Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization

H. Rizos*, A. P. Darmanian, G. J. Mann, R. F. Kefford

*Corresponding author for this work

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

The INK4a/ARF locus encodes two distinct tumour suppressors, p16(INK4a) and p14ARF, that regulate cell cycle progression via the pRB and p53 pathways, respectively. The ARF protein inhibits hdm2 activity, leading to the stabilization of the p53 tumour suppressor and cell cycle inhibition. The amino-terminal domain of human p14ARF and of the mouse homologue, p19ARF, is sufficient for these effects. This domain is also sufficient for the nucleolar localization of the mouse ARF protein. In contrast, we show that the human ARF protein requires two arginine rich domains, one in the amino- and the other in the carboxy-terminus, for nucleolar targeting. The amino-terminal nucleolar-targeting domain of p14ARF is also important for ARF-hdm2 binding and cell cycle inhibition. The carboxy-terminal p14ARF nucleolar localization domain lies within the shared INK4a/ARF exon 2, and is mutated in a small number of melanoma-prone kindreds. The INK4a/ARF exon2-mutations could affect the function of both the p16(INK4a) and p14ARF tumour suppressors.

Original languageEnglish
Pages (from-to)2978-2985
Number of pages8
JournalOncogene
Volume19
Issue number26
Publication statusPublished - 15 Jun 2000
Externally publishedYes

Keywords

  • Hdm2
  • Nucleolar localization
  • p14ARF
  • p53

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