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ARF function does not require p53 stabilization or Mdm2 relocalization.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2002 Jan; Vol. 22 (1), pp. 196-206. - Publication Year :
- 2002
-
Abstract
- It is generally accepted that the ARF tumor suppressor induces p53-dependent growth arrest by sequestering the p53 antagonist Mdm2 in the nucleolus. Previous mutagenic studies of murine ARF suggested that residues 1 through 14 and 26 through 37 were critical for Mdm2 binding, while the latter domain also governed ARF nucleolar localization. We show that mouse ARF residues 6 to 10 and 21 to 25 are required for ARF-induced growth arrest whereas residues 1 to 5 and 29 to 34 are dispensable. Deletion of the putative nucleolar localization signal (31)RRPR(34) did not prevent nucleolar localization. Surprisingly, unlike wild-type ARF, growth-inhibitory mutants D1-5 and D29-34 failed to stabilize p53 yet induced its transcriptional activation in reporter assays. This suggests that p53 stabilization is not essential for ARF-mediated activation of p53. Like wild-type ARF, both mutants also exhibited p53-independent function since they were able to arrest p53/Mdm2-null cells. Notably, other mutants lacking conserved residues 6 to 10 or 21 to 25 were unable to suppress growth in p53-positive cells despite nucleolar localization and the ability to import Mdm2. Those observations stood in apparent contrast to the ability of wild-type ARF to block growth in some cells without relocalizing endogenous Mdm2 to nucleoli. Together, these data show a lack of correlation between ARF activity and Mdm2 relocalization, suggesting that additional events other than Mdm2 import are required for ARF function.
- Subjects :
- 3T3 Cells
Active Transport, Cell Nucleus physiology
Amino Acid Sequence
Animals
Cell Cycle physiology
Cell Division physiology
Cell Line
Cell Nucleolus chemistry
Cell Nucleolus metabolism
Cyclin-Dependent Kinase Inhibitor p16
Flow Cytometry
Genes, Reporter
Humans
Immunohistochemistry
Mice
Molecular Sequence Data
Mutation
Neoplasm Proteins metabolism
Nuclear Proteins genetics
Nuclear Proteins metabolism
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins c-mdm2
Tumor Suppressor Protein p14ARF chemistry
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Proteins genetics
Proto-Oncogene Proteins metabolism
Tumor Suppressor Protein p14ARF metabolism
Tumor Suppressor Protein p53 metabolism
Tumor Suppressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 11739734
- Full Text :
- https://doi.org/10.1128/MCB.22.1.196-206.2002