ARF function does not require p53 stabilization or Mdm2 relocalization

Chandrashekhar Korgaonkar; Lili Zhao; Modestos Modestou; Dawn E Quelle

doi:10.1128/MCB.22.1.196-206.2002

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ARF function does not require p53 stabilization or Mdm2 relocalization

Journal article

Open access

Peer reviewed

ARF function does not require p53 stabilization or Mdm2 relocalization

Chandrashekhar Korgaonkar, Lili Zhao, Modestos Modestou and Dawn E Quelle

Molecular and cellular biology, Vol.22(1), pp.196-206

01/2002

DOI: 10.1128/MCB.22.1.196-206.2002

PMCID: PMC134207

PMID: 11739734

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https://www.ncbi.nlm.nih.gov/pmc/articles/134207View

Open Access

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.

Immunohistochemistry

Flow Cytometry

Mutation

Active Transport, Cell Nucleus - physiology

Humans

Molecular Sequence Data

Neoplasm Proteins - metabolism

Tumor Suppressor Protein p53 - genetics

Cyclin-Dependent Kinase Inhibitor p16

Cell Nucleolus - metabolism

Tumor Suppressor Proteins - genetics

Nuclear Proteins - genetics

Genes, Reporter

Tumor Suppressor Protein p14ARF - chemistry

Proto-Oncogene Proteins - metabolism

Amino Acid Sequence

Cell Line

Tumor Suppressor Proteins - metabolism

Cell Nucleolus - chemistry

Tumor Suppressor Protein p53 - metabolism

Nuclear Proteins - metabolism

Proto-Oncogene Proteins - genetics

Cell Division - physiology

Proto-Oncogene Proteins c-mdm2

Animals

Cell Cycle - physiology

Mice

Tumor Suppressor Protein p14ARF - metabolism

3T3 Cells

Details

Title: Subtitle: ARF function does not require p53 stabilization or Mdm2 relocalization
Creators: Chandrashekhar Korgaonkar - Department of Pharmacology. Molecular Biology Graduate Program, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA
Lili Zhao
Modestos Modestou
Dawn E Quelle
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.22(1), pp.196-206
DOI: 10.1128/MCB.22.1.196-206.2002
PMID: 11739734
PMCID: PMC134207
NLM abbreviation: Mol Cell Biol
ISSN: 0270-7306
eISSN: 1098-5549
Publisher: United States
Language: English
Date published: 01/2002
Academic Unit: Pathology; Neuroscience and Pharmacology
Record Identifier: 9984040311902771

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