| Structural highlights
Function
[CD2A2_MOUSE] 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. Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination (By similarity). 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 4 may be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [UniProtKB:Q8N726]
Publication Abstract from PubMed
Arf is a tumor suppressor that regulates p53 function and is a frequent target for loss in human cancers. Through two novel mechanisms, Arf inhibits the oncoprotein Hdm2, a negative regulator of p53. (1) Arf inhibits the E3 ubiquitin ligase activity of Hdm2 that leads to p53 degradation, and (2) Arf sequesters Hdm2 within nucleoli. These activities of Arf promote p53-mediated cell cycle arrest and apoptosis. Fundamental to these processes are interactions between Arf and Hdm2. Here we show that a peptide containing the 37 N-terminal amino acids of mouse Arf (mArfN37) localizes to nucleoli, sequesters Hdm2 within nucleoli, and causes cell cycle arrest. Circular dichroism and NMR spectroscopy show that mArfN37 is largely unstructured under aqueous conditions; however, the peptide adopts two alpha-helices (helix 1, residues 4-14; and helix 2, residues 20-29) in 2,2,2-trifluoroethanol (TFE). Each helix contains an amino acid motif that is repeated twice in mArfN37, once in each helix. The two helices, however, do not interact but are connected by an apparently flexible linker. The repeated motif contains Arg residues spaced by a hydrophobic segment that may be involved in Hdm2 recognition and binding. The RRPR nucleolar localization signal, contained within residues 31-34, appears to be disordered under all conditions. The identification of two Arf structural modules suggests that short peptides containing the repeated motif may function as Arf mimics and may allow the design of small molecule Arf mimics in the future.
Solution structure of the p53 regulatory domain of the p19Arf tumor suppressor protein.,DiGiammarino EL, Filippov I, Weber JD, Bothner B, Kriwacki RW Biochemistry. 2001 Feb 27;40(8):2379-86. PMID:11327858[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 1995 Dec 15;83(6):993-1000. PMID:8521522
- ↑ Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 1997 Nov 28;91(5):649-59. PMID:9393858
- ↑ Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell. 1998 Mar 20;92(6):713-23. PMID:9529248
- ↑ Tao W, Levine AJ. P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6937-41. PMID:10359817
- ↑ Qi Y, Gregory MA, Li Z, Brousal JP, West K, Hann SR. p19ARF directly and differentially controls the functions of c-Myc independently of p53. Nature. 2004 Oct 7;431(7009):712-7. Epub 2004 Sep 8. PMID:15361884 doi:http://dx.doi.org/10.1038/nature02958
- ↑ Suzuki H, Kurita M, Mizumoto K, Moriyama M, Aiso S, Nishimoto I, Matsuoka M. The ARF tumor suppressor inhibits BCL6-mediated transcriptional repression. Biochem Biophys Res Commun. 2005 Jan 7;326(1):242-8. PMID:15567177 doi:http://dx.doi.org/S0006-291X(04)02555-0
- ↑ Sreeramaneni R, Chaudhry A, McMahon M, Sherr CJ, Inoue K. Ras-Raf-Arf signaling critically depends on the Dmp1 transcription factor. Mol Cell Biol. 2005 Jan;25(1):220-32. PMID:15601844 doi:http://dx.doi.org/25/1/220
- ↑ Reef S, Zalckvar E, Shifman O, Bialik S, Sabanay H, Oren M, Kimchi A. A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death. Mol Cell. 2006 May 19;22(4):463-75. PMID:16713577 doi:http://dx.doi.org/10.1016/j.molcel.2006.04.014
- ↑ Mallakin A, Sugiyama T, Taneja P, Matise LA, Frazier DP, Choudhary M, Hawkins GA, D'Agostino RB Jr, Willingham MC, Inoue K. Mutually exclusive inactivation of DMP1 and ARF/p53 in lung cancer. Cancer Cell. 2007 Oct;12(4):381-94. PMID:17936562 doi:http://dx.doi.org/S1535-6108(07)00267-X
- ↑ Yi Y, Shepard A, Kittrell F, Mulac-Jericevic B, Medina D, Said TK. p19ARF determines the balance between normal cell proliferation rate and apoptosis during mammary gland development. Mol Biol Cell. 2004 May;15(5):2302-11. PMID:15105443 doi:http://dx.doi.org/10.1091/mbc.E03-11-0785
- ↑ Quelle DE, Cheng M, Ashmun RA, Sherr CJ. Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):669-73. PMID:9012842
- ↑ DiGiammarino EL, Filippov I, Weber JD, Bothner B, Kriwacki RW. Solution structure of the p53 regulatory domain of the p19Arf tumor suppressor protein. Biochemistry. 2001 Feb 27;40(8):2379-86. PMID:11327858
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