The p14ARF tumour suppressor coordinates
cell growth and proliferation
The p14ARF tumour suppressor is one of the most frequently altered proteins in
human cancer (Sherr, 1996). It is not surprising, therefore, that the accumulation
of ARF can potently restrict the effect of hyperproliferative stimuli by arresting
the cell cycle at the G1 and G2 phases. In particular, p14ARF associates with
the p53 antagonist and ubiquitin ligase, hdm2 to inhibit the ubiquitination,
nuclear export and subsequent degradation of p53 (Stott et al., 1998).
Emerging evidence suggests that p14ARF can, albeit less effectively, also suppress
the proliferation of cells that are p53-deficient, and p14ARF has been shown
to interact with many other regulators, including the E1A-regulated transcription
repressor p120E4F 12, the E2F-1, -2 and -3 transcription factors,
the a-subunit of hypoxia-inducible factor-1 (HIF-1a), the nucleolar B23 protein
and Werners helicase.
In addition to modulating cell cycle progression, the ARF tumour suppressor also
regulates ribosome assembly. p14ARF is a highly basic nucleolar protein that
inhibits the processing of 47/45S and 32S precursor ribosomal RNAs (Sugimoto et
al., 2003). This ARF activity is partly through its ability to interact
with and induce the degradation of B23, a nucleolar endoribonuclease involved
in the maturation of 28S rRNA. The extent of rRNA inhibition by ARF was not identical
to that observed by silencing B23, however; the downregulation of B23 inhibited
the processing of the 32S rRNA, whereas ARF inhibited processing of both the
47S and 32S rRNA precursors. It appears that p14ARF is a critical surveillance
protein, monitoring ribosome biogenesis within the nucleolus and cell cycle progression
in the nucleoplasm. Thus, p14ARF integrates ribosome synthesis with cell proliferation
(see Figure 1).
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Figure 1 Proposed model for the role
of ARF in coordinating the inhibitions of cell growth and proliferation.
The dashed line highlights our preliminary data, indicating that
p14ARF directly associates with pre-60S ribosomes.
References:
Sherr CJ. Cancer cell cycles. Science 1996; 274:1672-1677.
Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I,
Ryan K, Hara E, Vousden KH, Peters G. The alternative product from the human CDKN2A locus,
p14ARF, participates in a regulatory feedback loop with p53 and MDM2. EMBO J 1998;
17:5001-5014.
Sugimoto M, Kuo M-L, Roussel MF, Sherr CJ. Nucleolar Arf tumor suppressor inhibits
ribosomal RNA processing. Mol Cell 2003; 11:415-424. |
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