Content Brief]

[9]. Koji Itahana, et al. Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol Cell. 2003 Nov;12(5):1151-64. [Content Brief]

[10]. Olivier Ayrault, et al. Human Arf tumor suppressor specifically interacts with chromatin containing the promoter of rRNA genes. Oncogene. 2004 Oct 21;23(49):8097-104. [Content Brief]

[11]. F J Stott, et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998 Sep 1;17(17):5001-14. [Content Brief]

[12]. Béatrice Eymin, et al. p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice. Oncogene. 2003 Mar 27;22(12):1822-35. [Content Brief]

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