P14/19ARF as Tumor Suppressor 20118135 Moon, Hyerin

PART I. Introduction GenERAL INFORMATION

P14/19ARF(Alternative Reading Frame) - Locates on human chromosme band 9p21(chromosome 4 in mice). - Exon2 have in common, but different reading frames - INK4a and ARF is totally differnet proteins ARF is ubiquitously expressed and is elevated in cells lacking p53.

P14/19ARF(Alternative Reading Frame) - arginine rich, hydrophobic proteins. - poorly conserved, sharing only 50% amino acid identity full-length ARF preferentially localizes in the nucleoli, thanks to nucleolar localization signals (NoLS)

Characterization of Arf PART II. History Characterization of Arf

1. Identification

2. Phenotype analysis

3. Finding molecular mechanisms - Induction of p53 by Arf requires nucleolar recruitment of Mdm2

3. Finding molecular mechanisms

PART III. Cellular Function ARF As tumor Supressor

1. Cell Growth control Activation of p53 leading to cell cycle arrest or apoptosis Llanos S et al. Nat Cell Biol. 2011;3:445-52. Stabilization of MDM2 and p53 by non-nucleolar ARF.

1. Cell Growth control p53-independent cell cycle arrest or apoptosis Wever JD et al. Genes Dev. 2000;14:2358–65. Ectopic expression of ARF causes an S-phase cell cycle arrest in p53-deficient tumor-derived cells

2. Ribosome biogenesis Decreased rRNA transcription and processing Itahana K et al. Mol Cell 2003;12:1151–64. ARF promotes polyubiquitination of B23. Blocking of 28S rRNA maturation by ARF overexpression and by B23 inhibition. ARF interacts with and inhibits the function of B23, a nucleolar endoribonuclease involved in maturation of 28S rRNA

3. DNA Damage Response Activation of p53 pathways Rocha S et al. EMBO J. 2005;24:1157–69. ATR is required for ARF-induced p53 activation

3. DNA Damage Response Activation of ATM/ATR/CHK pathways Eymin B et al. Mol Cell Biol 2006;26:4339–50. p14ARF activates CHK1/2 kinases to arrest cells in G2 p14ARF activates ATM/ATR pathways to mediate G2 arrest.

PART VI. Physiological Meanings Why ARF?

conclusion ARF functions as important sensor of hyperproliferative stimuli. Because of its peculiar structure and localization, its function identified through intensive study. ARF can be critical sensor of genomic instability

REFERENCES Ozenne et al. Int. J. Cancer: 127, 2239–2247 (2010) S.J. Gallagher et al.IJBCB(2006) 1637–1641 Carmen DB et al. Cell Cycle 9:1, 86-89(2010) - & each figure, references are noted below.

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