Download P14/19ARF as Tumor Suppressor

ARF
P14/19
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)
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 tumorderived 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.
Thank You!