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Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53.
- Source :
-
Molecular cell [Mol Cell] 1999 May; Vol. 3 (5), pp. 579-91. - Publication Year :
- 1999
-
Abstract
- The mammalian ARF-INK4a locus uniquely encodes two cell cycle inhibitors by using separate promoters and alternative reading frames. p16INK4a maintains the retinoblastoma protein in its growth suppressive state while ARF stabilizes p53. We report that human ARF protein predominantly localizes to the nucleolus via a sequence within the exon 2-encoded C-terminal domain and is induced to leave the nucleolus by MDM2. ARF forms nuclear bodies with MDM2 and p53 and blocks p53 and MDM2 nuclear export. Tumor-associated mutations in ARF exon 2 disrupt ARF's nucleolus localization and reduce ARF's ability to block p53 nuclear export and to stabilize p53. Our results suggest an ARF-regulated MDM2-dependent p53 stabilization and link the human tumor-associated mutations in ARF with a functional alteration.
- Subjects :
- ADP-Ribosylation Factors
Adenylyl Cyclases metabolism
Biological Transport genetics
Cyclin-Dependent Kinase Inhibitor p16 genetics
Cyclin-Dependent Kinase Inhibitor p16 metabolism
Cysteine Endopeptidases metabolism
GTP-Binding Proteins metabolism
Gene Deletion
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
HeLa Cells
Humans
Molecular Sequence Data
Multienzyme Complexes metabolism
Mutagenesis physiology
Nuclear Localization Signals physiology
Nuclear Proteins genetics
Nuclear Proteins metabolism
Point Mutation
Proteasome Endopeptidase Complex
Protein Binding physiology
Proto-Oncogene Proteins c-mdm2
Sequence Homology, Amino Acid
Cell Nucleolus enzymology
Exons genetics
GTP-Binding Proteins genetics
Proto-Oncogene Proteins metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-2765
- Volume :
- 3
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 10360174
- Full Text :
- https://doi.org/10.1016/s1097-2765(00)80351-2